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Mokhtar ER, Elshennawy SI, Elhakeem H, Saleh RAM, Elsawy SB, Salama KSM, Mohamed MF, Bahi RH, Mansour HH, Kasim Mahmoud SA, Hassan MM, Elhadad SM, Eid El Sayed HM, Mohamed AN, Hamdy NM. The Association of Toll-like Receptor-9 Gene Single-Nucleotide Polymorphism and AK155(IL-26) Serum Levels with Chronic Obstructive Pulmonary Disease Exacerbation Risk: A Case-Controlled Study with Bioinformatics Analysis. Biomedicines 2025; 13:613. [PMID: 40149591 PMCID: PMC11939906 DOI: 10.3390/biomedicines13030613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2025] [Revised: 01/28/2025] [Accepted: 02/06/2025] [Indexed: 03/29/2025] Open
Abstract
Background: A crucial challenge is the determination of chronic obstructive pulmonary disease (COPD) immune-related mechanisms, where one of the important components of the inflammatory axes in COPD is Toll-like receptor-9 (TLR9) and interleukin-26 AK155(IL-26). Aim: To examine the relation between TLR9 (T1237C) SNP rs5743836 and serum levels of AK155(IL-26) with the exacerbation of COPD. Subjects: A total of 96 COPD patients sub-classified into two groups. Materials: DNA was purified from blood samples of stable COPD patients (n = 48) vs. exacerbated COPD patients (n = 48) as well as 42 age- and sex-matched healthy smokers and passive smokers as a control group. Methods: Genotyping for TLR9 rs5743836 (T1237C) polymorphism was performed using real time polymerase chain reaction (RT-PCR). AK155(IL-26) serum levels were determined using ELISA. Results: There is a significantly higher frequency of the mutant homozygous genotype (C/C) and the mutated C allele of TLR9 rs5743836 (T1237C) in COPD patients and in the exacerbated group when compared with the control group and stable COPD patients, respectively, with OR 31.98, 1.8 to 57.7, and OR 3.64, 0.98 to 13.36, respectively. For the mutated C allele, the OR was 3.57, 1.94 to 6.56, p = 0.001, OR 1.83, 1.02 to 3.27, p = 0.041, respectively. In the exacerbated COPD group, there was a significant association between TLR9 rs5743836 SNP and BMI and the lung vital function measures, CRP, and AK155(IL-26). The exacerbated COPD group has higher serum levels of AK155(IL-26) compared with the stable group or when compared with the control group (p = 0.001) for both. AK155(IL-26) serum levels have a positive significant correlation with CRP and BMI and a significant negative correlation with FEV1% and FEV1/FVC in exacerbated COPD patients. Conclusions: Our results demonstrated a relation linking TLR-9 rs5743836 (T1237C) expression and the risk of COPD development and its exacerbation, indicating that dysfunctional polymorphisms of the innate immune genes can affect COPD development and its exacerbation. AK155(IL-26) upregulation was related to decreased lung functionality, systematic inflammatory disease, and COPD exacerbation.
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Affiliation(s)
- Entsar R. Mokhtar
- Clinical Pathology Department, Faculty of Medicine (for Girls), Al-Azhar University, Nasr City, Cairo 11884, Egypt
| | - Salwa I. Elshennawy
- Clinical Pathology Department, Faculty of Medicine (for Girls), Al-Azhar University, Nasr City, Cairo 11884, Egypt
| | - Heba Elhakeem
- Clinical Pathology Department, Faculty of Medicine (for Girls), Al-Azhar University, Nasr City, Cairo 11884, Egypt
| | - Rayyh A. M. Saleh
- Clinical Pathology Department, Faculty of Medicine (for Girls), Al-Azhar University, Nasr City, Cairo 11884, Egypt
| | - Sawsan Bakr Elsawy
- Chest Disease Department, Faculty of Medicine (for Girls), Al-Azhar University, Nasr City, Cairo 11884, Egypt
- Chest Disease Department, King Abdul-Aziz Specialized Hospital, Taif 26521, Saudi Arabia
| | - Khadiga S. M. Salama
- Chest Disease Department, Faculty of Medicine (for Girls), Al-Azhar University, Nasr City, Cairo 11884, Egypt
| | - Maha Fathy Mohamed
- Chest Disease Department, Faculty of Medicine, Beni-Suef University, Beni-Suef 62521, Egypt
| | - Rania Hamid Bahi
- Chest Disease Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Hayam H. Mansour
- Internal Medicine Department, Faculty of Medicine (for Girls), Al-Azhar University, Nasr City, Cairo 11884, Egypt
- Internal Medicine Department, College of Medicine, Taibah University, Al-Madinah P.O. Box 30097, Saudi Arabia
| | - Sammar Ahmed Kasim Mahmoud
- Internal Medicine Department, Faculty of Medicine (for Girls), Al-Azhar University, Nasr City, Cairo 11884, Egypt
| | - Marwa M. Hassan
- Internal Medicine Department, Faculty of Medicine (for Girls), Al-Azhar University, Nasr City, Cairo 11884, Egypt
| | - Sara M. Elhadad
- Internal Medicine Department, Faculty of Medicine (for Girls), Al-Azhar University, Nasr City, Cairo 11884, Egypt
| | - Hanaa Mohammed Eid El Sayed
- Internal Medicine Department, Faculty of Medicine (for Girls), Al-Azhar University, Nasr City, Cairo 11884, Egypt
| | - Aliaa N. Mohamed
- Faculty of Medicine, New Mansoura University, Mansoura 35712, Egypt
| | - Nadia M. Hamdy
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt
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Sandhu KK, Scott A, Tatler AL, Belchamber KBR, Cox MJ. Macrophages and the microbiome in chronic obstructive pulmonary disease. Eur Respir Rev 2024; 33:240053. [PMID: 39631929 PMCID: PMC11615662 DOI: 10.1183/16000617.0053-2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 08/22/2024] [Indexed: 12/07/2024] Open
Abstract
COPD is a heterogeneous disease of the lungs characterised by restricted airflow. Chronic inflammation and recurrent bacterial infections are known to be important driving factors in exacerbations of this disease. Despite a marked increase in the number of alveolar macrophages present in the lungs of COPD patients, there is evidence of reduced clearance of pathogenic bacteria, leading to recurrent infection, exacerbation and subsequent lung function decline. This is thought to be attributed to a defect in the phagocytic capability of both alveolar and monocyte-derived macrophages in COPD. In addition to this defect, there is apparent selectivity in bacterial uptake by COPD macrophages because certain pathogenic genera, such as Haemophilus, Moraxella and Streptococcus, are taken up more readily than others. The respiratory microbiome plays a key role in regulating the host immune response both in health and during chronic inflammation. In patients with COPD, there are distinct changes in the composition of the respiratory microbiome, particularly the lower respiratory tract, where dominance of clinically relevant pathogenic species is commonly observed. Whether there are links between these changes in the microbiome and dysfunctional macrophage phagocytosis has not yet been widely studied. This review aims to discuss what is currently known about these phenomena and to explore interactions between macrophages and the respiratory microbiome.
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Affiliation(s)
- Karanjot K Sandhu
- Department of Microbes, Infection and Microbiomes, Institute of Microbiology and Infection, School of Infection, Inflammation and Immunity, College of Medicine and Health, University of Birmingham, Birmingham, UK
- Department of Inflammation and Ageing, School of Infection, Inflammation and Immunity, College of Medicine and Health, University of Birmingham, Birmingham, UK
| | - Aaron Scott
- Department of Inflammation and Ageing, School of Infection, Inflammation and Immunity, College of Medicine and Health, University of Birmingham, Birmingham, UK
| | - Amanda L Tatler
- Centre for Respiratory Research, School of Medicine, University of Nottingham, Nottingham, UK
- Biodiscovery Institute, University of Nottingham, Nottingham, UK
- NIHR Nottingham Biomedical Research Centre, Nottingham, UK
| | - Kylie B R Belchamber
- Department of Inflammation and Ageing, School of Infection, Inflammation and Immunity, College of Medicine and Health, University of Birmingham, Birmingham, UK
- These authors contributed equally
| | - Michael J Cox
- Department of Microbes, Infection and Microbiomes, Institute of Microbiology and Infection, School of Infection, Inflammation and Immunity, College of Medicine and Health, University of Birmingham, Birmingham, UK
- These authors contributed equally
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Mohammed AN, Yadav N, Kaur P, Jandarov R, Yadav JS. Immunomodulation of susceptibility to pneumococcal pneumonia infection in mouse lungs exposed to carbon nanoparticles via dysregulation of innate and adaptive immune responses. Toxicol Appl Pharmacol 2024; 483:116820. [PMID: 38218205 DOI: 10.1016/j.taap.2024.116820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 01/05/2024] [Accepted: 01/10/2024] [Indexed: 01/15/2024]
Abstract
Carbon nanotubes (CNTs) are emerging pollutants of occupational and environmental health concern. While toxicological mechanisms of CNTs are emerging, there is paucity of information on their modulatory effects on susceptibility to infections. Here, we investigated cellular and molecular events underlying the effect of multi-walled CNT (MWCNT) exposure on susceptibility to Streptococcus pneumoniae infection in our 28-day sub-chronic exposure mouse model. Data indicated reduced phagocytic function in alveolar macrophages (AMs) from MWCNT-exposed lungs evidenced by lower pathogen uptake in 1-h infection assay. At 24-h post-infection, intracellular pathogen count in exposed AMs showed 2.5 times higher net increase (2-fold in vehicle- versus 5-fold in MWCNT-treated), indicating a greater rate of intracellular multiplication and/or survival due to MWCNT exposure. AMs from MWCNT-exposed lungs exhibited downregulation of pathogen-uptake receptors CD163, Phosphatidyl-serine receptor (Ptdsr), and Macrophage scavenger receptors class A type 1 (Msr1) and type 2 (MSr2). In whole lung, MWCNT exposure shifted the macrophage polarization state towards the immunosuppressive phenotype M2b and increased the CD11c+ dendritic cell population required to activate the adaptive immune response. Notably, the MWCNT pre-exposure dysregulated T-cell immunity, evidenced by diminished CD4 and Th17 response, and exacerbated Th1 and Treg responses (skewed Th17/Treg ratio), thereby favoring the pneumococcal infection. Overall, these findings indicated that MWCNT exposure compromises both innate and adaptive immunity leading to diminished host lung defense against pneumonia infection. To our knowledge, this is the first report on an immunomodulatory role of CNT pre-exposure on pneumococcal infection susceptibility due to dysregulation of both innate and adaptive immunity targets.
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Affiliation(s)
- Afzaal Nadeem Mohammed
- Pulmonary Pathogenesis and Immunotoxicology Laboratory, Division of Environmental Genetics and Molecular Toxicology, Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Niket Yadav
- Medical Scientist Training Program, University of Virginia School of Medicine, Charlottesville, VA 22908-0738, USA
| | - Perminder Kaur
- Pulmonary Pathogenesis and Immunotoxicology Laboratory, Division of Environmental Genetics and Molecular Toxicology, Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Roman Jandarov
- Division of Biostatistics and Bioinformatics, Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Jagjit Singh Yadav
- Pulmonary Pathogenesis and Immunotoxicology Laboratory, Division of Environmental Genetics and Molecular Toxicology, Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
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Asare PF, Hurtado PR, Tran HB, Perkins GB, Roscioli E, Hodge S. Reduction in Rubicon by cigarette smoke is associated with impaired phagocytosis and occurs through lysosomal degradation pathway. Clin Exp Med 2023; 23:4041-4055. [PMID: 37310658 DOI: 10.1007/s10238-023-01105-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 05/26/2023] [Indexed: 06/14/2023]
Abstract
BACKGROUND A common feature of COPD is a defective lung macrophage phagocytic capacity that can contribute to chronic lung inflammation and infection. The precise mechanisms remain incompletely understood, although cigarette smoke is a known contributor. We previously showed deficiency of the LC3-associated phagocytosis (LAP) regulator, Rubicon, in macrophages from COPD subjects and in response to cigarette smoke. The current study investigated the molecular basis by which cigarette smoke extract (CSE) reduces Rubicon in THP-1, alveolar and blood monocyte-derived macrophages, and the relationship between Rubicon deficiency and CSE-impaired phagocytosis. METHODOLOGY Phagocytic capacity of CSE-treated macrophages was measured by flow cytometry, Rubicon expression by Western blot and real time polymerase chain reaction, and autophagic-flux by LC3 and p62 levels. The effect of CSE on Rubicon degradation was determined using cycloheximide inhibition and Rubicon protein synthesis and half-life assessment. RESULTS Phagocytosis was significantly impaired in CSE-exposed macrophages and strongly correlated with Rubicon expression. CSE-impaired autophagy, accelerated Rubicon degradation, and reduced its half-life. Lysosomal protease inhibitors, but not proteasome inhibitors, attenuated this effect. Autophagy induction did not significantly affect Rubicon expression. CONCLUSIONS CSE decreases Rubicon through the lysosomal degradation pathway. Rubicon degradation and/or LAP impairment may contribute to dysregulated phagocytosis perpetuated by CSE.
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Affiliation(s)
- Patrick F Asare
- Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, Australia.
- Department of Thoracic Medicine, Faculty of Health and Medical Science, The University of Adelaide, Adelaide, Australia.
| | - Plinio R Hurtado
- School of Medicine, University of Adelaide, Adelaide, Australia
- Department of Renal Medicine, Royal Adelaide Hospital, Adelaide, Australia
| | - Hai B Tran
- School of Medicine, University of Adelaide, Adelaide, Australia
- Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, Australia
| | - Griffith B Perkins
- Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia
| | - Eugene Roscioli
- School of Medicine, University of Adelaide, Adelaide, Australia
- Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, Australia
| | - Sandra Hodge
- School of Medicine, University of Adelaide, Adelaide, Australia
- Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, Australia
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Vanherle L, Matthes F, Uhl FE, Meissner A. Ivacaftor therapy post myocardial infarction augments systemic inflammation and evokes contrasting effects with respect to tissue inflammation in brain and lung. Biomed Pharmacother 2023; 162:114628. [PMID: 37018991 DOI: 10.1016/j.biopha.2023.114628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 03/27/2023] [Accepted: 03/29/2023] [Indexed: 04/05/2023] Open
Abstract
Acquired cystic fibrosis transmembrane regulator (CFTR) dysfunctions have been associated with several conditions, including myocardial infarction (MI). Here, CFTR is downregulated in brain, heart, and lung tissue and associates with inflammation and degenerative processes. Therapeutically increasing CFTR expression attenuates these effects. Whether potentiating CFTR function yields similar beneficial effects post-MI is unknown. The CFTR potentiator ivacaftor is currently in clinical trials for treatment of acquired CFTR dysfunction associated with chronic obstructive pulmonary disease and chronic bronchitis. Thus, we tested ivacaftor as therapeutic strategy for MI-associated target tissue inflammation that is characterized by CFTR alterations. MI was induced in male C57Bl/6 mice by ligation of the left anterior descending coronary artery. Mice were treated with ivacaftor starting ten weeks post-MI for two consecutive weeks. Systemic ivacaftor treatment ameliorates hippocampal neuron dendritic atrophy and spine loss and attenuates hippocampus-dependent memory deficits occurring post-MI. Similarly, ivacaftor therapy mitigates MI-associated neuroinflammation (i.e., reduces higher proportions of activated microglia). Systemically, ivacaftor leads to higher frequencies of circulating Ly6C+ and Ly6Chi cells compared to vehicle-treated MI mice. Likewise, an ivacaftor-mediated augmentation of MI-associated pro-inflammatory macrophage phenotype characterized by higher CD80-positivity is observed in the MI lung. In vitro, ivacaftor does not alter LPS-induced CD80 and tumor necrosis factor alpha mRNA increases in BV2 microglial cells, while augmenting mRNA levels of these markers in mouse macrophages and differentiated human THP-1-derived macrophages. Our results suggest that ivacaftor promotes contrasting effects depending on target tissue post-MI, which may be largely dependent on its effects on different myeloid cell types.
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Affiliation(s)
- Lotte Vanherle
- Department of Experimental Medical Science, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden.
| | - Frank Matthes
- Department of Experimental Medical Science, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden; Department of Physiology, Institute for Theoretical Medicine, University of Augsburg, Augsburg, Germany.
| | - Franziska E Uhl
- Department of Experimental Medical Science, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden.
| | - Anja Meissner
- Department of Experimental Medical Science, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden; Department of Physiology, Institute for Theoretical Medicine, University of Augsburg, Augsburg, Germany.
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Fleischmann M, Jarnicki AG, Brown AS, Yang C, Anderson GP, Garbi N, Hartland EL, van Driel IR, Ng GZ. Cigarette smoke depletes alveolar macrophages and delays clearance of Legionella pneumophila. Am J Physiol Lung Cell Mol Physiol 2023; 324:L373-L384. [PMID: 36719079 PMCID: PMC10026984 DOI: 10.1152/ajplung.00268.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 12/23/2022] [Accepted: 01/25/2023] [Indexed: 02/01/2023] Open
Abstract
Legionella pneumophila is the main etiological agent of Legionnaires' disease, a severe bacterial pneumonia. L. pneumophila is initially engulfed by alveolar macrophages (AMs) and subvert normal cellular functions to establish a replicative vacuole. Cigarette smokers are particularly susceptible to developing Legionnaires' disease and other pulmonary infections; however, little is known about the cellular mechanisms underlying this susceptibility. To investigate this, we used a mouse model of acute cigarette smoke exposure to examine the immune response to cigarette smoke and subsequent L. pneumophila infection. Contrary to previous reports, we show that cigarette smoke exposure alone causes a significant depletion of AMs using enzymatic digestion to extract cells, or via imaging intact lung lobes by light-sheet microscopy. Furthermore, treatment of mice deficient in specific types of cell death with smoke suggests that NLRP3-driven pyroptosis is a contributor to smoke-induced death of AMs. After infection, smoke-exposed mice displayed increased pulmonary L. pneumophila loads and developed more severe disease compared with air-exposed controls. We tested if depletion of AMs was related to this phenotype by directly depleting them with clodronate liposomes and found that this also resulted in increased L. pneumophila loads. In summary, our results showed that cigarette smoke depleted AMs from the lung and that this likely contributed to more severe Legionnaires' disease. Furthermore, the role of AMs in L. pneumophila infection is more nuanced than simply providing a replicative niche, and our studies suggest they play a major role in bacterial clearance.
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Affiliation(s)
- Markus Fleischmann
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia
- Institute for Experimental Immunology, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Andrew G Jarnicki
- Lung Health Research Centre, Department of Biochemistry and Pharmacology, University of Melbourne, Parkville, Victoria, Australia
| | - Andrew S Brown
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia
| | - Chao Yang
- Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia
| | - Gary P Anderson
- Lung Health Research Centre, Department of Biochemistry and Pharmacology, University of Melbourne, Parkville, Victoria, Australia
| | - Natalio Garbi
- Institute for Experimental Immunology, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Elizabeth L Hartland
- Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia
- Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia
| | - Ian R van Driel
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia
| | - Garrett Z Ng
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia
- Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia
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Cho SJ, Pronko A, Yang J, Pagan K, Stout-Delgado H. Role of Cholesterol 25-Hydroxylase (Ch25h) in Mediating Innate Immune Responses to Streptococcus pneumoniae Infection. Cells 2023; 12:570. [PMID: 36831236 PMCID: PMC9953875 DOI: 10.3390/cells12040570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 02/02/2023] [Accepted: 02/09/2023] [Indexed: 02/12/2023] Open
Abstract
Alveolar macrophages (AM) are long-lived tissue-resident innate immune cells of the airways. AM are key effectors of recognition, initiation, and resolution of the host defense against microbes and play an essential role in mediating host responses to Streptococcus pneumoniae infection. Lipid metabolism in AM can significantly impact cellular function and biology. Dysregulated metabolism contributes to an accumulation of lipids, unfolded protein response induction, and inflammatory cytokine production. Our study was designed to investigate the impact of Ch25h on mediating innate immune responses by macrophages during S. pneumoniae infection. Using wild-type and Ch25-/- mice, we examined the role of cholesterol metabolism on inflammatory cytokine production and bacterial clearance. Our results demonstrate that Ch25h plays an important role in the initiation and intensity of cytokine and chemokine production in the lung during S. pneumoniae infection. In the absence of Ch25h, there was enhanced phagocytosis and bacterial clearance. Taken together, our findings demonstrate the important role of Ch25h in modulating host responsiveness to S. pneumoniae infection.
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White A, Wang Z, Wang X, King M, Guo C, Mantsounga C, Ayala A, Morrison AR, Choudhary G, Sellke F, Chambers E, Ware LB, Rounds S, Lu Q. NLRP3 inflammasome activation in cigarette smoke priming for Pseudomonas aeruginosa-induced acute lung injury. Redox Biol 2022; 57:102467. [PMID: 36175355 PMCID: PMC9618465 DOI: 10.1016/j.redox.2022.102467] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 08/30/2022] [Accepted: 09/02/2022] [Indexed: 02/04/2023] Open
Abstract
It is increasingly recognized that cigarette smoke (CS) exposure increases the incidence and severity of acute respiratory distress syndrome (ARDS) in critical ill humans and animals. However, the mechanism(s) is not well understood. This study aims to investigate mechanism underlying the priming effect of CS on Pseudomonas aeruginosa-triggered acute lung injury, by using pre-clinic animal models and genetically modified mice. We demonstrated that CS impaired P. aeruginosa-induced mitophagy flux, promoted p62 accumulation, and exacerbated P. aeruginosa-triggered mitochondrial damage and NLRP3 inflammasome activation in alveolar macrophages; an effect associated with increased acute lung injury and mortality. Pharmacological inhibition of caspase-1, a component of inflammasome, attenuated CS primed P. aeruginosa-triggered acute lung injury and improved animal survival. Global or myeloid-specific knockout of IL-1β, a downstream component of inflammasome activation, also attenuated CS primed P. aeruginosa-triggered acute lung injury. Our results suggest that NLRP3 inflammasome activation is an important mechanism for CS primed P. aeruginosa-triggered acute lung injury. (total words: 155).
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Affiliation(s)
- Alexis White
- Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, RI, USA
| | - Zhengke Wang
- Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, RI, USA
| | - Xing Wang
- Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, RI, USA
| | - Michelle King
- Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, RI, USA
| | - Cynthia Guo
- Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, RI, USA
| | - Chris Mantsounga
- Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, RI, USA
| | - Alfred Ayala
- Department of Surgery, The Warren Alpert Medical School of Brown University and Lifespan-Rhode Island Hospital, Providence, RI, USA
| | - Alan R Morrison
- Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, RI, USA; Department of Medicine, The Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Gaurav Choudhary
- Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, RI, USA; Department of Medicine, The Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Frank Sellke
- Cardiothoracic Surgery, The Warren Alpert Medical School of Brown University and Lifespan-Rhode Island Hospital, Providence, RI, USA
| | - Eboni Chambers
- Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, RI, USA
| | - Lorraine B Ware
- Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Sharon Rounds
- Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, RI, USA; Department of Medicine, The Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Qing Lu
- Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, RI, USA; Department of Medicine, The Warren Alpert Medical School of Brown University, Providence, RI, USA.
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Marrocco A, Singh D, Christiani DC, Demokritou P. E-Cigarette (E-Cig) Liquid Composition and Operational Voltage Define the In Vitro Toxicity of Δ8Tetrahydrocannabinol/Vitamin E Acetate (Δ8THC/VEA) E-Cig Aerosols. Toxicol Sci 2022; 187:279-297. [PMID: 35478015 PMCID: PMC9154258 DOI: 10.1093/toxsci/kfac047] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
The 2019 United States outbreak of E-cigarette (e-cig), or Vaping, Associated Acute Lung Injury (EVALI) has been linked to presence of vitamin E acetate (VEA) in Δ8tetrahydrocannabinol (Δ8THC)-containing e-liquids, as supported by VEA detection in patient biological samples. However, the pathogenesis of EVALI and the complex physicochemical properties of e-cig emissions remain unclear, raising concerns on health risks of vaping. This study investigates the effect of Δ8THC/VEA e-liquids and e-cig operational voltage on in vitro toxicity of e-cig aerosols. A novel E-cigExposure Generation System platform was used to generate and characterize e-cig aerosols from a panel of Δ8THC/VEA or nicotine-based e-liquids at 3.7 or 5 V. Human lung Calu-3 cells and THP-1 monocytes were exposed to cell culture media conditioned with collected e-cig aerosol condensate at doses of 85 and 257 puffs/m2 lung surface for 24 h, whereafter specific toxicological endpoints were assessed (including cytotoxicity, metabolic activity, reactive oxygen species generation, apoptosis, and inflammatory cytokines). Higher concentrations of gaseous volatile organic compounds were emitted from Δ8THC/VEA compared with nicotine-based e-liquids, especially at 5 V. Emitted PM2.5 concentrations in aerosol were higher for Δ8THC/VEA at 5 V and averagely for nicotine-based e-liquids at 3.7 V. Overall, aerosols from nicotine-based e-liquids showed higher bioactivity than Δ8THC/VEA aerosols in THP-1 cells, with no apparent differences in Calu-3 cells. Importantly, presence of VEA in Δ8THC and menthol flavoring in nicotine-based e-liquids increased cytotoxicity of aerosols across both cell lines, especially at 5 V. This study systematically investigates the physicochemical and toxicological properties of a model of Δ8THC/VEA and nicotine e-cigarette condensate exposure demonstrating that pyrolysis of these mixtures can generate hazardous toxicants whose synergistic actions potentially drive acute lung injury upon inhalation.
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Affiliation(s)
- Antonella Marrocco
- To whom correspondence should be addressed at Department of Environmental Health, Center for Nanotechnology and Nanotoxicology, Harvard T.H. Chan School of Public Health, Harvard University, 665 Huntington Avenue, Building 1, Room 1310, Boston, MA 02115, USA. E-mail:
| | - Dilpreet Singh
- Department of Environmental Health, Center for Nanotechnology and Nanotoxicology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts 02115, USA
| | - David C Christiani
- Department of Environmental Health, Center for Nanotechnology and Nanotoxicology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts 02115, USA
| | - Philip Demokritou
- Department of Environmental Health, Center for Nanotechnology and Nanotoxicology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts 02115, USA,Department of Environmental and Population Health Bio-Sciences, Environmental Occupational Health Sciences Institute, School of Public Health, Rutgers University, Piscataway, New Jersey 08854, USA
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10
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Mancuso P, Curtis JL, Weitzel AM, Griffin CA, Bouchard B, Freeman CM, Bridges D, Singer K. Diet-induced obesity in mice impairs host defense against Klebsiella pneumonia in vivo and glucose transport and bactericidal functions in neutrophils in vitro. Am J Physiol Lung Cell Mol Physiol 2022; 322:L116-L128. [PMID: 34850640 PMCID: PMC8794018 DOI: 10.1152/ajplung.00008.2021] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 11/16/2021] [Accepted: 11/16/2021] [Indexed: 01/03/2023] Open
Abstract
Obesity impairs host defense against Klebsiella pneumoniae, but responsible mechanisms are incompletely understood. To determine the impact of diet-induced obesity on pulmonary host defense against K. pneumoniae, we fed 6-wk-old male C57BL/6j mice a normal diet (ND) or high-fat diet (HFD) (13% vs. 60% fat, respectively) for 16 wk. Mice were intratracheally infected with Klebsiella, assayed at 24 or 48 h for bacterial colony-forming units, lung cytokines, and leukocytes from alveolar spaces, lung parenchyma, and gonadal adipose tissue were assessed using flow cytometry. Neutrophils from uninfected mice were cultured with and without 2-deoxy-d-glucose (2-DG) and assessed for phagocytosis, killing, reactive oxygen intermediates (ROI), transport of 2-DG, and glucose transporter (GLUT1-4) transcripts, and protein expression of GLUT1 and GLUT3. HFD mice had higher lung and splenic bacterial burdens. In HFD mice, baseline lung homogenate concentrations of IL-1β, IL-6, IL-17, IFN-γ, CXCL2, and TNF-α were reduced relative to ND mice, but following infection were greater for IL-6, CCL2, CXCL2, and IL-1β (24 h only). Despite equivalent lung homogenate leukocytes, HFD mice had fewer intraalveolar neutrophils. HFD neutrophils exhibited decreased Klebsiella phagocytosis and killing and reduced ROI to heat-killed Klebsiella in vitro. 2-DG transport was lower in HFD neutrophils, with reduced GLUT1 and GLUT3 transcripts and protein (GLUT3 only). Blocking glycolysis with 2-DG impaired bacterial killing and ROI production in neutrophils from mice fed ND but not HFD. Diet-induced obesity impairs pulmonary Klebsiella clearance and augments blood dissemination by reducing neutrophil killing and ROI due to impaired glucose transport.
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Affiliation(s)
- Peter Mancuso
- Department of Nutritional Sciences, School of Public Health, University of Michigan, Ann Arbor, Michigan
- Graduate Program in Immunology, University of Michigan, Ann Arbor, Michigan
| | - Jeffrey L Curtis
- Graduate Program in Immunology, University of Michigan, Ann Arbor, Michigan
- Division of Pulmonary & Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
- Medical Service, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan
| | - Anne M Weitzel
- Department of Nutritional Sciences, School of Public Health, University of Michigan, Ann Arbor, Michigan
| | - Cameron A Griffin
- Division of Pediatric Endocrinology, Department of Pediatrics, University of Michigan, Ann Arbor, Michigan
| | - Benjamin Bouchard
- Department of Nutritional Sciences, School of Public Health, University of Michigan, Ann Arbor, Michigan
| | - Christine M Freeman
- Graduate Program in Immunology, University of Michigan, Ann Arbor, Michigan
- Division of Pulmonary & Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
- Research Service, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan
| | - Dave Bridges
- Department of Nutritional Sciences, School of Public Health, University of Michigan, Ann Arbor, Michigan
| | - Kanakadurga Singer
- Graduate Program in Immunology, University of Michigan, Ann Arbor, Michigan
- Division of Pediatric Endocrinology, Department of Pediatrics, University of Michigan, Ann Arbor, Michigan
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11
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Tajbakhsh A, Gheibihayat SM, Mortazavi D, Medhati P, Rostami B, Savardashtaki A, Momtazi-Borojeni AA. The Effect of Cigarette Smoke Exposure on Efferocytosis in Chronic Obstructive Pulmonary Disease; Molecular Mechanisms and Treatment Opportunities. COPD 2021; 18:723-736. [PMID: 34865568 DOI: 10.1080/15412555.2021.1978419] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Cigarette smoking-related inflammation, cellular stresses, and tissue destruction play a key role in lung disease, such as chronic obstructive pulmonary disease (COPD). Notably, augmented apoptosis and impaired clearance of apoptotic cells, efferocytosis, contribute to the chronic inflammatory response and tissue destruction in patients with COPD. Of note, exposure to cigarette smoke can impair alveolar macrophages efferocytosis activity, which leads to secondary necrosis formation and tissue inflammation. A better understanding of the processes behind the effect of cigarette smoke on efferocytosis concerning lung disorders can help to design more efficient treatment approaches and also delay the development of lung disease, such as COPD. To this end, we aimed to seek mechanisms underlying the impairing effect of cigarette smoke on macrophages-mediated efferocytosis in COPD. Further, available therapeutic opportunities for restoring efferocytosis activity and ameliorating respiratory tract inflammation in smokers with COPD were also discussed.
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Affiliation(s)
- Amir Tajbakhsh
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyed Mohammad Gheibihayat
- Department of Medical Genetics, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Deniz Mortazavi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Pourya Medhati
- Student research committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Behrouz Rostami
- Health & Treatment Center of Rostam, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amir Savardashtaki
- Epilepsy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amir Abbas Momtazi-Borojeni
- Department of Medical Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Iran's National Elites Foundation, Tehran, Iran
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12
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Abstract
Alveolar macrophages (AMs) are lung-resident myeloid cells that sit at the interface of the airway and lung tissue. Under homeostatic conditions, their primary function is to clear debris, dead cells and excess surfactant from the airways. They also serve as innate pulmonary sentinels for respiratory pathogens and environmental airborne particles and as regulators of pulmonary inflammation. However, they have not typically been viewed as primary therapeutic targets for respiratory diseases. Here, we discuss the role of AMs in various lung diseases, explore the potential therapeutic strategies to target these innate cells and weigh the potential risks and challenges of such therapies. Additionally, in the context of the COVID-19 pandemic, we examine the role AMs play in severe disease and the therapeutic strategies that have been harnessed to modulate their function and protect against severe lung damage. There are many novel approaches in development to target AMs, such as inhaled antibiotics, liposomal and microparticle delivery systems, and host-directed therapies, which have the potential to provide critical treatment to patients suffering from severe respiratory diseases, yet there is still much work to be done to fully understand the possible benefits and risks of such approaches.
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13
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Moschovis PP, Lu M, Hayden D, Yonker LM, Lombay J, Taveras E, Arauz Boudreau A, Triant VA, Foulkes AS, Bassett I, Hibberd PL, Kinane TB. Effect modification by age of the association between obstructive lung diseases, smoking, and COVID-19 severity. BMJ Open Respir Res 2021; 8:8/1/e001038. [PMID: 34740944 PMCID: PMC8573665 DOI: 10.1136/bmjresp-2021-001038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 10/11/2021] [Indexed: 11/21/2022] Open
Abstract
Introduction Obstructive lung diseases (asthma and chronic obstructive pulmonary disease (COPD)) and smoking are associated with greater risk of respiratory infections and hospitalisations, but conflicting data exist regarding their association with severity of COVID-19, and few studies have evaluated whether these associations differ by age. Objectives To examine the associations between asthma, COPD and smoking on the severity of COVID-19 among a cohort of hospitalised patients, and to test for effect modification by age. Methods We performed a retrospective analysis of electronic health record data of patients admitted to Massachusetts General Hospital, assigning the maximal WHO Clinical Progression Scale score for each patient during the first 28 days following hospital admission. Using ordered logistic regression, we measured the association between maximal severity score and asthma, COPD and smoking and their interaction with age. Measurements and main results Among 1391 patients hospitalised with COVID-19, we found an increased risk of severe disease among patients with COPD and prior smoking, independent of age. We also found evidence of effect modification by age with asthma and current smoking; in particular, asthma was associated with decreased COVID-19 severity among older adults, and current smoking was associated with decreased severity among younger patients. Conclusions This cohort study identifies age as a modifying factor for the association between asthma and smoking on severity of COVID-19. Our findings highlight the complexities of determining risk factors for COVID-19 severity, and suggest that the effect of risk factors may vary across the age spectrum.
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Affiliation(s)
- Peter P Moschovis
- Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Mengdi Lu
- Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Douglas Hayden
- Biostatistics Center, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Lael M Yonker
- Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Jesiel Lombay
- Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Elsie Taveras
- Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Alexy Arauz Boudreau
- Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Virginia A Triant
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Andrea S Foulkes
- Biostatistics Center, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Ingrid Bassett
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Patricia L Hibberd
- Department of Global Health, Boston University School of Public Health, Boston, Massachusetts, USA
| | - T Bernard Kinane
- Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USA
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14
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Elgamal Z, Singh P, Geraghty P. The Upper Airway Microbiota, Environmental Exposures, Inflammation, and Disease. ACTA ACUST UNITED AC 2021; 57:medicina57080823. [PMID: 34441029 PMCID: PMC8402057 DOI: 10.3390/medicina57080823] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/09/2021] [Accepted: 08/10/2021] [Indexed: 02/07/2023]
Abstract
Along with playing vital roles in pathogen exclusion and immune system priming, the upper airways (UAs) and their microbiota are essential for myriad physiological functions such as conditioning and transferring inhaled air. Dysbiosis, a microbial imbalance, is linked with various diseases and significantly impedes the quality of one’s life. Daily inhaled exposures and/or underlying conditions contribute to adverse changes to the UA microbiota. Such variations in the microbial community exacerbate UA and pulmonary disorders via modulating inflammatory and immune pathways. Hence, exploring the UA microbiota’s role in maintaining homeostasis is imperative. The microbial composition and subsequent relationship with airborne exposures, inflammation, and disease are crucial for strategizing innovating UA diagnostics and therapeutics. The development of a healthy UA microbiota early in life contributes to normal respiratory development and function in the succeeding years. Although different UA cavities present a unique microbial profile, geriatrics have similar microbes across their UAs. This lost community segregation may contribute to inflammation and disease, as it stimulates disadvantageous microbial–microbial and microbial–host interactions. Varying inflammatory profiles are associated with specific microbial compositions, while the same is true for many disease conditions and environmental exposures. A shift in the microbial composition is also detected upon the administration of numerous therapeutics, highlighting other beneficial and adverse side effects. This review examines the role of the UA microbiota in achieving homeostasis, and the impact on the UAs of environmental airborne pollutants, inflammation, and disease.
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Affiliation(s)
- Ziyad Elgamal
- Department of Biomedical Science, University of Guelph, Guelph, ON N1G 2W1, Canada;
- Department of Medicine, Division of Pulmonary & Critical Care Medicine, State University of New York Downstate Medical Centre, Brooklyn, NY 11203, USA
| | - Pratyush Singh
- Department of Biology, University of Western Ontario, London, ON N6A 5B7, Canada;
| | - Patrick Geraghty
- Department of Medicine, Division of Pulmonary & Critical Care Medicine, State University of New York Downstate Medical Centre, Brooklyn, NY 11203, USA
- Correspondence: ; Tel.: +1-718-270-3141
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15
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Paarwater BA, Mouton JM, Sampson SL, Malherbe ST, Shaw JA, Walzl G, Kotze LA, du Plessis N. Inhaled particulate matter affects immune responsiveness of human lung phagocytes to mycobacteria. Am J Physiol Lung Cell Mol Physiol 2021; 321:L566-L575. [PMID: 34287085 DOI: 10.1152/ajplung.00014.2021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The influence of smoke-derived or air pollution-derived cytoplasmic particulate matter (PM) can be detrimental and can lead to failed lung immunity. We investigated mycobacterial uptake, intracellular replication, and soluble immune-mediator responses of human bronchoalveolar lavage cells (BALCs) loaded with/without PM, to infection with mycobacterial strains. We observed that only BALCs containing PM display an ex vivo phenotypic profile dominated by spontaneous interleukin (IL)-10 production. PM-loaded BALCs retained the ability to phagocytose both Mycobacterium bovis Bacille Calmette Guérin (BCG) and Mycobacterium tuberculosis (M.tb) ΔleuDΔpanCD at equal efficacy as clear non-PM-loaded BALCs. However, immune responsiveness, such as the production of IL-6 (P = 0.015) and tumor necrosis factor-α (TNF)-α (P = 0.0172) immediately post M. bovis BCG infection, were dramatically lower in black BALCs loaded with PM versus clear non-PM-loaded BALCs. By 24 h post infection, differential immune responses to M. bovis BCG between black versus clear BALC waned, and instead, production of IL-6 (P = 0.03) and IL-1α (P = 0.04) by black BALCs was lower versus clear BALCs following M.tb ΔleuDΔpanCD infection. Considering that TNF-α and IL-6 are characterized as critical to host protection against mycobacteria, our findings suggest that BALCs loaded with inhaled PM, display lower levels of antimycobacterial mediators and that the response magnitude differs according to infective mycobacterial strain. Even though this did not translate into altered mycobacterial killing at early time points post infection, the long-term impact of such changes remains to be established.
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Affiliation(s)
- Brandon A Paarwater
- DST-NRF Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, grid.11956.3aStellenbosch University, Cape Town, South Africa
| | - Jomien M Mouton
- DST-NRF Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, grid.11956.3aStellenbosch University, Cape Town, South Africa
| | - Samantha L Sampson
- DST-NRF Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, grid.11956.3aStellenbosch University, Cape Town, South Africa
| | - Stephanus T Malherbe
- DST-NRF Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, grid.11956.3aStellenbosch University, Cape Town, South Africa
| | - Jane A Shaw
- DST-NRF Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, grid.11956.3aStellenbosch University, Cape Town, South Africa
| | - Gerhard Walzl
- DST-NRF Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, grid.11956.3aStellenbosch University, Cape Town, South Africa
| | - Leigh A Kotze
- DST-NRF Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, grid.11956.3aStellenbosch University, Cape Town, South Africa
| | - Nelita du Plessis
- DST-NRF Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, grid.11956.3aStellenbosch University, Cape Town, South Africa
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16
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Axelrod T, Eltzov E, Lerman M, Harpaz D, Marks RS. Cigarette smoke toxicity modes of action estimated by a bioluminescent bioreporter bacterial panel. Talanta 2021; 226:122076. [PMID: 33676644 DOI: 10.1016/j.talanta.2020.122076] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 12/28/2020] [Accepted: 12/29/2020] [Indexed: 12/15/2022]
Abstract
Cigarette smoking is considered to be a risk factor for several chronic diseases and even premature death. However, despite the importance of this detrimental habit, little seems known in terms of the overall toxicity potential of its ingredients in humans. In this study, a panel of genetically modified bioluminescent bioreporter bacteria was used to evaluate its usefulness in estimating the cigarette smoke's complex molecular mixture on a bacterial toxicity-bioreporter panel, both filtered or unfiltered. This work enabled to confirm the usefulness of cigarette filters, with better protection found in higher priced brands despite both having genotoxic and cytotoxic attributes. Quorum sensing interference was also shown, which may explain why cigarette smokers are at greater risk for pulmonary infections. Moreover, the findings of this study support the fact that the filter is a dominating contributor to reducing the harm caused by cigarette smoke. Increased efforts should be conducted to reduce the harmful effects of cigarette smoke, via increasingly effective filters. To conclude, the panel of bioreporter bacteria was found to be useful in the evaluation of the general effect of the toxic mixture found in cigarette smoke and therefore has the potential to be used in cigarette research, helping researchers pinpoint the reduction of toxicity when working with filter improvement.
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Affiliation(s)
- Tim Axelrod
- Avram and Stella Goldstein-Goren Department of Biotechnology Engineering, Faculty of Engineering Science, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel
| | - Evgeni Eltzov
- Institute of Postharvest and Food Science, Department of Postharvest Science, The Volcani Center, Agricultural Research Organization, Rishon LeZion, 7505101, Israel
| | - Merav Lerman
- Avram and Stella Goldstein-Goren Department of Biotechnology Engineering, Faculty of Engineering Science, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel
| | - Dorin Harpaz
- Institute of Postharvest and Food Science, Department of Postharvest Science, The Volcani Center, Agricultural Research Organization, Rishon LeZion, 7505101, Israel; Institute of Plant Sciences and Genetics in Agriculture, Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, 761001, Israel
| | - Robert S Marks
- Avram and Stella Goldstein-Goren Department of Biotechnology Engineering, Faculty of Engineering Science, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel; National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel; The Ilse Katz Center for Meso and Nanoscale Science and Technology, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel.
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17
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Nutritional immunity: the impact of metals on lung immune cells and the airway microbiome during chronic respiratory disease. Respir Res 2021; 22:133. [PMID: 33926483 PMCID: PMC8082489 DOI: 10.1186/s12931-021-01722-y] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 04/15/2021] [Indexed: 12/15/2022] Open
Abstract
Nutritional immunity is the sequestration of bioavailable trace metals such as iron, zinc and copper by the host to limit pathogenicity by invading microorganisms. As one of the most conserved activities of the innate immune system, limiting the availability of free trace metals by cells of the immune system serves not only to conceal these vital nutrients from invading bacteria but also operates to tightly regulate host immune cell responses and function. In the setting of chronic lung disease, the regulation of trace metals by the host is often disrupted, leading to the altered availability of these nutrients to commensal and invading opportunistic pathogenic microbes. Similarly, alterations in the uptake, secretion, turnover and redox activity of these vitally important metals has significant repercussions for immune cell function including the response to and resolution of infection. This review will discuss the intricate role of nutritional immunity in host immune cells of the lung and how changes in this fundamental process as a result of chronic lung disease may alter the airway microbiome, disease progression and the response to infection.
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18
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Kc R, O'Toole RF. Draft genome sequence of a nontypeable Haemophilus influenzae strain used in the study of human respiratory infection. BMC Res Notes 2021; 14:123. [PMID: 33794985 PMCID: PMC8015102 DOI: 10.1186/s13104-021-05528-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 03/13/2021] [Indexed: 11/21/2022] Open
Abstract
Objectives Nontypeable Haemophilus influenzae (NTHi) is an important human respiratory bacterium that can cause a range of diseases including sinusitis, otitis media, conjunctivitis, pneumonia as well as acute exacerbations of chronic obstructive pulmonary disease (COPD). A number of studies have used NTHi clinical isolate RHH-3 as a laboratory strain for experimentation examining the effect of cigarette smoke and more recently, biomass smoke, on the susceptibility and response of cells lining the respiratory tract to infection. Therefore, definition of the genome content of RHH-3 is required to fully elucidate human-NTHi interactions associated with initial infection and subsequent development of respiratory disease. Data description Here, we present the draft genome sequence of NTHi RHH-3 collected from the sputum of a patient at the Royal Hobart Hospital, Tasmania, Australia. The assembled genome size was 1,839,376 bp consisting of 61 contigs (> 500 bp), with a G+C content of 38.1%. This draft genome data can be accessed at DDBJ/ENA/GenBank under the accession number JADPRR000000000.
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Affiliation(s)
- Rajendra Kc
- Menzies Institute for Medical Research, University of Tasmania, Tasmania, 7005, Australia
| | - Ronan F O'Toole
- Department of Pharmacy and Biomedical Sciences, School of Molecular Sciences, College of Science, Health and Engineering, La Trobe University, Victoria, 3690, Australia.
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19
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Chiang AJ, Thanabalasuriar A, Boo CC. Proteomics: An advanced tool to unravel the role of alveolar macrophages in respiratory diseases. Int J Biochem Cell Biol 2021; 134:105966. [PMID: 33677070 DOI: 10.1016/j.biocel.2021.105966] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 02/05/2021] [Accepted: 03/03/2021] [Indexed: 02/08/2023]
Abstract
As we learn more about chronic lung diseases, we are seeing that an unbalanced immune system plays a key role in disease pathogenesis. Innate immune cells, particularly tissue-resident macrophages, are important navigators of immunity, both during infection and in non-communicable lung disease. In the lung, alveolar macrophages are considered some of the most critical and diverse immune cells, yet despite an array of studies over the years, alveolar macrophages remain poorly understood. In this review, we highlight the importance of alveolar macrophages in health and disease, and discuss how proteomics can be used to elucidate mechanistic information and identify potential targets for therapy development.
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Affiliation(s)
- Abby J Chiang
- Dynamic Omics, Antibody Discovery and Protein Engineering, R&D AstraZeneca, Gaithersburg, MD 20878, USA
| | | | - Chelsea C Boo
- Dynamic Omics, Antibody Discovery and Protein Engineering, R&D AstraZeneca, Gaithersburg, MD 20878, USA.
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20
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Bhat TA, Kalathil SG, Bogner PN, Lehmann PV, Thatcher TH, Sime PJ, Thanavala Y. AT-RvD1 Mitigates Secondhand Smoke-Exacerbated Pulmonary Inflammation and Restores Secondhand Smoke-Suppressed Antibacterial Immunity. THE JOURNAL OF IMMUNOLOGY 2021; 206:1348-1360. [PMID: 33558371 DOI: 10.4049/jimmunol.2001228] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 01/09/2021] [Indexed: 02/07/2023]
Abstract
Cigarette smoke is a potent proinflammatory trigger contributing to acute lung injury and the development of chronic lung diseases via mechanisms that include the impairment of inflammation resolution. We have previously demonstrated that secondhand smoke (SHS) exposure exacerbates bacterial infection-induced pulmonary inflammation and suppresses immune responses. It is now recognized that resolution of inflammation is a bioactive process mediated by lipid-derived specialized proresolving mediators that counterregulate proinflammatory signaling and promote resolution pathways. We therefore hypothesized that proresolving mediators could reduce the burden of inflammation due to chronic lung infection following SHS exposure and restore normal immune responses to respiratory pathogens. To address this question, we exposed mice to SHS followed by chronic infection with nontypeable Haemophilus influenzae (NTHI). Some groups of mice were treated with aspirin-triggered resolvin D1 (AT-RvD1) during the latter half of the smoke exposure period or during a period of smoking cessation and before infection. Treatment with AT-RvD1 markedly reduced the recruitment of neutrophils, macrophages, and T cells in lung tissue and bronchoalveolar lavage and levels of proinflammatory cytokines in the bronchoalveolar lavage. Additionally, treatment with AT-RvD1 improved Ab titers against the NTHI outer membrane lipoprotein Ag P6 following infection. Furthermore, treatment with AT-RvD1 prior to classically adjuvanted immunization with P6 increased Ag-specific Ab titers, resulting in rapid clearance of NTHI from the lungs after acute challenge. Collectively, we have demonstrated that AT-RvD1 potently reverses the detrimental effects of SHS on pulmonary inflammation and immunity and thus could be beneficial in reducing lung injury associated with smoke exposure and infection.
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Affiliation(s)
- Tariq A Bhat
- Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263
| | | | - Paul N Bogner
- Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY 14263
| | | | - Thomas H Thatcher
- Department of Medicine, University of Rochester, Rochester, NY 14620; and.,Department of Environmental Medicine, University of Rochester, Rochester, NY 14620
| | - Patricia J Sime
- Department of Medicine, University of Rochester, Rochester, NY 14620; and.,Department of Environmental Medicine, University of Rochester, Rochester, NY 14620
| | - Yasmin Thanavala
- Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263;
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21
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Yee J, Cho YA, Yoo HJ, Yun H, Gwak HS. Short-term exposure to air pollution and hospital admission for pneumonia: a systematic review and meta-analysis. Environ Health 2021; 20:6. [PMID: 33413431 PMCID: PMC7792212 DOI: 10.1186/s12940-020-00687-7] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 12/14/2020] [Indexed: 05/30/2023]
Abstract
BACKGROUND Air pollution is a major issue that poses a health threat worldwide. Although several studies investigated the adverse effects of air pollution on various diseases, few have directly demonstrated the effects on pneumonia. Therefore, we performed a systematic review and meta-analysis on the associations between short-term exposure of air pollutants and hospital admission or emergency room (ER) visit for pneumonia. METHODS A literature search was performed using PubMed, Embase, and Web of Science up to April 10, 2020. Pooled estimates were calculated as % increase with 95% confidence intervals using a random-effects model. A sensitivity analysis using the leave-one-out method and subgroup analysis by region were performed. RESULTS A total of 21 studies were included in the analysis. Every 10 μg/m3 increment in PM2.5 and PM10 resulted in a 1.0% (95% CI: 0.5-1.5) and 0.4% (95% CI: 0.2-0.6) increase in hospital admission or ER visit for pneumonia, respectively. Every 1 ppm increase of CO and 10 ppb increase of NO2, SO2, and O3 was associated with 4.2% (95% CI: 0.6-7.9), 3.2% (95% CI: 1.3-5.1), 2.4% (95% CI: - 2.0-7.1), and 0.4% (95% CI: 0-0.8) increase in pneumonia-specific hospital admission or ER visit, respectively. Except for CO, the sensitivity analyses yielded similar results, demonstrating the robustness of the results. In a subgroup analysis by region, PM2.5 increased hospital admission or ER visit for pneumonia in East Asia but not in North America. CONCLUSION By combining the inconsistent findings of several studies, this study revealed the associations between short-term exposure of air pollutants and pneumonia-specific hospital admission or ER visit, especially for PM and NO2. Based on the results, stricter intervention policies regarding air pollution and programs for protecting human respiratory health should be implemented.
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Affiliation(s)
- Jeong Yee
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul, 03760, Republic of Korea
| | - Young Ah Cho
- College of Pharmacy, Gyeongsang National University, Jinju, Gyeongnam, 52828, Republic of Korea
- Mokhwa Convalescent Hospital, Jinju, Gyeongnam, 52828, Republic of Korea
| | - Hee Jeong Yoo
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul, 03760, Republic of Korea
- Department of Pharmacy, National Medical Center, Seoul, 04564, Republic of Korea
| | - Hyunseo Yun
- Graduate School of Clinical Biohealth, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Hye Sun Gwak
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul, 03760, Republic of Korea.
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22
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Srinivasan K, Sathiyaseelan M, Raj J, Ranganadin P, Subramanian B. Potential health impacts and lung microbiome changes among smoking and smokeless tobacco use : A technical scan. EURASIAN JOURNAL OF PULMONOLOGY 2021. [DOI: 10.4103/ejop.ejop_108_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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23
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Ahmad S, Arora S, Khan S, Mohsin M, Mohan A, Manda K, Syed MA. Vitamin D and its therapeutic relevance in pulmonary diseases. J Nutr Biochem 2020; 90:108571. [PMID: 33388351 DOI: 10.1016/j.jnutbio.2020.108571] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 09/20/2020] [Accepted: 12/24/2020] [Indexed: 01/15/2023]
Abstract
Vitamin D is customarily involved in maintaining bone and calcium homeostasis. However, contemporary studies have identified the implication of vitamin D in several cellular processes including cellular proliferation, differentiation, wound healing, repair and regulatory systems inclusive of host defence, immunity, and inflammation. Multiple studies have indicated corelations between low serum levels of vitamin D, perturbed pulmonary functions and enhanced incidences of inflammatory diseases. Almost all of the pulmonary diseases including acute lung injury, cystic fibrosis, asthma, COPD, Pneumonia and Tuberculosis, all are inflammatory in nature. Studies have displayed strong inter-relations with vitamin D deficiency and progression of lung disorders; however, the underlying mechanism is still unknown. Vitamin D has emerged to possess inhibiting effects on pulmonary inflammation while exaggerating innate immune defenses by strongly influencing functions of inflammatory cells including dendritic cells, monocyte/macrophages, T cells, and B cells along with structural epithelial cells. This review dissects the effects of vitamin D on the inflammatory cells and their therapeutic relevance in pulmonary diseases. Although, the data obtained is very limited and needs further corroboration but presents an exciting area of further research. This is because of its ease of supplementation and development of personalized medicine which could lead us to an effective adjunct and cost-effective method of therapeutic modality for highly fatal pulmonary diseases.
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Affiliation(s)
- Shaniya Ahmad
- Translational Research Lab, Department of Biotechnology, Jamia Millia Islamia, New Delhi, India; Institute of Nuclear Medicine and Allied Science, Defence Research and Development Organisation, New Delhi, India
| | - Shweta Arora
- Translational Research Lab, Department of Biotechnology, Jamia Millia Islamia, New Delhi, India
| | - Salman Khan
- Translational Research Lab, Department of Biotechnology, Jamia Millia Islamia, New Delhi, India
| | - Mohd Mohsin
- Translational Research Lab, Department of Biotechnology, Jamia Millia Islamia, New Delhi, India
| | - Anant Mohan
- Department of Pulmonary Medicine, AIIMS, New Delhi, India
| | - Kailash Manda
- Institute of Nuclear Medicine and Allied Science, Defence Research and Development Organisation, New Delhi, India
| | - Mansoor Ali Syed
- Translational Research Lab, Department of Biotechnology, Jamia Millia Islamia, New Delhi, India.
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24
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Hilty M, Wüthrich TM, Godel A, Adelfio R, Aebi S, Burgener SS, Illgen-Wilcke B, Benarafa C. Chronic cigarette smoke exposure and pneumococcal infection induce oropharyngeal microbiota dysbiosis and contribute to long-lasting lung damage in mice. Microb Genom 2020; 6:mgen000485. [PMID: 33295863 PMCID: PMC8116676 DOI: 10.1099/mgen.0.000485] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 11/10/2020] [Indexed: 12/17/2022] Open
Abstract
Environmental factors, such as cigarette smoking or lung infections, may influence chronic obstructive pulmonary disease (COPD) progression by modifying the respiratory tract microbiome. However, whether the disease itself induces or maintains dysbiosis remains undefined. In this longitudinal study, we investigated the oropharyngeal microbiota composition and disease progression of mice (in cages of 5-10 mice per cage) before, during and up to 3 months after chronic cigarette smoke exposure or exposure to room air for 6 months. Cigarette smoke exposure induced pulmonary emphysema measurable at the end of exposure for 6 months, as well as 3 months following smoke exposure cessation. Using both classical culture methods and 16S rRNA sequencing, we observed that cigarette smoke exposure altered the relative composition of the oropharyngeal microbiota and reduced its diversity (P <0.001). More than 60 taxa were substantially reduced after 6 months of smoke exposure (P <0.001) However, oropharyngeal microbiota disordering was reversed 3 months after smoke exposure cessation and no significant difference was observed compared to age-matched control mice. The effects of lung infection with Streptococcus pneumoniae on established smoke-induced emphysema and on the oropharyngeal microbiota were also evaluated. Inoculation with S. pneumoniae induced lung damage and altered the microbiota composition for a longer time compared to control groups infected but not previously exposed to smoke (P=0.01). Our data demonstrate effects of cigarette smoke and pneumococcus infection leading to altered microbiota and emphysema development. The reversal of the disordering of the microbiota composition, but not lung damage, following smoke exposure cessation and after clearance of infection suggest that changes in lung structure are not sufficient to sustain a disordered microbiota in mice. Whether changes in the airway microbiota contribute to inducing emphysema requires further investigation.
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Affiliation(s)
- Markus Hilty
- Institute for Infectious Diseases, University of Bern, Bern, Switzerland
| | - Tsering M. Wüthrich
- Institute for Infectious Diseases, University of Bern, Bern, Switzerland
- Institute of Virology and Immunology, 3147 Mittelhäusern, Switzerland
- Graduate School for Cellular and Biomedical Sciences, University of Bern, Freiestrasse 1, 3012 Bern, Switzerland
| | - Aurélie Godel
- Institute of Virology and Immunology, 3147 Mittelhäusern, Switzerland
| | - Roberto Adelfio
- Department of Infectious Diseases and Pathobiology (DIP), Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland
| | - Susanne Aebi
- Institute for Infectious Diseases, University of Bern, Bern, Switzerland
| | - Sabrina S. Burgener
- Institute of Virology and Immunology, 3147 Mittelhäusern, Switzerland
- Department of Infectious Diseases and Pathobiology (DIP), Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland
| | | | - Charaf Benarafa
- Institute of Virology and Immunology, 3147 Mittelhäusern, Switzerland
- Department of Infectious Diseases and Pathobiology (DIP), Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland
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25
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Abundance of Non-Polarized Lung Macrophages with Poor Phagocytic Function in Chronic Obstructive Pulmonary Disease (COPD). Biomedicines 2020; 8:biomedicines8100398. [PMID: 33050042 PMCID: PMC7650830 DOI: 10.3390/biomedicines8100398] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 09/24/2020] [Accepted: 09/29/2020] [Indexed: 02/08/2023] Open
Abstract
Lung macrophages are the key immune effector cells in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). Several studies have shown an increase in their numbers in bronchoalveolar lavage fluid (BAL) of subjects with COPD compared to controls, suggesting a pathogenic role in disease initiation and progression. Although reduced lung macrophage phagocytic ability has been previously shown in COPD, the relationship between lung macrophages' phenotypic characteristics and functional properties in COPD is still unclear. (1) Methods: Macrophages harvested from bronchoalveolar lavage (BAL) fluid of subjects with and without COPD (GOLD grades, I-III) were immuno-phenotyped, and their function and gene expression profiles were assessed using targeted assays. (2) Results: BAL macrophages from 18 COPD and 10 (non-COPD) control subjects were evaluated. The majority of macrophages from COPD subjects were non-polarized (negative for both M1 and M2 markers; 77.9%) in contrast to controls (23.9%; p < 0.001). The percentages of these non-polarized macrophages strongly correlated with the severity of COPD (p = 0.006) and current smoking status (p = 0.008). Non-polarized macrophages demonstrated poor phagocytic function in both the control (p = 0.02) and COPD (p < 0.001) subjects. Non-polarized macrophages demonstrated impaired ability to phagocytose Staphylococcus aureus (p < 0.001). They also demonstrated reduced gene expression for CD163, CD40, CCL13 and C1QA&B, which are involved in pathogen recognition and processing and showed an increased gene expression for CXCR4, RAF1, amphiregulin and MAP3K5, which are all involved in promoting the inflammatory response. (3) Conclusions: COPD is associated with an abundance of non-polarized airway macrophages that is related to the severity of COPD. These non-polarized macrophages are predominantly responsible for the poor phagocytic capacity of lung macrophages in COPD, having reduced capacity for pathogen recognition and processing. This could be a key risk factor for COPD exacerbation and could contribute to disease progression.
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26
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Penke LR, Speth JM, Draijer C, Zaslona Z, Chen J, Mancuso P, Freeman CM, Curtis JL, Goldstein DR, Peters-Golden M. PGE 2 accounts for bidirectional changes in alveolar macrophage self-renewal with aging and smoking. Life Sci Alliance 2020; 3:3/11/e202000800. [PMID: 32820026 PMCID: PMC7441521 DOI: 10.26508/lsa.202000800] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 08/13/2020] [Accepted: 08/14/2020] [Indexed: 11/24/2022] Open
Abstract
Alveolar macrophages (AMs) are resident immune cells of the lung that are critical for host defense. AMs are capable of proliferative renewal, yet their numbers are known to decrease with aging and increase with cigarette smoking. The mechanism by which AM proliferation is physiologically restrained, and whether dysregulation of this brake contributes to altered AM numbers in pathologic circumstances, however, remains unknown. Mice of advanced age exhibited diminished basal AM numbers and contained elevated PGE2 levels in their bronchoalveolar lavage fluid (BALF) as compared with young mice. Exogenous PGE2 inhibited AM proliferation in an E prostanoid receptor 2 (EP2)-cyclic AMP-dependent manner. Furthermore, EP2 knockout (EP2 KO) mice exhibited elevated basal AM numbers, and their AMs resisted the ability of PGE2 and aged BALF to inhibit proliferation. In contrast, increased numbers of AMs in mice exposed to cigarette smoking were associated with reduced PGE2 levels in BALF and were further exaggerated in EP2 KO mice. Collectively, our findings demonstrate that PGE2 functions as a tunable brake on AM numbers under physiologic and pathophysiological conditions.
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Affiliation(s)
- Loka R Penke
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Jennifer M Speth
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Christina Draijer
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Zbigniew Zaslona
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Judy Chen
- Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI, USA.,Division of Cardiology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Peter Mancuso
- Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI, USA.,Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Christine M Freeman
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.,Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI, USA.,Research Service, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, USA
| | - Jeffrey L Curtis
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.,Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI, USA.,Medical Service, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, USA
| | - Daniel R Goldstein
- Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI, USA.,Division of Cardiology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.,Institute of Gerontology, University of Michigan, Ann Arbor, MI, USA
| | - Marc Peters-Golden
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA .,Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI, USA
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27
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Schneider DJ, Smith KA, Latuszek CE, Wilke CA, Lyons DM, Penke LR, Speth JM, Marthi M, Swanson JA, Moore BB, Lauring AS, Peters‐Golden M. Alveolar macrophage-derived extracellular vesicles inhibit endosomal fusion of influenza virus. EMBO J 2020; 39:e105057. [PMID: 32643835 PMCID: PMC7429743 DOI: 10.15252/embj.2020105057] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 06/05/2020] [Accepted: 06/15/2020] [Indexed: 01/09/2023] Open
Abstract
Alveolar macrophages (AMs) and epithelial cells (ECs) are the lone resident lung cells positioned to respond to pathogens at early stages of infection. Extracellular vesicles (EVs) are important vectors of paracrine signaling implicated in a range of (patho)physiologic contexts. Here we demonstrate that AMs, but not ECs, constitutively secrete paracrine activity localized to EVs which inhibits influenza infection of ECs in vitro and in vivo. AMs exposed to cigarette smoke extract lost the inhibitory activity of their secreted EVs. Influenza strains varied in their susceptibility to inhibition by AM-EVs. Only those exhibiting early endosomal escape and high pH of fusion were inhibited via a reduction in endosomal pH. By contrast, strains exhibiting later endosomal escape and lower fusion pH proved resistant to inhibition. These results extend our understanding of how resident AMs participate in host defense and have broader implications in the defense and treatment of pathogens internalized within endosomes.
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Affiliation(s)
- Daniel J Schneider
- Division of Pulmonary and Critical Care MedicineDepartment of Internal MedicineUniversity of Michigan Medical SchoolAnn ArborMIUSA
| | - Katherine A Smith
- Division of Pulmonary and Critical Care MedicineDepartment of Internal MedicineUniversity of Michigan Medical SchoolAnn ArborMIUSA
| | - Catrina E Latuszek
- Division of Pulmonary and Critical Care MedicineDepartment of Internal MedicineUniversity of Michigan Medical SchoolAnn ArborMIUSA
| | - Carol A Wilke
- Division of Pulmonary and Critical Care MedicineDepartment of Internal MedicineUniversity of Michigan Medical SchoolAnn ArborMIUSA
- Department of Microbiology and ImmunologyUniversity of Michigan Medical SchoolAnn ArborMIUSA
| | - Danny M Lyons
- Department of Microbiology and ImmunologyUniversity of Michigan Medical SchoolAnn ArborMIUSA
- Division of Infectious DiseaseDepartment of Internal MedicineUniversity of Michigan Medical SchoolAnn ArborMIUSA
| | - Loka R Penke
- Division of Pulmonary and Critical Care MedicineDepartment of Internal MedicineUniversity of Michigan Medical SchoolAnn ArborMIUSA
| | - Jennifer M Speth
- Division of Pulmonary and Critical Care MedicineDepartment of Internal MedicineUniversity of Michigan Medical SchoolAnn ArborMIUSA
| | - Matangi Marthi
- Department of Microbiology and ImmunologyUniversity of Michigan Medical SchoolAnn ArborMIUSA
| | - Joel A Swanson
- Department of Microbiology and ImmunologyUniversity of Michigan Medical SchoolAnn ArborMIUSA
| | - Bethany B Moore
- Division of Pulmonary and Critical Care MedicineDepartment of Internal MedicineUniversity of Michigan Medical SchoolAnn ArborMIUSA
- Department of Microbiology and ImmunologyUniversity of Michigan Medical SchoolAnn ArborMIUSA
- Graduate Program in ImmunologyUniversity of Michigan Medical SchoolAnn ArborMIUSA
| | - Adam S Lauring
- Department of Microbiology and ImmunologyUniversity of Michigan Medical SchoolAnn ArborMIUSA
- Division of Infectious DiseaseDepartment of Internal MedicineUniversity of Michigan Medical SchoolAnn ArborMIUSA
- Graduate Program in ImmunologyUniversity of Michigan Medical SchoolAnn ArborMIUSA
| | - Marc Peters‐Golden
- Division of Pulmonary and Critical Care MedicineDepartment of Internal MedicineUniversity of Michigan Medical SchoolAnn ArborMIUSA
- Graduate Program in ImmunologyUniversity of Michigan Medical SchoolAnn ArborMIUSA
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28
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Macrophages-the immune effector guardians of the lung: impact of corticosteroids on their functional responses. Clin Sci (Lond) 2020; 134:1631-1635. [PMID: 32608490 PMCID: PMC7330501 DOI: 10.1042/cs20200382] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Revised: 06/23/2020] [Accepted: 06/25/2020] [Indexed: 12/27/2022]
Abstract
Lung macrophages (LMs) are key immune effector cells that protect the lung from inhaled particulate matter, noxious gases and pathogens. In Chronic Obstructive Pulmonary Disease (COPD), there is an abundance of macrophages in airspaces and lung tissues suggesting that they play an important role in the pathogenesis of the disease. Furthermore, macrophage phenotype and functional properties are altered in COPD toward a more pro-inflammatory state, characterized by reduced pathogen recognition and processing ability and dysfunctional tissue repair qualities. Inhaled corticosteroids (ICSs), used in the management of COPD, has been shown to reduce acute exacerbations of COPD but is also associated with increased occurrence of pneumonia. Corticosteroids treatment altered LM phenotypic characteristics and their functional properties, and this commentary discusses current knowledge and also the gaps in our understanding of the impact of ICS on LMs phenotype and function. A better understanding of how ICSs impact the immune-inflammatory responses in the lung, in particular ICSs’ effects on LMs, could allow more selective personalized tailoring of the use of ICSs in COPD to improve disease progression, morbidity and mortality.
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29
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Herman M, Tarran R. E-cigarettes, nicotine, the lung and the brain: multi-level cascading pathophysiology. J Physiol 2020; 598:5063-5071. [PMID: 32515030 DOI: 10.1113/jp278388] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 03/13/2020] [Indexed: 12/13/2022] Open
Abstract
Tobacco smoking is highly addictive and causes respiratory disease, cardiovascular disease and multiple types of cancer. Electronic-cigarettes (e-cigarettes) are non-combustible tobacco alternatives that aerosolize nicotine and flavouring agents in a propylene glycol-vegetable glycerine vehicle. They were originally envisaged as a tobacco cessation aid, but whether or not they help people to quit tobacco use is controversial. In this review, we have compared and contrasted what is known regarding the effects of nicotine on the lungs vs. the effects of nicotine in the brain in the context of addiction. Critically, both combustible tobacco products and e-cigarettes contain nicotine, a highly addictive, plant-derived alkaloid that binds to nicotinic acetylcholine receptors (nAChRs). Nicotine's reinforcing properties are primarily mediated by activation of the brain's mesolimbic reward circuitry and release of the neurotransmitter dopamine that contribute to the development of addiction. Moreover, nicotine addiction drives repeated intake that results in chronic pulmonary exposure to either tobacco smoke or e-cigarettes despite negative respiratory symptoms. Beyond the brain, nAChRs are also highly expressed in peripheral neurons, epithelia and immune cells, where their activation may cause harmful effects. Thus, nicotine, a key ingredient of both conventional and electronic cigarettes, produces neurological effects that drive addiction and may damage the lungs in the process, producing a complex, multilevel pathological state. We conclude that vaping needs to be studied by multi-disciplinary teams that include pulmonary and neurophysiologists as well as behaviourists and addiction specialists to fully understand their impact on human physiology.
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Affiliation(s)
- Melissa Herman
- Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.,Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Robert Tarran
- Department of Cell Biology & Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
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30
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Haggadone MD, Mancuso P, Peters-Golden M. Oxidative Inactivation of the Proteasome Augments Alveolar Macrophage Secretion of Vesicular SOCS3. Cells 2020; 9:cells9071589. [PMID: 32630102 PMCID: PMC7408579 DOI: 10.3390/cells9071589] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Revised: 06/25/2020] [Accepted: 06/27/2020] [Indexed: 01/26/2023] Open
Abstract
Extracellular vesicles (EVs) contain a diverse array of molecular cargoes that alter cellular phenotype and function following internalization by recipient cells. In the lung, alveolar macrophages (AMs) secrete EVs containing suppressor of cytokine signaling 3 (SOCS3), a cytosolic protein that promotes homeostasis via vesicular transfer to neighboring alveolar epithelial cells. Although changes in the secretion of EV molecules-including but not limited to SOCS3-have been described in response to microenvironmental stimuli, the cellular and molecular machinery that control alterations in vesicular cargo packaging remain poorly understood. Furthermore, the use of quantitative methods to assess the sorting of cytosolic cargo molecules into EVs is lacking. Here, we utilized cigarette smoke extract (CSE) exposure of AMs as an in vitro model of oxidative stress to address these gaps in knowledge. We demonstrate that the accumulation of reactive oxygen species (ROS) in AMs was sufficient to augment vesicular SOCS3 release in this model. Using nanoparticle tracking analysis (NTA) in tandem with a new carboxyfluorescein succinimidyl ester (CFSE)-based intracellular protein packaging assay, we show that the stimulatory effects of CSE were at least in part attributable to elevated amounts of SOCS3 packaged per EV secreted by AMs. Furthermore, the use of a 20S proteasome activity assay alongside treatment of AMs with conventional proteasome inhibitors strongly suggest that ROS stimulated SOCS3 release via inactivation of the proteasome. These data demonstrate that tuning of AM proteasome function by microenvironmental oxidants is a critical determinant of the packaging and secretion of cytosolic SOCS3 protein within EVs.
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Affiliation(s)
- Mikel D. Haggadone
- Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; (M.D.H.); (P.M.)
- Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
| | - Peter Mancuso
- Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; (M.D.H.); (P.M.)
- Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA
| | - Marc Peters-Golden
- Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; (M.D.H.); (P.M.)
- Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
- Correspondence: ; Tel.: +1-734-936-5047
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31
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da Silva Araújo NP, de Matos NA, Leticia Antunes Mota S, Farias de Souza AB, Dantas Cangussú S, Cunha Alvim de Menezes R, Silva Bezerra F. Quercetin Attenuates Acute Lung Injury Caused by Cigarette Smoke Both In Vitro and In Vivo. COPD 2020; 17:205-214. [PMID: 32237913 DOI: 10.1080/15412555.2020.1749253] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Cigarette smoke is highly toxic and is a major risk factor for airway inflammation, oxidative stress, and decline in lung function-the starting points for chronic obstructive pulmonary disease. Quercetin is a potent dietary antioxidant that displays anti-inflammatory activities. The goal of this study was to evaluate the effects of quercetin on reducing the redox imbalance and inflammation induced by short-term cigarette smoke exposure. In vitro, 25 and 50 μM quercetin attenuated the effects of cigarette smoke extract (increased generation of reactive oxygen species and nitric oxide) on J774A.1 cells (macrophages). We further examined the effects of quercetin in vivo. Male C57Bl/6 mice that received 10 mg/kg/day of quercetin via orogastric gavage before exposure to five days of cigarette smoke demonstrated reduced levels of leukocyte, oxidative stress, histological pattern changes of pulmonary parenchyma, and lung function alterations compared to the group that did not receive quercetin. These results suggest that quercetin may be an effective adjuvant for treating the effects of cigarette smoke exposure.
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Affiliation(s)
- Natália Pereira da Silva Araújo
- Laboratory of Experimental Pathophysiology, Department of Biological Sciences and Center of Research in Biological Sciences, Federal University of Ouro Preto, Ouro Preto, Brazil
| | - Natália Alves de Matos
- Laboratory of Experimental Pathophysiology, Department of Biological Sciences and Center of Research in Biological Sciences, Federal University of Ouro Preto, Ouro Preto, Brazil
| | - Suianne Leticia Antunes Mota
- Laboratory of Parasitic Diseases, School of Medicine, Department of Biological Sciences and NUPEB, Federal University of Ouro Preto, Ouro Preto, Brazil
| | - Ana Beatriz Farias de Souza
- Laboratory of Experimental Pathophysiology, Department of Biological Sciences and Center of Research in Biological Sciences, Federal University of Ouro Preto, Ouro Preto, Brazil
| | - Sílvia Dantas Cangussú
- Laboratory of Experimental Pathophysiology, Department of Biological Sciences and Center of Research in Biological Sciences, Federal University of Ouro Preto, Ouro Preto, Brazil
| | - Rodrigo Cunha Alvim de Menezes
- Laboratory of Cardiovascular Physiology, Department of Biological Sciences and Center of Research in Biological Sciences, Federal University of Ouro Preto, Ouro Preto, Brazil
| | - Frank Silva Bezerra
- Laboratory of Experimental Pathophysiology, Department of Biological Sciences and Center of Research in Biological Sciences, Federal University of Ouro Preto, Ouro Preto, Brazil
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32
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Yang Q, Gao P, Mu M, Tao X, He J, Wu F, Guo S, Qian Z, Song C. [Phagocytosis of alveolar macrophages is suppressed in a mouse model of lipopolysaccharide-induced acute lung injury]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2020; 40:376-381. [PMID: 32376590 DOI: 10.12122/j.issn.1673-4254.2020.03.15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
OBJECTIVE To investigate the changes in phagocytic function of alveolar macrophages (AMs) in mice with lipopolysaccharide (LPS)-induced acute lung injury (ALI) and explore the possible mechanism. METHODS Kunming mice were randomly divided into normal control group and ALI (induced by LPS instillation in the airway) model group. AMs were obtained from bronchoalveolar lavage fluid in both groups, and phagocytosis of the AMs was observed using flow cytometry and fluorescence microscopy. Western blotting and ELISA were used to detect the expression and secretion of IL-33 in the lung tissue of the mice. We also detected the secretion of IL-33 by an alveolar epithelial cell line MLE-12 in response to stimulation with different concentrations of LPS. The AMs from the normal control mice were treated with different concentrations of LPS and IL-33, and the changes in the phagocytic activity of the cells were observed. RESULTS Compared with those in normal control group, the percentage of AMs phagocytosing fluorescent microspheres was significantly decreased, and the expression of IL-33 in lung tissue and IL-33 level in the bronchoalveolar lavage fluid were significantly increased in ALI mice (P < 0.01). LPS (100-1000 ng/mL) obviously promoted the secretion of IL-33 in cultured MLE-12 cells (P < 0.01). Both LPS (10-500 ng/mL) and IL-33 (100 ng/mL) significantly inhibited the phagocytic activity of the AMs from normal control mice (P < 0.01). CONCLUSIONS The phagocytic activity of AMs is weakened in ALI mice possibly due to direct LPS stimulation and the inhibitory effect of the alarmin IL-33 produced by LPS-stimulated alveolar epithelial cells.
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Affiliation(s)
- Qian Yang
- Department of Immunology, School of Laboratory Medicine, Bengbu Medical College; Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu 233030, China
| | - Peiyu Gao
- Department of Immunology, School of Laboratory Medicine, Bengbu Medical College; Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu 233030, China
| | - Mimi Mu
- Department of Immunology, School of Laboratory Medicine, Bengbu Medical College; Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu 233030, China
| | - Xiangnan Tao
- Department of Clinical Laboratory, Second Affiliated Hospital of Bengbu Medical College, Bengbu 233040, China
| | - Jing He
- Department of Immunology, School of Laboratory Medicine, Bengbu Medical College; Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu 233030, China
| | - Fengjiao Wu
- Department of Immunology, School of Laboratory Medicine, Bengbu Medical College; Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu 233030, China
| | - Shujun Guo
- Department of Immunology, School of Laboratory Medicine, Bengbu Medical College; Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu 233030, China
| | - Zhongqing Qian
- Department of Immunology, School of Laboratory Medicine, Bengbu Medical College; Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu 233030, China
| | - Chuanwang Song
- Department of Immunology, School of Laboratory Medicine, Bengbu Medical College; Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu 233030, China
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33
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Lung Macrophage Functional Properties in Chronic Obstructive Pulmonary Disease. Int J Mol Sci 2020; 21:ijms21030853. [PMID: 32013028 PMCID: PMC7037150 DOI: 10.3390/ijms21030853] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 01/21/2020] [Accepted: 01/23/2020] [Indexed: 12/13/2022] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is caused by the chronic exposure of the lungs to toxic particles and gases. These exposures initiate a persistent innate and adaptive immune inflammatory response in the airways and lung tissues. Lung macrophages (LMs) are key innate immune effector cells that identify, engulf, and destroy pathogens and process inhaled particles, including cigarette smoke and particulate matter (PM), the main environmental triggers for COPD. The number of LMs in lung tissues and airspaces is increased in COPD, suggesting a potential key role for LMs in initiating and perpetuating the chronic inflammatory response that underpins the progressive nature of COPD. The purpose of this brief review is to discuss the origins of LMs, their functional properties (chemotaxis, recruitment, mediator production, phagocytosis and apoptosis) and changes in these properties due to exposure to cigarette smoke, ambient particulate and pathogens, as well as their persistent altered functional properties in subjects with established COPD. We also explore the potential to therapeutically modulate and restore LMs functional properties, to improve impaired immune system, prevent the progression of lung tissue destruction, and improve both morbidity and mortality related to COPD.
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Kumpitsch C, Koskinen K, Schöpf V, Moissl-Eichinger C. The microbiome of the upper respiratory tract in health and disease. BMC Biol 2019; 17:87. [PMID: 31699101 PMCID: PMC6836414 DOI: 10.1186/s12915-019-0703-z] [Citation(s) in RCA: 258] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Accepted: 09/19/2019] [Indexed: 02/08/2023] Open
Abstract
The human upper respiratory tract (URT) offers a variety of niches for microbial colonization. Local microbial communities are shaped by the different characteristics of the specific location within the URT, but also by the interaction with both external and intrinsic factors, such as ageing, diseases, immune responses, olfactory function, and lifestyle habits such as smoking. We summarize here the current knowledge about the URT microbiome in health and disease, discuss methodological issues, and consider the potential of the nasal microbiome to be used for medical diagnostics and as a target for therapy.
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Affiliation(s)
- Christina Kumpitsch
- Diagnostic and Research Institute of Hygiene, Microbiology and Environmental Medicine, Medical University of Graz, Neue Stiftingtalstraße 6, 8010 Graz, Austria
| | - Kaisa Koskinen
- Diagnostic and Research Institute of Hygiene, Microbiology and Environmental Medicine, Medical University of Graz, Neue Stiftingtalstraße 6, 8010 Graz, Austria
| | - Veronika Schöpf
- Institute of Psychology, University of Graz, Universitaetsplatz 2, 8010 Graz, Austria
- BioTechMed-Graz, Mozartgasse 12/II, 8010 Graz, Austria
- Present address: Medical University Vienna, Spitalgasse 23, 1090 Vienna, Austria
| | - Christine Moissl-Eichinger
- Diagnostic and Research Institute of Hygiene, Microbiology and Environmental Medicine, Medical University of Graz, Neue Stiftingtalstraße 6, 8010 Graz, Austria
- BioTechMed-Graz, Mozartgasse 12/II, 8010 Graz, Austria
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35
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Alawieh A, Langley EF, Tomlinson S. Targeted complement inhibition salvages stressed neurons and inhibits neuroinflammation after stroke in mice. Sci Transl Med 2019; 10:10/441/eaao6459. [PMID: 29769288 DOI: 10.1126/scitranslmed.aao6459] [Citation(s) in RCA: 122] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Revised: 11/22/2017] [Accepted: 04/27/2018] [Indexed: 12/20/2022]
Abstract
Ischemic stroke results from the interruption of blood flow to the brain resulting in long-term motor and cognitive neurological deficits, and it is a leading cause of death and disability. Current interventions focus on the restoration of blood flow to limit neuronal death, but these treatments have a therapeutic window of only a few hours and do not address post-stroke cerebral inflammation. The complement system, a component of the innate immune system, is activated by natural immunoglobulin M (IgM) antibodies that recognize neoepitopes expressed in the brain after ischemic stroke. We took advantage of this recognition system to inhibit complement activation locally in the ischemic area in mice. A single chain antibody recognizing a post-ischemic neoepitope linked to a complement inhibitor (termed B4Crry) was administered systemically as a single dose after stroke and shown to specifically target the ischemic hemisphere and improve long-term motor and cognitive recovery. We show that complement opsonins guide microglial phagocytosis of stressed but salvageable neurons, and that by locally and transiently inhibiting complement deposition, B4Crry prevented phagocytosis of penumbral neurons and inhibited pathologic complement and microglial activation that otherwise persisted for several weeks after stroke. B4Crry was protective in adult, aged, male and female mice and had a therapeutic window of at least 24 hours after stroke. Furthermore, the epitope recognized by B4Crry in mice is overexpressed in the ischemic penumbra of acute stroke patients, but not in the contralateral tissue, highlighting the translational potential of this approach.
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Affiliation(s)
- Ali Alawieh
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA.,Medical Scientist Training Program, College of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
| | - E Farris Langley
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Stephen Tomlinson
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA. .,Ralph H. Johnson VA Medical Center, Charleston, SC 29425, USA
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36
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Gou X, Zhang Q, More S, Bamunuarachchi G, Liang Y, Haider Khan F, Maranville R, Zuniga E, Wang C, Liu L. Repeated Exposure to Streptococcus pneumoniae Exacerbates Chronic Obstructive Pulmonary Disease. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:1711-1720. [PMID: 31220453 DOI: 10.1016/j.ajpath.2019.05.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 05/15/2019] [Accepted: 05/23/2019] [Indexed: 01/07/2023]
Abstract
Streptococcus pneumoniae is commonly found in patients with chronic obstructive pulmonary disease (COPD) and is linked to acute exacerbation of COPD. However, current clinical therapy neglects asymptomatic insidious S. pneumoniae colonization. We studied the roles of repeated exposure to S. pneumoniae in COPD progression using a mouse model. C57BL/6J mice were intranasally inoculated with S. pneumoniae ST262 every 4 weeks with or without cigarette smoke (CS) exposure up to 20 weeks to maintain persistent S. pneumoniae presence in the lower airways. Streptococcus pneumoniae enhanced CS-induced inflammatory cell infiltration at 12 to 20 weeks of exposure. Streptococcus pneumoniae also increased CS-induced release of inflammatory cytokines, including IL-1β, tumor necrosis factor-α, IL-12 (p70), and IL-5 at 20 weeks of exposure. Moreover, a combination of CS and S. pneumoniae caused alveolar epithelial injury, a decline in lung function, and an increased expression of platelet-activating factor receptor and bacterial load. Our results suggest that repeated exposure to S. pneumoniae in lower airways exacerbates CS-induced COPD.
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Affiliation(s)
- Xuxu Gou
- Lundberg-Kienlen Lung Biology and Toxicology Laboratory, Department of Physiological Sciences, Oklahoma State University, Stillwater, Oklahoma; Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, Oklahoma
| | - Qiao Zhang
- Lundberg-Kienlen Lung Biology and Toxicology Laboratory, Department of Physiological Sciences, Oklahoma State University, Stillwater, Oklahoma; Institute of Respiratory Diseases, Xinqiao Hospital, Chongqing, China
| | - Sunil More
- Lundberg-Kienlen Lung Biology and Toxicology Laboratory, Department of Physiological Sciences, Oklahoma State University, Stillwater, Oklahoma; Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, Oklahoma
| | - Gayan Bamunuarachchi
- Lundberg-Kienlen Lung Biology and Toxicology Laboratory, Department of Physiological Sciences, Oklahoma State University, Stillwater, Oklahoma; Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, Oklahoma
| | - Yurong Liang
- Lundberg-Kienlen Lung Biology and Toxicology Laboratory, Department of Physiological Sciences, Oklahoma State University, Stillwater, Oklahoma; Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, Oklahoma
| | - Faizan Haider Khan
- Lundberg-Kienlen Lung Biology and Toxicology Laboratory, Department of Physiological Sciences, Oklahoma State University, Stillwater, Oklahoma; Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, Oklahoma
| | - Rachel Maranville
- Lundberg-Kienlen Lung Biology and Toxicology Laboratory, Department of Physiological Sciences, Oklahoma State University, Stillwater, Oklahoma
| | - Emily Zuniga
- Lundberg-Kienlen Lung Biology and Toxicology Laboratory, Department of Physiological Sciences, Oklahoma State University, Stillwater, Oklahoma
| | - Changzheng Wang
- Institute of Respiratory Diseases, Xinqiao Hospital, Chongqing, China
| | - Lin Liu
- Lundberg-Kienlen Lung Biology and Toxicology Laboratory, Department of Physiological Sciences, Oklahoma State University, Stillwater, Oklahoma; Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, Oklahoma.
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37
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Chen IL, Todd I, Fairclough LC. Immunological and pathological effects of electronic cigarettes. Basic Clin Pharmacol Toxicol 2019; 125:237-252. [PMID: 30861614 DOI: 10.1111/bcpt.13225] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 03/04/2019] [Indexed: 12/12/2022]
Abstract
Electronic cigarettes (E-cigarettes) are considered a preferable alternative to conventional cigarettes due to the lack of combustion and the absence of tobacco-specific toxicants. E-cigarettes have rapidly gained in popularity in recent years amongst both existing smokers and previous non-smokers. However, a growing literature demonstrates that E-cigarettes are not as safe as generally believed. Here, we discuss the immunological, and other, deleterious effects of E-cigarettes on a variety of cell types and host defence mechanisms in humans and in murine models. We review not only the effects of complete E-cigarette liquids, but also each of the main components-nicotine, humectants and flavourings. This MiniReview thus highlights the possible role of E-cigarettes in the pathogenesis of disease and raises awareness of the potential harm that E-cigarettes may cause.
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Affiliation(s)
- I-Ling Chen
- School of Life Sciences, University of Nottingham, Nottingham, UK
| | - Ian Todd
- School of Life Sciences, University of Nottingham, Nottingham, UK
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38
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Zhang WZ, Butler JJ, Cloonan SM. Smoking-induced iron dysregulation in the lung. Free Radic Biol Med 2019; 133:238-247. [PMID: 30075191 PMCID: PMC6355389 DOI: 10.1016/j.freeradbiomed.2018.07.024] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Revised: 07/26/2018] [Accepted: 07/30/2018] [Indexed: 12/12/2022]
Abstract
Iron is one of the most abundant transition elements and is indispensable for almost all organisms. While the ability of iron to participate in redox chemistry is an essential requirement for participation in a range of vital enzymatic reactions, this same feature of iron also makes it dangerous in the generation of hydroxyl radicals and superoxide anions. Given the high local oxygen tensions in the lung, the regulation of iron acquisition, utilization, and storage therefore becomes vitally important, perhaps more so than in any other biological system. Iron plays a critical role in the biology of essentially every cell type in the lung, and in particular, changes in iron levels have important ramifications on immune function and the local lung microenvironment. There is substantial evidence that cigarette smoke causes iron dysregulation, with the implication that iron may be the link between smoking and smoking-related lung diseases. A better understanding of the connection between cigarette smoke, iron, and respiratory diseases will help to elucidate pathogenic mechanisms and aid in the identification of novel therapeutic targets.
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Affiliation(s)
- William Z Zhang
- Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, NY 10021, USA; Department of Medicine, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, NY 10021, USA
| | - James J Butler
- Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, NY 10021, USA
| | - Suzanne M Cloonan
- Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, NY 10021, USA.
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39
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Larson-Casey JL, Carter AB. Reply to Eapen et al.: Dysfunctional Immunity and Microbial Adhesion Molecules in Smoking-induced Pneumonia. Am J Respir Crit Care Med 2019; 199:251-252. [PMID: 30290120 DOI: 10.1164/rccm.201809-1727le] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Affiliation(s)
| | - A Brent Carter
- 1 University of Alabama at Birmingham Birmingham, Alabama and.,2 Birmingham Veterans Administration Medical Center Birmingham, Alabama
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40
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Manna S, Waring A, Papanicolaou A, Hall NE, Bozinovski S, Dunne EM, Satzke C. The transcriptomic response of Streptococcus pneumoniae following exposure to cigarette smoke extract. Sci Rep 2018; 8:15716. [PMID: 30356075 PMCID: PMC6200755 DOI: 10.1038/s41598-018-34103-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 10/11/2018] [Indexed: 11/09/2022] Open
Abstract
Exposure to cigarette smoke is a risk factor for respiratory diseases. Although most research has focused on its effects on the host, cigarette smoke can also directly affect respiratory pathogens, in some cases enhancing virulence. Streptococcus pneumoniae (the pneumococcus) is a leading cause of community-acquired pneumonia worldwide, however data on the effects of cigarette smoke on the pneumococcus are sparse. Using RNA-seq, we show that pneumococci exposed to cigarette smoke extract in a concentrated acute exposure in vitro model initiate a 'survival' transcriptional response including the upregulation of detoxification enzymes, efflux pumps and osmoregulator transporters, as well as the downregulation of fatty acid and D-alanyl lipoteichoic acid biosynthesis genes. Except for the downregulation of the pneumolysin gene, there were no changes in the expression of major virulence factors following exposure to cigarette smoke. Compared to unexposed pneumococci, smoke-exposed pneumococci did not exhibit any changes in viability, adherence, hydrophobicity or cell lysis susceptibility. In this study, we demonstrate that pneumococci adapt to acute noxious cigarette smoke exposure by inducing a gene expression signature that allows the bacteria to resist its harmful effects.
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Affiliation(s)
- Sam Manna
- Pneumococcal Research, Murdoch Children's Research Institute, Infection and Immunity, Parkville, 3052, Australia.
| | - Alicia Waring
- Pneumococcal Research, Murdoch Children's Research Institute, Infection and Immunity, Parkville, 3052, Australia
| | - Angelica Papanicolaou
- Chronic Infectious and Inflammatory Disease Programme, School of Health & Biomedical Sciences, RMIT University, Bundoora, 3083, Australia
| | - Nathan E Hall
- Department of Animal, Plant and Soil Sciences, La Trobe University, Melbourne, Victoria, 3086, Australia
| | - Steven Bozinovski
- Chronic Infectious and Inflammatory Disease Programme, School of Health & Biomedical Sciences, RMIT University, Bundoora, 3083, Australia
| | - Eileen M Dunne
- Pneumococcal Research, Murdoch Children's Research Institute, Infection and Immunity, Parkville, 3052, Australia.,Department of Paediatrics, The University of Melbourne, Parkville, 3052, Australia
| | - Catherine Satzke
- Pneumococcal Research, Murdoch Children's Research Institute, Infection and Immunity, Parkville, 3052, Australia.,Department of Paediatrics, The University of Melbourne, Parkville, 3052, Australia.,Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, 3010, Australia
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41
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Howard LM, Grijalva CG. The central role of pneumococcal colonization in the pathogenesis and control of pneumococcal diseases. Future Microbiol 2018; 13:1453-1456. [PMID: 30311793 DOI: 10.2217/fmb-2018-0198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Affiliation(s)
- Leigh M Howard
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Carlos G Grijalva
- Department of Health Policy, Vanderbilt University Medical Center, Nashville, TN 37212, USA
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42
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Effects of cigarette smoke on immunity, neuroinflammation and multiple sclerosis. J Neuroimmunol 2018; 329:24-34. [PMID: 30361070 DOI: 10.1016/j.jneuroim.2018.10.004] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2018] [Revised: 09/30/2018] [Accepted: 10/05/2018] [Indexed: 12/18/2022]
Abstract
Cigarette smoking is the most prominent significant cause of death and morbidity. It is recognised as a risk factor for a number of immune mediated, inflammatory diseases including multiple sclerosis (MS). Here, we review the complex immunological effects of smoking on the immune system, which include enhancement of inflammatory responses with a parallel reduction of some immune defences, resulting in an increased susceptibility to infection and a persistent proinflammatory environment. We discuss the effect of smoking on the susceptibility, clinical course, disability, and mortality in MS, the likely benefits of smoking cessation, and the specific immunological effects of smoking in MS. In conclusion, smoking is an important environmental risk factor for MS occurrence and outcome, and it acts in significant part through immunological mechanisms.
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Bewley MA, Budd RC, Ryan E, Cole J, Collini P, Marshall J, Kolsum U, Beech G, Emes RD, Tcherniaeva I, Berbers GAM, Walmsley SR, Donaldson G, Wedzicha JA, Kilty I, Rumsey W, Sanchez Y, Brightling CE, Donnelly LE, Barnes PJ, Singh D, Whyte MKB, Dockrell DH. Opsonic Phagocytosis in Chronic Obstructive Pulmonary Disease Is Enhanced by Nrf2 Agonists. Am J Respir Crit Care Med 2018; 198:739-750. [PMID: 29547002 PMCID: PMC6222469 DOI: 10.1164/rccm.201705-0903oc] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2017] [Accepted: 03/14/2018] [Indexed: 01/01/2023] Open
Abstract
RATIONALE Previous studies have identified defects in bacterial phagocytosis by alveolar macrophages (AMs) in patients with chronic obstructive pulmonary disease (COPD), but the mechanisms and clinical consequences remain incompletely defined. OBJECTIVES To examine the effect of COPD on AM phagocytic responses and identify the mechanisms, clinical consequences, and potential for therapeutic manipulation of these defects. METHODS We isolated AMs and monocyte-derived macrophages (MDMs) from a cohort of patients with COPD and control subjects within the Medical Research Council COPDMAP consortium and measured phagocytosis of bacteria in relation to opsonic conditions and clinical features. MEASUREMENTS AND MAIN RESULTS COPD AMs and MDMs have impaired phagocytosis of Streptococcus pneumoniae. COPD AMs have a selective defect in uptake of opsonized bacteria, despite the presence of antipneumococcal antibodies in BAL, not observed in MDMs or healthy donor AMs. AM defects in phagocytosis in COPD are significantly associated with exacerbation frequency, isolation of pathogenic bacteria, and health-related quality-of-life scores. Bacterial binding and initial intracellular killing of opsonized bacteria in COPD AMs was not reduced. COPD AMs have reduced transcriptional responses to opsonized bacteria, such as cellular stress responses that include transcriptional modules involving antioxidant defenses and Nrf2 (nuclear factor erythroid 2-related factor 2)-regulated genes. Agonists of the cytoprotective transcription factor Nrf2 (sulforaphane and compound 7) reverse defects in phagocytosis of S. pneumoniae and nontypeable Haemophilus influenzae by COPD AMs. CONCLUSIONS Patients with COPD have clinically relevant defects in opsonic phagocytosis by AMs, associated with impaired transcriptional responses to cellular stress, which are reversed by therapeutic targeting with Nrf2 agonists.
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Affiliation(s)
- Martin A Bewley
- 1 Department of Infection, Immunity and Cardiovascular Disease and
- 2 The Florey Institute for Host-Pathogen Interactions, University of Sheffield Medical School, Sheffield, United Kingdom
| | - Richard C Budd
- 1 Department of Infection, Immunity and Cardiovascular Disease and
- 2 The Florey Institute for Host-Pathogen Interactions, University of Sheffield Medical School, Sheffield, United Kingdom
- 3 Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
| | - Eilise Ryan
- 4 Department of Respiratory Medicine
- 5 MRC Centre for Inflammation Research, and
| | - Joby Cole
- 1 Department of Infection, Immunity and Cardiovascular Disease and
- 2 The Florey Institute for Host-Pathogen Interactions, University of Sheffield Medical School, Sheffield, United Kingdom
- 3 Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
| | - Paul Collini
- 1 Department of Infection, Immunity and Cardiovascular Disease and
- 2 The Florey Institute for Host-Pathogen Interactions, University of Sheffield Medical School, Sheffield, United Kingdom
- 3 Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
| | - Jennifer Marshall
- 5 MRC Centre for Inflammation Research, and
- 6 Department of Infection Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Umme Kolsum
- 7 Medicines Evaluation Unit, University of Manchester, Manchester, United Kingdom
- 8 University Hospital of South Manchester NHS Foundation Trust, Manchester, United Kingdom
| | - Gussie Beech
- 7 Medicines Evaluation Unit, University of Manchester, Manchester, United Kingdom
- 8 University Hospital of South Manchester NHS Foundation Trust, Manchester, United Kingdom
| | - Richard D Emes
- 9 School of Veterinary Medicine and Science and
- 10 Advanced Data Analysis Centre, University of Nottingham, United Kingdom
| | - Irina Tcherniaeva
- 11 Centre for Infectious Disease Control (CIb), National Institute for Public Health and the Environment (RIVM), Utrecht, the Netherlands
| | - Guy A M Berbers
- 11 Centre for Infectious Disease Control (CIb), National Institute for Public Health and the Environment (RIVM), Utrecht, the Netherlands
| | - Sarah R Walmsley
- 4 Department of Respiratory Medicine
- 5 MRC Centre for Inflammation Research, and
| | - Gavin Donaldson
- 12 National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Jadwiga A Wedzicha
- 12 National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Iain Kilty
- 13 Pfizer Inc., Cambridge, Massachusetts
| | - William Rumsey
- 14 Stress and Repair Discovery Performance Unit, Respiratory Therapy Area, GSK, King of Prussia, Pennsylvania; and
| | - Yolanda Sanchez
- 14 Stress and Repair Discovery Performance Unit, Respiratory Therapy Area, GSK, King of Prussia, Pennsylvania; and
| | | | - Louise E Donnelly
- 12 National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Peter J Barnes
- 12 National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Dave Singh
- 7 Medicines Evaluation Unit, University of Manchester, Manchester, United Kingdom
- 8 University Hospital of South Manchester NHS Foundation Trust, Manchester, United Kingdom
| | - Moira K B Whyte
- 4 Department of Respiratory Medicine
- 5 MRC Centre for Inflammation Research, and
| | - David H Dockrell
- 5 MRC Centre for Inflammation Research, and
- 6 Department of Infection Medicine, University of Edinburgh, Edinburgh, United Kingdom
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Long F, Jiang H, Yi H, Su L, Sun J. Particulate matter 2.5 induced bronchial epithelial cell injury via activation of 5′‐adenosine monophosphate‐activated protein kinase‐mediated autophagy. J Cell Biochem 2018; 120:3294-3305. [PMID: 30203496 DOI: 10.1002/jcb.27597] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Accepted: 08/07/2018] [Indexed: 12/12/2022]
Affiliation(s)
- Fei Long
- Department of Respiratory Medicine Shandong Provincial Hospital Affiliated to Shandong University Jinan China
| | - Hong Jiang
- Department of Respiratory Medicine Yiyuan County People’s Hospital Yiyuan Shandong Province China
| | - Hongli Yi
- Department of Respiratory Medicine Shandong Provincial Hospital Affiliated to Shandong University Jinan China
| | - Lili Su
- Department of Respiratory Medicine Shandong Provincial Hospital Affiliated to Shandong University Jinan China
| | - Jian Sun
- Department of Respiratory Medicine Shandong Provincial Hospital Affiliated to Shandong University Jinan China
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Strzelak A, Ratajczak A, Adamiec A, Feleszko W. Tobacco Smoke Induces and Alters Immune Responses in the Lung Triggering Inflammation, Allergy, Asthma and Other Lung Diseases: A Mechanistic Review. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2018; 15:E1033. [PMID: 29883409 PMCID: PMC5982072 DOI: 10.3390/ijerph15051033] [Citation(s) in RCA: 374] [Impact Index Per Article: 53.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Revised: 05/08/2018] [Accepted: 05/09/2018] [Indexed: 02/06/2023]
Abstract
Many studies have been undertaken to reveal how tobacco smoke skews immune responses contributing to the development of chronic obstructive pulmonary disease (COPD) and other lung diseases. Recently, environmental tobacco smoke (ETS) has been linked with asthma and allergic diseases in children. This review presents the most actual knowledge on exact molecular mechanisms responsible for the skewed inflammatory profile that aggravates inflammation, promotes infections, induces tissue damage, and may promote the development of allergy in individuals exposed to ETS. We demonstrate how the imbalance between oxidants and antioxidants resulting from exposure to tobacco smoke leads to oxidative stress, increased mucosal inflammation, and increased expression of inflammatory cytokines (such as interleukin (IL)-8, IL-6 and tumor necrosis factor α ([TNF]-α). Direct cellular effects of ETS on epithelial cells results in increased permeability, mucus overproduction, impaired mucociliary clearance, increased release of proinflammatory cytokines and chemokines, enhanced recruitment of macrophages and neutrophils and disturbed lymphocyte balance towards Th2. The plethora of presented phenomena fully justifies a restrictive policy aiming at limiting the domestic and public exposure to ETS.
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Affiliation(s)
- Agnieszka Strzelak
- Department of Pediatric Pulmonology and Allergy, Medical University of Warsaw, Zwirki i Wigury 61, 02-091 Warszawa, Poland.
| | - Aleksandra Ratajczak
- Department of Pediatric Pulmonology and Allergy, Medical University of Warsaw, Zwirki i Wigury 61, 02-091 Warszawa, Poland.
| | - Aleksander Adamiec
- Department of Pediatric Pulmonology and Allergy, Medical University of Warsaw, Zwirki i Wigury 61, 02-091 Warszawa, Poland.
| | - Wojciech Feleszko
- Department of Pediatric Pulmonology and Allergy, Medical University of Warsaw, Zwirki i Wigury 61, 02-091 Warszawa, Poland.
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Mancuso P, Curtis JL, Freeman CM, Peters-Golden M, Weinberg JB, Myers MG. Ablation of the leptin receptor in myeloid cells impairs pulmonary clearance of Streptococcus pneumoniae and alveolar macrophage bactericidal function. Am J Physiol Lung Cell Mol Physiol 2018; 315:L78-L86. [PMID: 29565180 DOI: 10.1152/ajplung.00447.2017] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Leptin is a pleiotropic hormone produced by white adipose tissue that regulates appetite and many physiological functions, including the immune response to infection. Genetic leptin deficiency in humans and mice impairs host defenses against respiratory tract infections. Since leptin deficiency is associated with obesity and other metabolic abnormalities, we generated mice that lack the leptin receptor (LepRb) in cells of the myeloid linage (LysM-LepRb-KO) to evaluate its impact in lean metabolically normal mice in a murine model of pneumococcal pneumonia. We observed higher lung and spleen bacterial burdens in LysM-LepRb-KO mice following an intratracheal challenge with Streptococcus pneumoniae. Although numbers of leukocytes recovered from bronchoalveolar lavage fluid did not differ between groups, we did observe higher levels of pulmonary IL-13 and TNFα in LysM-LepRb-KO mice 48 h post infection. Phagocytosis and killing of ingested S. pneumoniae were also impaired in alveolar macrophages (AMs) from LysM-LepRb-KO mice in vitro and were associated with reduced LTB4 and enhanced PGE2 synthesis in vitro. Pretreatment of AMs with LTB4 and the cyclooxygenase inhibitor, indomethacin, restored phagocytosis but not bacterial killing in vitro. These results confirm our previous observations in leptin-deficient ( ob/ob) and fasted mice and demonstrate that decreased leptin action, as opposed to metabolic irregularities associated with obesity or starvation, is responsible for the defective host defense against pneumococcal pneumonia. They also provide novel targets for therapeutic intervention in humans with bacterial pneumonia.
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Affiliation(s)
- Peter Mancuso
- Department of Environmental Health Sciences, University of Michigan , Ann Arbor, Michigan.,Department of Nutritional Sciences, School of Public Health, University of Michigan , Ann Arbor, Michigan.,Graduate Program in Immunology, University of Michigan , Ann Arbor, Michigan
| | - Jeffrey L Curtis
- Graduate Program in Immunology, University of Michigan , Ann Arbor, Michigan.,Division of Pulmonary and Critical Care Medicine, University of Michigan , Ann Arbor, Michigan.,Veterans Affairs, Ann Arbor Healthcare System, Ann Arbor, Michigan
| | - Christine M Freeman
- Graduate Program in Immunology, University of Michigan , Ann Arbor, Michigan.,Division of Pulmonary and Critical Care Medicine, University of Michigan , Ann Arbor, Michigan.,Veterans Affairs, Ann Arbor Healthcare System, Ann Arbor, Michigan
| | - Marc Peters-Golden
- Graduate Program in Immunology, University of Michigan , Ann Arbor, Michigan.,Division of Pulmonary and Critical Care Medicine, University of Michigan , Ann Arbor, Michigan
| | - Jason B Weinberg
- Department of Pediatrics and Communicable Diseases, University of Michigan , Ann Arbor, Michigan.,Department of Microbiology and Immunology, University of Michigan , Ann Arbor, Michigan
| | - Martin G Myers
- Department of Integrative and Molecular Physiology, University of Michigan , Ann Arbor, Michigan
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Bhat TA, Kalathil SG, Bogner PN, Miller A, Lehmann PV, Thatcher TH, Phipps RP, Sime PJ, Thanavala Y. Secondhand Smoke Induces Inflammation and Impairs Immunity to Respiratory Infections. THE JOURNAL OF IMMUNOLOGY 2018; 200:2927-2940. [PMID: 29555783 DOI: 10.4049/jimmunol.1701417] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Accepted: 02/16/2018] [Indexed: 12/29/2022]
Abstract
Despite advocacy to reduce smoking-related diseases, >1 billion people worldwide continue to smoke. Smoking is immunosuppressive and an important etiological factor in the development of several human disorders including respiratory diseases like chronic obstructive pulmonary disease. However, there is a critical gap in the knowledge of the role of secondhand smoke (SHS) in inflammation and immunity. We therefore studied the influence of SHS on pulmonary inflammation and immune responses to respiratory infection by nontypeable Haemophilus influenzae (NTHI) recurrently found in chronic obstructive pulmonary disease patients. Chronic SHS-exposed mice were chronically infected with NTHI and pulmonary inflammation was evaluated by histology. Immune cell numbers and cytokines were measured by flow cytometry and ELISA, respectively. Chronic SHS exposure impaired NTHI P6 Ag-specific B and T cell responses following chronic NTHI infection as measured by ELISPOT assays, reduced the production of Abs in serum and bronchoalveolar lavage, and enhanced albumin leak into the bronchoalveolar lavage as determined by ELISA. Histopathological examination of lungs revealed lymphocytic accumulation surrounding airways and bronchovasculature following chronic SHS exposure and chronic infection. Chronic SHS exposure enhanced the levels of inflammatory cytokines IL-17A, IL-6, IL-1β, and TNF-α in the lungs, and impaired the generation of adaptive immunity following either chronic infection or P6 vaccination. Chronic SHS exposure diminished bacterial clearance from the lungs after acute NTHI challenge, whereas P6 vaccination improved clearance equivalent to the level seen in air-exposed, non-vaccinated mice. Our study provides unequivocal evidence that SHS exposure has long-term detrimental effects on the pulmonary inflammatory microenvironment and immunity to infection and vaccination.
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Affiliation(s)
- Tariq A Bhat
- Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263
| | | | - Paul N Bogner
- Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY 14263
| | - Austin Miller
- Department of Biostatistics, Roswell Park Cancer Institute, Buffalo, NY 14263
| | | | - Thomas H Thatcher
- Department of Medicine, University of Rochester, Rochester, NY 14620; and
| | - Richard P Phipps
- Department of Medicine, University of Rochester, Rochester, NY 14620; and.,Department of Environmental Medicine, University of Rochester, Rochester, NY 14620
| | - Patricia J Sime
- Department of Medicine, University of Rochester, Rochester, NY 14620; and.,Department of Environmental Medicine, University of Rochester, Rochester, NY 14620
| | - Yasmin Thanavala
- Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263;
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Gotts JE, Chun L, Abbott J, Fang X, Takasaka N, Nishimura SL, Springer ML, Schick SF, Calfee CS, Matthay MA. Cigarette smoke exposure worsens acute lung injury in antibiotic-treated bacterial pneumonia in mice. Am J Physiol Lung Cell Mol Physiol 2018. [PMID: 29543040 DOI: 10.1152/ajplung.00405.2017] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Evidence is accumulating that exposure to cigarette smoke (CS) increases the risk of developing acute respiratory distress syndrome (ARDS). Streptococcus pneumoniae is the most common cause of bacterial pneumonia, which in turn is the leading cause of ARDS. Chronic smokers have increased rates of pneumococcal colonization and develop more severe pneumococcal pneumonia than nonsmokers; yet mechanistic connections between CS exposure, bacterial pneumonia, and ARDS pathogenesis remain relatively unexplored. We exposed mice to 3 wk of moderate whole body CS or air, followed by intranasal inoculation with an invasive serotype of S. pneumoniae. CS exposure alone caused no detectable lung injury or bronchoalveolar lavage (BAL) inflammation. During pneumococcal infection, CS-exposed mice had greater survival than air-exposed mice, in association with reduced systemic spread of bacteria from the lungs. However, when mice were treated with antibiotics after infection to improve clinical relevance, the survival benefit was lost, and CS-exposed mice had more pulmonary edema, increased numbers of BAL monocytes, and elevated monocyte and lymphocyte chemokines. CS-exposed antibiotic-treated mice also had higher serum surfactant protein D and angiopoietin-2, consistent with more severe lung epithelial and endothelial injury. The results indicate that acute CS exposure enhances the recruitment of immune cells to the lung during bacterial pneumonia, an effect that may provide microbiological benefit but simultaneously exposes the mice to more severe inflammatory lung injury. The inclusion of antibiotic treatment in preclinical studies of acute lung injury in bacterial pneumonia may enhance clinical relevance, particularly for future studies of current or emerging tobacco products.
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Affiliation(s)
- Jeffrey E Gotts
- Departments of Medicine and Anesthesia, Cardiovascular Research Institute, University of California , San Francisco, California
| | - Lauren Chun
- Departments of Medicine and Anesthesia, Cardiovascular Research Institute, University of California , San Francisco, California
| | - Jason Abbott
- Departments of Medicine and Anesthesia, Cardiovascular Research Institute, University of California , San Francisco, California
| | - Xiaohui Fang
- Departments of Medicine and Anesthesia, Cardiovascular Research Institute, University of California , San Francisco, California
| | - Naoki Takasaka
- Department of Pathology, University of California , San Francisco, California
| | - Stephen L Nishimura
- Department of Pathology, University of California , San Francisco, California
| | - Matthew L Springer
- Department of Medicine, Cardiovascular Research Institute, University of California , San Francisco, California
| | - Suzaynn F Schick
- Department of Medicine, Cardiovascular Research Institute, University of California , San Francisco, California
| | - Carolyn S Calfee
- Departments of Medicine and Anesthesia, Cardiovascular Research Institute, University of California , San Francisco, California
| | - Michael A Matthay
- Departments of Medicine and Anesthesia, Cardiovascular Research Institute, University of California , San Francisco, California
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Dysregulated Functions of Lung Macrophage Populations in COPD. J Immunol Res 2018; 2018:2349045. [PMID: 29670919 PMCID: PMC5835245 DOI: 10.1155/2018/2349045] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2017] [Accepted: 11/29/2017] [Indexed: 01/02/2023] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is a diverse respiratory disease characterised by bronchiolitis, small airway obstruction, and emphysema. Innate immune cells play a pivotal role in the disease's progression, and in particular, lung macrophages exploit their prevalence and strategic localisation to orchestrate immune responses. To date, alveolar and interstitial resident macrophages as well as blood monocytes have been described in the lungs of patients with COPD contributing to disease pathology by changes in their functional repertoire. In this review, we summarise recent evidence from human studies and work with animal models of COPD with regard to altered functions of each of these myeloid cell populations. We primarily focus on the dysregulated capacity of alveolar macrophages to secrete proinflammatory mediators and proteases, induce oxidative stress, engulf microbes and apoptotic cells, and express surface and intracellular markers in patients with COPD. In addition, we discuss the differences in the responses between alveolar macrophages and interstitial macrophages/monocytes in the disease and propose how the field should advance to better understand the implications of lung macrophage functions in COPD.
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50
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Pehote G, Bodas M, Brucia K, Vij N. Cigarette Smoke Exposure Inhibits Bacterial Killing via TFEB-Mediated Autophagy Impairment and Resulting Phagocytosis Defect. Mediators Inflamm 2017; 2017:3028082. [PMID: 29445254 PMCID: PMC5763241 DOI: 10.1155/2017/3028082] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2017] [Accepted: 10/03/2017] [Indexed: 01/07/2023] Open
Abstract
INTRODUCTION Cigarette smoke (CS) exposure is the leading risk factor for COPD-emphysema pathogenesis. A common characteristic of COPD is impaired phagocytosis that causes frequent exacerbations in patients leading to increased morbidity. However, the underlying mechanism is unclear. Hence, we investigated if CS exposure causes autophagy impairment as a mechanism for diminished bacterial clearance via phagocytosis by utilizing murine macrophages (RAW264.7 cells) and Pseudomonas aeruginosa (PA01-GFP) as an experimental model. METHODS Briefly, RAW cells were treated with cigarette smoke extract (CSE), chloroquine (autophagy inhibitor), TFEB-shRNA, CFTR(inh)-172, and/or fisetin prior to bacterial infection for functional analysis. RESULTS Bacterial clearance of PA01-GFP was significantly impaired while its survival was promoted by CSE (p < 0.01), autophagy inhibition (p < 0.05; p < 0.01), TFEB knockdown (p < 0.01; p < 0.001), and inhibition of CFTR function (p < 0.001; p < 0.01) in comparison to the control group(s) that was significantly recovered by autophagy-inducing antioxidant drug, fisetin, treatment (p < 0.05; p < 0.01; and p < 0.001). Moreover, investigations into other pharmacological properties of fisetin show that it has significant mucolytic and bactericidal activities (p < 0.01; p < 0.001), which warrants further investigation. CONCLUSIONS Our data suggests that CS-mediated autophagy impairment as a critical mechanism involved in the resulting phagocytic defect, as well as the therapeutic potential of autophagy-inducing drugs in restoring is CS-impaired phagocytosis.
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Affiliation(s)
- Garrett Pehote
- College of Medicine, Central Michigan University, Mount Pleasant, MI, USA
| | - Manish Bodas
- College of Medicine, Central Michigan University, Mount Pleasant, MI, USA
| | - Kathryn Brucia
- College of Medicine, Central Michigan University, Mount Pleasant, MI, USA
| | - Neeraj Vij
- College of Medicine, Central Michigan University, Mount Pleasant, MI, USA
- Department of Pediatrics and Pulmonary Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
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