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Kim SI, Jang YD, Ji JG, Kim YS, Kang IH, Kim SJ, Han SM, Choi MS. The Usefulness of Carotid Artery Doppler Measurement as a Predictor of Early Death in Sepsis Patients Admitted to the Emergency Department. J Clin Med 2024; 13:6912. [PMID: 39598057 PMCID: PMC11594309 DOI: 10.3390/jcm13226912] [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: 10/07/2024] [Revised: 11/10/2024] [Accepted: 11/11/2024] [Indexed: 11/29/2024] Open
Abstract
Background: This study aims to verify whether the blood flow velocity and the diameter size, measured through intra-carotid artery Doppler measurements performed on sepsis patients visiting the emergency department, are useful as tools for predicting the risk of early death. Methods: As a prospective study, this research was performed on sepsis patients who visited a local emergency medical center from August 2021 to February 2023. The sepsis patients' carotid artery was measured using Doppler imaging, and they were divided into patients measured for the size of systolic and diastolic mean blood flow velocity and diameter size: those measured for their qSOFA (quick sequential organ failure assessment) score and those measured using the SIRS (systemic inflammatory response syndrome) criteria. By measuring and comparing their mortality prediction accuracies, this study sought to verify the usefulness of blood flow velocity and the diameter size of the intra-carotid artery as tools to predict early death. Results: This study was conducted on 1026 patients, excluding 45 patients out of the total of 1071 patients. All sepsis patients were measured using systolic and diastolic blood flow velocity and diameter by Doppler imaging of the intra-carotid artery, assessed using qSOFA and evaluated using SIRS criteria. The results of the analysis performed to compare the mortality prediction accuracy were as follows. First, the hazard ratio (95% CI) of the intra-carotid artery was significant (p < 0.05), at 1.020 (1.004-1.036); the hazard ratio (95% CI) of qSOFA was significant (p < 0.05), at 3.871 (2.526-5.931); and the hazard ratio (95% CI) of SIRS showed no significant difference, at 1.002 (0.995-1.009). After 2 h of infusion treatment, the diameter size was 4.72 ± 1.23, showing a significant difference (p < 0.05). After 2 h of fluid treatment, the blood flow velocity was 101 m/s ± 21.12, which showed a significant difference (p < 0.05). Conclusions: Measuring the mean blood flow velocity in the intra-carotid arteries of sepsis patients who visit the emergency department is useful for predicting the risk of death at an early stage. And this study showed that Doppler measurement of the diameter size of the carotid artery significantly increased after performing fluid treatment after early recognition.
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Affiliation(s)
- Su-Il Kim
- Department of Paramedicine, Sunlin University, Pohang 37560, Republic of Korea;
| | - Yun-Deok Jang
- Department of Emergency Medicine, Inje University Busan Paik Hospital, Busan 47392, Republic of Korea;
| | - Jae-Gu Ji
- Department of Emergency Medicine, Inje University Busan Paik Hospital, Busan 47392, Republic of Korea;
| | - Yong-Seok Kim
- Department of Paramedicine, Konyang University, Daejeon 32992, Republic of Korea;
| | - In-Hye Kang
- Department of Paramedicine, Daewon University College, Jecheon 27135, Republic of Korea;
| | - Seong-Ju Kim
- Department of Paramedicine, Tongmyong University, Busan 48520, Republic of Korea;
| | - Seong-Min Han
- Department of Paramedicine, Seoyeong University, Gwangju 61268, Republic of Korea;
| | - Min-Seok Choi
- Department of Paramedicine, Yeungnam University, Gyeongsan 38541, Republic of Korea;
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Takahama M, Patil A, Richey G, Cipurko D, Johnson K, Carbonetto P, Plaster M, Pandey S, Cheronis K, Ueda T, Gruenbaum A, Kawamoto T, Stephens M, Chevrier N. A pairwise cytokine code explains the organism-wide response to sepsis. Nat Immunol 2024; 25:226-239. [PMID: 38191855 PMCID: PMC10834370 DOI: 10.1038/s41590-023-01722-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 11/29/2023] [Indexed: 01/10/2024]
Abstract
Sepsis is a systemic response to infection with life-threatening consequences. Our understanding of the molecular and cellular impact of sepsis across organs remains rudimentary. Here, we characterize the pathogenesis of sepsis by measuring dynamic changes in gene expression across organs. To pinpoint molecules controlling organ states in sepsis, we compare the effects of sepsis on organ gene expression to those of 6 singles and 15 pairs of recombinant cytokines. Strikingly, we find that the pairwise effects of tumor necrosis factor plus interleukin (IL)-18, interferon-gamma or IL-1β suffice to mirror the impact of sepsis across tissues. Mechanistically, we map the cellular effects of sepsis and cytokines by computing changes in the abundance of 195 cell types across 9 organs, which we validate by whole-mouse spatial profiling. Our work decodes the cytokine cacophony in sepsis into a pairwise cytokine message capturing the gene, cell and tissue responses of the host to the disease.
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Affiliation(s)
- Michihiro Takahama
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA
- Laboratory of Bioresponse Regulation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
| | | | - Gabriella Richey
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA
| | - Denis Cipurko
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA
| | - Katherine Johnson
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA
| | - Peter Carbonetto
- Department of Human Genetics, University of Chicago, Chicago, IL, USA
- Research Computing Center, University of Chicago, Chicago, IL, USA
| | - Madison Plaster
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA
| | - Surya Pandey
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA
| | - Katerina Cheronis
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA
| | - Tatsuki Ueda
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA
| | - Adam Gruenbaum
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA
| | | | - Matthew Stephens
- Department of Human Genetics, University of Chicago, Chicago, IL, USA
- Department of Statistics, University of Chicago, Chicago, IL, USA
| | - Nicolas Chevrier
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA.
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Cavalcante-Silva J, Koh TJ. Targeting the NOD-Like Receptor Pyrin Domain Containing 3 Inflammasome to Improve Healing of Diabetic Wounds. Adv Wound Care (New Rochelle) 2023; 12:644-656. [PMID: 34841901 PMCID: PMC10701516 DOI: 10.1089/wound.2021.0148] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Accepted: 11/08/2021] [Indexed: 12/21/2022] Open
Abstract
Significance: Chronic skin wounds are a significant health problem around the world, often leading to amputation and even death. Although persistent inflammation is a hallmark of these poorly healing wounds, few available therapies have been designed to target inflammation. In this review, we summarize available evidence of the role of the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome in impaired wound healing and describe strategies to inhibit the inflammasome to improve wound healing. Recent Advances: The NLRP3 inflammasome plays an important physiological role in skin wound healing, during which transient inflammasome activity contributes to both epidermal and dermal healing. In contrast, sustained activity of the NLRP3 inflammasome leads to impaired epidermal and dermal healing associated with diabetes. Of importance, preclinical studies have demonstrated that inhibiting the NLRP3 inflammasome-induced resolution of inflammation, increased granulation tissue formation and collagen deposition, and accelerated reepithelialization and wound closure. Critical Issues: NLRP3 inflammasome inhibitors have appealing potential for translation into therapies for chronic wounds. Although preclinical studies have shown promising results, there is a need for human/clinical studies to evaluate dosing formulations, potential therapeutic effects, dose-response relationships, and possible side effects. Future Directions: Among strategies to inhibit the NLRP3 inflammasome, glyburide, metformin, peroxisome proliferator-activated receptor agonists, and the dipeptidyl peptidase 4 inhibitor saxagliptin appear to be closest to clinical translation, as these drugs are already Food and Drug Administration approved for other indications. Future clinical studies are needed to develop topical formulations of these drugs, and to assess the safety and efficacy of these inhibitors, to improve healing of chronic wounds.
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Affiliation(s)
- Jacqueline Cavalcante-Silva
- Center for Wound Healing and Tissue Regeneration; University of Illinois at Chicago, Chicago, Illinois, USA
- Department of Kinesiology and Nutrition; University of Illinois at Chicago, Chicago, Illinois, USA
| | - Timothy J. Koh
- Center for Wound Healing and Tissue Regeneration; University of Illinois at Chicago, Chicago, Illinois, USA
- Department of Kinesiology and Nutrition; University of Illinois at Chicago, Chicago, Illinois, USA
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Shen J, Wang S, Huang Y, Wu Z, Han S, Xia H, Chen H, Li L. Lactobacillus reuteri Ameliorates Lipopolysaccharide-Induced Acute Lung Injury by Modulating the Gut Microbiota in Mice. Nutrients 2023; 15:4256. [PMID: 37836540 PMCID: PMC10574429 DOI: 10.3390/nu15194256] [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: 09/14/2023] [Revised: 09/25/2023] [Accepted: 09/30/2023] [Indexed: 10/15/2023] Open
Abstract
Acute lung injury (ALI) causes lung inflammation and edema as well as resulting in gut microbiota disorder. Probiotics, however, can improve the gut microbiota composition and modulate its immune response, playing an important role in ALI pathogenesis. Therefore, our study aims to investigate the effect of Lactobacillus reuteri on Lipopolysaccharide (LPS)-induced ALI in mice and to probe the mechanism of its synergistic modulatory effect on the lungs and intestines. We assessed the therapeutic effects of L. reuteri in the ALI mouse model by histopathology, alveolar lavage fluid and serum inflammatory factor analysis and explored microbiome and transcriptome alterations. L. reuteri intervention effectively attenuated lung tissue injury and significantly reduced the LPS-induced inflammatory response and macrophage and neutrophil infiltration. Additionally, L. reuteri improved the intestinal barrier function and remodeled the disordered microbiota. In conclusion, our study showed that L. reuteri attenuated the inflammatory response, ameliorated the pulmonary edema, repaired the intestinal barrier, and remodeled the gut microbiota in ALI mice. This study provides new perspectives on the clinical treatment of ALI.
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Affiliation(s)
- Jian Shen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Centre for Infectious Diseases, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Shuting Wang
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Yong Huang
- Department of Infectious Disease, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou 310022, China
| | - Zhengjie Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Centre for Infectious Diseases, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Shengyi Han
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Centre for Infectious Diseases, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - He Xia
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Centre for Infectious Diseases, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Hui Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Centre for Infectious Diseases, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Centre for Infectious Diseases, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan 250021, China
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Takahama M, Patil A, Johnson K, Cipurko D, Miki Y, Taketomi Y, Carbonetto P, Plaster M, Richey G, Pandey S, Cheronis K, Ueda T, Gruenbaum A, Dudek SM, Stephens M, Murakami M, Chevrier N. Organism-Wide Analysis of Sepsis Reveals Mechanisms of Systemic Inflammation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.30.526342. [PMID: 36778287 PMCID: PMC9915512 DOI: 10.1101/2023.01.30.526342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Sepsis is a systemic response to infection with life-threatening consequences. Our understanding of the impact of sepsis across organs of the body is rudimentary. Here, using mouse models of sepsis, we generate a dynamic, organism-wide map of the pathogenesis of the disease, revealing the spatiotemporal patterns of the effects of sepsis across tissues. These data revealed two interorgan mechanisms key in sepsis. First, we discover a simplifying principle in the systemic behavior of the cytokine network during sepsis, whereby a hierarchical cytokine circuit arising from the pairwise effects of TNF plus IL-18, IFN-γ, or IL-1β explains half of all the cellular effects of sepsis on 195 cell types across 9 organs. Second, we find that the secreted phospholipase PLA2G5 mediates hemolysis in blood, contributing to organ failure during sepsis. These results provide fundamental insights to help build a unifying mechanistic framework for the pathophysiological effects of sepsis on the body.
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Hobai IA. CARDIOMYOCYTE REPROGRAMMING IN ANIMAL MODELS OF SEPTIC SHOCK. Shock 2023; 59:200-213. [PMID: 36730767 DOI: 10.1097/shk.0000000000002024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
ABSTRACT Cardiomyocyte reprogramming plays a pivotal role in sepsis-induced cardiomyopathy through the induction or overexpression of several factors and enzymes, ultimately leading to the characteristic decrease in cardiac contractility. The initial trigger is the binding of LPS to TLR-2, -3, -4, and -9 and of proinflammatory cytokines, such as TNF, IL-1, and IL-6, to their respective receptors. This induces the nuclear translocation of nuclear factors, such as NF-κB, via activation of MyD88, TRIF, IRAK, and MAPKs. Among the latter, ROS- and estrogen-dependent p38 and ERK 1/2 are proinflammatory, whereas JNK may play antagonistic, anti-inflammatory roles. Nuclear factors induce the synthesis of cytokines, which can amplify the inflammatory signal in a paracrine fashion, and of several effector enzymes, such as NOS-2, NOX-1, and others, which are ultimately responsible for the degradation of cardiomyocyte contractility. In parallel, the downregulation of enzymes involved in oxidative phosphorylation causes metabolic reprogramming, followed by a decrease in ATP production and the release of fragmented mitochondrial DNA, which may augment the process in a positive feedback loop. Other mediators, such as NO, ROS, the enzymes PI3K and Akt, and adrenergic stimulation may play regulatory roles, but not all signaling pathways that mediate cardiac dysfunction of sepsis do that by regulating reprogramming. Transcription may be globally modulated by miRs, which exert protective or amplifying effects. For all these mechanisms, differentiating between modulation of cardiomyocyte reprogramming versus systemic inflammation has been an ongoing but worthwhile experimental challenge.
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Affiliation(s)
- Ion A Hobai
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, 55 Fruit Street, GRB 444, Boston, MA
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7
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Nazerian Y, Ghasemi M, Yassaghi Y, Nazerian A, Mahmoud Hashemi S. Role of SARS-CoV-2-induced Cytokine Storm in Multi-Organ Failure: Molecular Pathways and Potential Therapeutic Options. Int Immunopharmacol 2022; 113:109428. [PMID: 36379152 PMCID: PMC9637536 DOI: 10.1016/j.intimp.2022.109428] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 10/19/2022] [Accepted: 11/01/2022] [Indexed: 11/09/2022]
Abstract
Coronavirus disease 2019 (COVID-19) outbreak has become a global public health emergency and has led to devastating results. Mounting evidence proposes that the disease causes severe pulmonary involvement and influences different organs, leading to a critical situation named multi-organ failure. It is yet to be fully clarified how the disease becomes so deadly in some patients. However, it is proven that a condition called “cytokine storm” is involved in the deterioration of COVID-19. Although beneficial, sustained production of cytokines and overabundance of inflammatory mediators causing cytokine storm can lead to collateral vital organ damages. Furthermore, cytokine storm can cause post-COVID-19 syndrome (PCS), an important cause of morbidity after the acute phase of COVID-19. Herein, we aim to explain the possible pathophysiology mechanisms involved in COVID-19-related cytokine storm and its association with multi-organ failure and PCS. We also discuss the latest advances in finding the potential therapeutic targets to control cytokine storm wishing to answer unmet clinical demands for treatment of COVID-19.
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Affiliation(s)
- Yasaman Nazerian
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mobina Ghasemi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Younes Yassaghi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Seyed Mahmoud Hashemi
- Medical nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran,Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran,Corresponding author at: Medical nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran / Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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8
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Medina G, Nosworthy MG, Petkau JC, Blewett H, Li S, House JD. Alteration of the dietary methionine:cysteine ratio modulates the inflammatory response to an inter-peritoneal injection of lipopolysaccharide in Wistar rats. J Nutr Biochem 2022; 102:108937. [PMID: 35017004 DOI: 10.1016/j.jnutbio.2022.108937] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 07/30/2021] [Accepted: 12/03/2021] [Indexed: 01/18/2023]
Abstract
Sulphur amino acids (SAA) are essential for multiple physiological/metabolic processes, with the ratio of dietary methionine:cysteine (Met:Cys) being an important contributor to pro-inflammatory responses, including TNF-α activity. The current study was designed to determine the effect an altered dietary SAA ratio, and the resulting reliance on the transsulfuration pathway to supply Cys, will have on the inflammatory response. In the present study, 100 µg/kg of an intraperitoneal (IP) injection of lipopolysaccharide (LPS) was used as a model for systemic inflammation. Male Wistar rats were randomized to one of two amino acid-defined diets, (100Met:0Cys or 50Met:50Cys) and subdivided to receive either IP LPS or saline injections. LPS significantly increased total plasma Cys, homocysteine (Hcy) and glutathione (GSH) 240 min post-IP injection in rats fed a 50Met:50Cys ratio compared to other treatments. The TNF-α area under the curve for LPS-treated rats consuming a dietary 50Met:50Cys ratio was significantly higher (p< 0.004) compared to those consuming a dietary 100Met:0Cys ratio. A significant increase in the percentage of leukocytes that were neutrophils was observed in rats injected with LPS when compared to saline with no effect of diet. These results demonstrate that an alteration of the dietary Met:Cys ratio did not attenuate the inflammatory response to an IP injection of LPS in Wistar rats; however, a diet with a balanced Met:Cys ratio increased concentrations of Cys and GSH which may result in a more rapid response to an LPS challenge.
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Affiliation(s)
- Gerardo Medina
- Department of Food and Human Nutritional Sciences, University of Manitoba, Winnipeg, MB, R3T 2N2, Canada.
| | - Matthew G Nosworthy
- Department of Food and Human Nutritional Sciences, University of Manitoba, Winnipeg, MB, R3T 2N2, Canada.
| | - Jay C Petkau
- Morden Research and Development Centre, Agriculture and Agri-Food Canada, Morden, MB, Canada; Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Research Centre, Winnipeg, MB, R2H 2A6, Canada.
| | - Heather Blewett
- Department of Food and Human Nutritional Sciences, University of Manitoba, Winnipeg, MB, R3T 2N2, Canada; Morden Research and Development Centre, Agriculture and Agri-Food Canada, Morden, MB, Canada; Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Research Centre, Winnipeg, MB, R2H 2A6, Canada.
| | - Shengnan Li
- Department of Animal Science, University of Manitoba, Winnipeg, MB, Canada, R3T 2N2.
| | - James D House
- Department of Food and Human Nutritional Sciences, University of Manitoba, Winnipeg, MB, R3T 2N2, Canada; Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Research Centre, Winnipeg, MB, R2H 2A6, Canada; Richardson Centre for Functional Foods and Nutraceuticals; Department of Animal Science, University of Manitoba, Winnipeg, MB, Canada, R3T 2N2.
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9
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Psaltis E, Zaitoun AM, Neal KR, Lobo DN. Immunohistochemical Inflammation in Histologically Normal Appendices in Patients with Right Iliac Fossa Pain. World J Surg 2021; 45:3592-3602. [PMID: 34392384 PMCID: PMC8572837 DOI: 10.1007/s00268-021-06288-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/31/2021] [Indexed: 12/02/2022]
Abstract
BACKGROUND Histologically normal appendices resected for right iliac fossa pain in children demonstrate immunohistochemical markers of inflammation. We aimed to establish if subclinical inflammation was present in histologically normal appendices resected from adults with right iliac fossa pain. METHODS Immunohistochemistry was performed on formalin-fixed paraffin-embedded appendices for tumour necrosis factor (TNF)-α, interleukin (IL)-6, IL-2R and serotonin in four groups: Group I (n = 120): uncomplicated appendicitis, Group II (n = 118): complicated appendicitis (perforation or gangrene), Group III (n = 104): histologically normal appendices resected for right iliac fossa pain and Group IV (n = 106) appendices resected at elective colectomy. Expression was quantified using the H-scoring system. RESULTS Median, interquartile range expression of TNF-α was increased in Groups I (5.9, 3.1-9.8), II (6.8, 3.6-12.1) and III (9.8, 6.2-15.2) when compared with Group IV (3.0, 1.4-4.7, p < 0.01). Epithelial expression of IL-6 in Groups II (44.0, 8.0-97.0) and III (71.0, 18.5-130.0) was increased when compared with Group IV (9.5, 1.0-60.2, p < 0.01). Expression of mucosal IL-2R in Groups I (47.4, 34.8-69.0), II (37.8, 25.4-60.4) and III (18.4, 10.1-34.7) was increased when compared with Group IV (2.8, 1.2-5.7, p < 0.01). Serotonin content in Groups I (3.0, 0-30.0) and II (0, 0-8.5) was decreased when compared with Groups III (49.7, 16.7-107.5) and IV (43.5, 9.5-115.8, p < 0.01). CONCLUSION Histologically normal appendices resected from symptomatic patients exhibited increased proinflammatory cytokine expression on immunohistochemistry suggesting the presence of an inflammatory process not detected on conventional microscopy.
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Affiliation(s)
- Emmanouil Psaltis
- Gastrointestinal Surgery, Nottingham Digestive Diseases Centre, National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Queen's Medical Centre, Nottingham, UK
| | - Abed M Zaitoun
- Pathology, Nottingham Digestive Diseases Centre, National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Queen's Medical Centre, Nottingham, UK
| | - Keith R Neal
- Public Health and Epidemiology, Nottingham Digestive Diseases Centre, National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Queen's Medical Centre, Nottingham, UK
| | - Dileep N Lobo
- Gastrointestinal Surgery, Nottingham Digestive Diseases Centre, National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Queen's Medical Centre, Nottingham, UK.
- MRC Versus Arthritis Centre for Musculoskeletal Ageing Research, School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, UK.
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10
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Boshtam M, Kouhpayeh S, Amini F, Azizi Y, Najaflu M, Shariati L, Khanahmad H. Anti-inflammatory effects of apocynin: a narrative review of the evidence. ALL LIFE 2021. [DOI: 10.1080/26895293.2021.1990136] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Affiliation(s)
- Maryam Boshtam
- Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shirin Kouhpayeh
- Department of Immunology, Erythron Genetics and Pathobiology Laboratory, Isfahan, Iran
| | - Farahnaz Amini
- Faculty of Medicine and Health Sciences, UCSI University, Kuala Lumpur, Malaysia
| | - Yadollah Azizi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Malihe Najaflu
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Laleh Shariati
- Department of Biomaterials, Nanotechnology and Tissue Engineering, School of Advanced Technologies in Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
- Applied physiology research center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hossein Khanahmad
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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11
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Yen JS, Wang IK, Liang CC, Fu JF, Hou YC, Chang CC, Gu PW, Tsai KF, Weng CH, Huang WH, Hsu CW, Yen TH. Cytokine changes in fatal cases of paraquat poisoning. Am J Transl Res 2021; 13:11571-11584. [PMID: 34786083 PMCID: PMC8581908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 08/21/2021] [Indexed: 06/13/2023]
Abstract
Cytokine-mediated inflammation is involved in the pathophysiology of paraquat toxicity. Nevertheless, few human studies have examined fluctuations in circulating cytokine levels. Blood samples were obtained from 21 patients with paraquat poisoning and compared to those of 18 healthy controls. All paraquat patients received a standard detoxification protocol composed of hemoperfusion, pulse therapies of methylprednisolone and cyclophosphamide, followed by dexamethasone therapy. Nonsurvivors not only had higher scores for the severity index of paraquat poisoning (P=0.004) but also presented with higher white blood cell counts (P=0.046) than survivors. Multiplex immunoassays revealed higher circulating levels of interleukin 2 (IL-2), interleukin 9 (IL-9), interleukin 10 (IL-10) and macrophage inflammatory protein-1 beta (MIP-1β) in survivors than in healthy controls. Furthermore, the circulating levels of interleukin 1 beta (IL-1β), IL-2, interleukin 5 (IL-5), interleukin 8 (IL-8), IL-9, IL-10, interleukin 12 (IL-12 p70), interleukin 17A (IL-17A), eotaxin, granulocyte colony-stimulating factor (G-CSF), monocyte chemoattractant protein-1 (MCP-1), interferon gamma-induced protein 10 (IP-10) and MIP-1β were higher in nonsurvivors than in healthy controls. Finally, the circulating levels of IL-1β and MCP-1 were higher in nonsurvivors than in survivors. Therefore, the observation of cytokine-mediated inflammation is in line with the detoxification protocol because glucocorticoids and cyclophosphamide are potent anti-inflammatory agents. Additionally, circulating levels of IL-1β and MCP-1 could serve as promising prognostic markers for patients with paraquat poisoning.
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Affiliation(s)
- Ju-Shao Yen
- Department of Nephrology, Clinical Poison Center, Chang Gung Memorial HospitalLinkou 333, Taiwan
| | - I-Kuan Wang
- Department of Nephrology, China Medical University HospitalTaichung 404, Taiwan
- College of Medicine, China Medical UniversityTaichung 406, Taiwan
| | - Chih-Chia Liang
- Department of Nephrology, China Medical University HospitalTaichung 404, Taiwan
- College of Medicine, China Medical UniversityTaichung 406, Taiwan
| | - Jen-Fen Fu
- Department of Medical Research, Chang Gung Memorial HospitalLinkou 333, Taiwan
- College of Medicine, Chang Gung UniversityTaoyuan 333, Taiwan
| | - Yi-Chou Hou
- Division of Nephrology, Department of Internal Medicine, Cardinal Tien HospitalNew Taipei City 231, Taiwan
- Fu-Jen Catholic UniversityNew Taipei City 242, Taiwan
| | - Chih-Chun Chang
- Department of Clinical Pathology, Far Eastern Memorial HospitalNew Taipei City 220, Taiwan
| | - Po-Wen Gu
- College of Medicine, Chang Gung UniversityTaoyuan 333, Taiwan
- Department of Laboratory Medicine, Chang Gung Memorial HospitalLinkou 333, Taiwan
| | - Kai-Fan Tsai
- Department of Nephrology, Chang Gung Memorial HospitalKaohsiung 833, Taiwan
| | - Cheng-Hao Weng
- Department of Nephrology, Clinical Poison Center, Chang Gung Memorial HospitalLinkou 333, Taiwan
- College of Medicine, Chang Gung UniversityTaoyuan 333, Taiwan
| | - Wen-Hung Huang
- Department of Nephrology, Clinical Poison Center, Chang Gung Memorial HospitalLinkou 333, Taiwan
- College of Medicine, Chang Gung UniversityTaoyuan 333, Taiwan
| | - Ching-Wei Hsu
- Department of Nephrology, Clinical Poison Center, Chang Gung Memorial HospitalLinkou 333, Taiwan
- College of Medicine, Chang Gung UniversityTaoyuan 333, Taiwan
| | - Tzung-Hai Yen
- Department of Nephrology, Clinical Poison Center, Chang Gung Memorial HospitalLinkou 333, Taiwan
- College of Medicine, Chang Gung UniversityTaoyuan 333, Taiwan
- Kidney Research Center, Center for Tissue Engineering, Chang Gung Memorial HospitalLinkou 333, Taiwan
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12
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Awonuga AO, Chatzicharalampous C, Thakur M, Rambhatla A, Qadri F, Awonuga M, Saed G, Diamond MP. Genetic and Epidemiological Similarities, and Differences Between Postoperative Intraperitoneal Adhesion Development and Other Benign Fibro-proliferative Disorders. Reprod Sci 2021; 29:3055-3077. [PMID: 34515982 DOI: 10.1007/s43032-021-00726-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Accepted: 08/22/2021] [Indexed: 12/11/2022]
Abstract
Intraperitoneal adhesions complicate over half of abdominal-pelvic surgeries with immediate, short, and long-term sequelae of major healthcare concern. The pathogenesis of adhesion development is similar to the pathogenesis of wound healing in all tissues, which if unchecked result in production of fibrotic conditions. Given the similarities, we explore the published literature to highlight the similarities in the pathogenesis of intra-abdominal adhesion development (IPAD) and other fibrotic diseases such as keloids, endometriosis, uterine fibroids, bronchopulmonary dysplasia, and pulmonary, intraperitoneal, and retroperitoneal fibrosis. Following a literature search using PubMed database for all relevant English language articles up to November 2020, we reviewed relevant articles addressing the genetic and epidemiological similarities and differences in the pathogenesis and pathobiology of fibrotic diseases. We found genetic and epidemiological similarities and differences between the pathobiology of postoperative IPAD and other diseases that involve altered fibroblast-derived cells. We also found several genes and single nucleotide polymorphisms that are up- or downregulated and whose products directly or indirectly increase the propensity for postoperative adhesion development and other fibrotic diseases. An understanding of the similarities in pathophysiology of adhesion development and other fibrotic diseases contributes to a greater understanding of IPAD and these disease processes. At a very fundamental level, blocking changes in the expression or function of genes necessary for the transformation of normal to altered fibroblasts may curtail adhesion formation and other fibrotic disease since this is a prerequisite for their development. Similarly, applying measures to induce apoptosis of altered fibroblast may do the same; however, apoptosis should be at a desired level to simultaneously ameliorate development of fibrotic diseases while allowing for normal healing. Scientists may use such information to develop pharmacologic interventions for those most at risk for developing these fibrotic conditions.
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Affiliation(s)
- Awoniyi O Awonuga
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, 48201, USA.
| | - Charalampos Chatzicharalampous
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Mili Thakur
- Reproductive Genomics Program, The Fertility Center, Grand Rapids, MI, USA.,Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA
| | - Anupama Rambhatla
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Farnoosh Qadri
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Modupe Awonuga
- Division of Neonatology, Department of Pediatrics and Human Development, Michigan State University, 1355 Bogue Street, East Lansing, MI, USA
| | - Ghassan Saed
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Michael P Diamond
- Department of Obstetrics and Gynecology, Augusta University, 1120 15th Street, CJ-1036, Augusta, GA, 30912, USA
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13
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Arulkumaran N, Pollen SJ, Tidswell R, Gaupp C, Peters VBM, Stanzani G, Snow TAC, Duchen MR, Singer M. Selective mitochondrial antioxidant MitoTEMPO reduces renal dysfunction and systemic inflammation in experimental sepsis. Br J Anaesth 2021; 127:577-586. [PMID: 34332740 DOI: 10.1016/j.bja.2021.05.036] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 05/04/2021] [Accepted: 05/27/2021] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Excess mitochondrial reactive oxygen species (mROS) in sepsis is associated with organ failure, in part by generating inflammation through the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. We determined the impact of a mitochondrial-targeted antioxidant (MitoTEMPO) on mitochondrial dysfunction in renal proximal tubular epithelial cells, peritoneal immune cell function ex vivo, and organ dysfunction in a rat model of sepsis. METHODS The effects of MitoTEMPO were assessed ex vivo using adenosine triphosphate and lipopolysaccharide-stimulated rat peritoneal immune cells and fresh rat kidney slices exposed to serum from septic rats. We assessed mROS production and phagocytotic capacity (flow cytometry), mitochondrial functionality (multiphoton imaging, respirometry), and NLRP3 inflammasome activation in cell culture. The effect of MitoTEMPO on organ dysfunction was evaluated in a rat model of faecal peritonitis. RESULTS MitoTEMPO decreased septic serum-induced mROS (P<0.001) and maintained normal reduced nicotinamide adenine dinucleotide redox state (P=0.02) and mitochondrial membrane potential (P<0.001) in renal proximal tubular epithelial cells ex vivo. In lipopolysaccharide-stimulated peritoneal immune cells, MitoTEMPO abrogated the increase in mROS (P=0.006) and interleukin-1β (IL-1β) (P=0.03) without affecting non-mitochondrial oxygen consumption or the phagocytotic-induced respiratory burst (P>0.05). In vivo, compared with untreated septic animals, MitoTEMPO reduced systemic IL-1β (P=0.01), reduced renal oxidative stress as determined by urine isoprostane levels (P=0.04), and ameliorated renal dysfunction (reduced serum urea (P<0.001) and creatinine (P=0.05). CONCLUSIONS Reduction of mROS by a mitochondria-targeted antioxidant reduced IL-1β, and protected mitochondrial, cellular, and organ functionality after septic insults.
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Affiliation(s)
- Nishkantha Arulkumaran
- Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, UK.
| | - Sean J Pollen
- Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, UK
| | - Robert Tidswell
- Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, UK
| | - Charlotte Gaupp
- Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, UK
| | - Vera B M Peters
- Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, UK
| | - Giacomo Stanzani
- Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, UK
| | - Timothy A C Snow
- Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, UK
| | - Michael R Duchen
- Department of Cell and Development Biology, University College London, London, UK
| | - Mervyn Singer
- Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, UK
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14
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Neutrophil Elastase Inhibition Ameliorates Endotoxin-induced Myocardial Injury Accompanying Degradation of Cardiac Capillary Glycocalyx. Shock 2021; 54:386-393. [PMID: 31764619 DOI: 10.1097/shk.0000000000001482] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Myocardial injury in sepsis may be caused by a burst of several inflammatory mediators, leading to vascular endothelial injuries. However, the contribution of neutrophil elastase (NE) to myocardial injury in sepsis is still unknown. We aimed to evaluate whether endotoxemia-induced myocardial injury is associated with NE. Lipopolysaccharide (LPS) was injected intraperitoneally at a dose of 20 mg/kg into granulocyte-colony-stimulating-factor knockout mice (G-CSF-KO), which have few neutrophils, and littermate control mice. The survival rate of G-CSF-KO mice 48 hours after LPS injection was significantly greater than that of control mice. The serum level of troponin I in G-CSF-KO mice was significantly lower than that in control mice. In addition, the concentration of inflammatory cytokine interleukin-6 (IL-6) was significantly decreased 6 and 12 hours after LPS administration compared with that in control mice. Ultrastructural analysis revealed that vascular endothelial structures and the endothelial glycocalyx in G-CSF-KO mice were clearly preserved. Next, mice were injected with 0.2 mg/kg sivelestat (an NE inhibitor) after LPS administration. The survival rate was significantly higher and the serum level of troponin I was lower in sivelestat-injected mice than in control mice, respectively. Furthermore, IL-6 levels were significantly decreased 6 and 12 hours after LPS administration compared with those in control mice. Vascular endothelial structures and the endothelial glycocalyx in sivelestat-treated mice were clearly preserved at the ultrastructural level. In conclusion, NE is significantly associated with myocardial injury in endotoxemia. Inhibition of NE may be a useful tool for the management of endotoxemia.
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15
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Phagocytosis of microparticles increases responsiveness of macrophage-like cell lines U937 and THP-1 to bacterial lipopolysaccharide and lipopeptide. Sci Rep 2021; 11:6782. [PMID: 33762618 PMCID: PMC7990916 DOI: 10.1038/s41598-021-86202-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 03/12/2021] [Indexed: 11/08/2022] Open
Abstract
Following bacterial infection, macrophages produce pro-inflammatory cytokines in response to bacterial cell components, including lipopolysaccharide (LPS) and lipopeptide, and simultaneously phagocytize and digest the invading bacteria. To study the effects of phagocytosis on pro-inflammatory responses, we determined if phagocytosis of polystyrene latex beads with ~ 1 µm diameter increases pro-inflammatory cytokine expression by human macrophage-like U937 and THP-1 cells stimulated with LPS. Treating macrophage-like cells with beads coated with IgG to facilitate Fcγ receptor-mediated phagocytosis increased LPS-induced expression of pro-inflammatory cytokines, including tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6. Treatment with beads coated with poly-L-lysine to facilitate Fcγ receptor-independent phagocytosis also increased LPS-induced cytokine expression. Our results indicate that LPS-induced pro-inflammatory responses are enhanced by bead phagocytosis regardless of the uptake mechanism. Additionally, phagocytosis enhanced LPS-induced NF-κB activation, suggesting that Toll-like receptor (TLR) 4 signaling is enhanced by phagocytosis. Furthermore, bead phagocytosis enhanced pro-inflammatory responses in U937 cells stimulated with lipopeptide, a ligand for the TLR2/TLR6 heterodimeric receptor. In conclusion, microparticle phagocytosis by macrophage-like U937 and THP-1 cells enhances the innate immune response induced by bacterial components.
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16
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Jin T, Mohammad M, Pullerits R, Ali A. Bacteria and Host Interplay in Staphylococcus aureus Septic Arthritis and Sepsis. Pathogens 2021; 10:158. [PMID: 33546401 PMCID: PMC7913561 DOI: 10.3390/pathogens10020158] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/28/2021] [Accepted: 01/30/2021] [Indexed: 12/22/2022] Open
Abstract
Staphylococcus aureus (S. aureus) infections are a major healthcare challenge and new treatment alternatives are needed. S. aureus septic arthritis, a debilitating joint disease, causes permanent joint dysfunction in almost 50% of the patients. S. aureus bacteremia is associated with higher mortalities than bacteremia caused by most other microbes and can develop to severe sepsis and death. The key to new therapies is understanding the interplay between bacterial virulence factors and host immune response, which decides the disease outcome. S. aureus produces numerous virulence factors that facilitate bacterial dissemination, invasion into joint cavity, and cause septic arthritis. Monocytes, activated by several components of S. aureus such as lipoproteins, are responsible for bone destructions. In S. aureus sepsis, cytokine storm induced by S. aureus components leads to the hyperinflammatory status, DIC, multiple organ failure, and later death. The immune suppressive therapies at the very early time point might be protective. However, the timing of treatment is crucial, as late treatment may aggravate the immune paralysis and lead to uncontrolled infection and death.
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Affiliation(s)
- Tao Jin
- Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, 413 46 Gothenburg, Sweden; (M.M.); (R.P.); (A.A.)
- Department of Rheumatology, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden
| | - Majd Mohammad
- Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, 413 46 Gothenburg, Sweden; (M.M.); (R.P.); (A.A.)
| | - Rille Pullerits
- Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, 413 46 Gothenburg, Sweden; (M.M.); (R.P.); (A.A.)
- Department of Rheumatology, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden
- Department of Clinical Immunology and Transfusion Medicine, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden
| | - Abukar Ali
- Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, 413 46 Gothenburg, Sweden; (M.M.); (R.P.); (A.A.)
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Is There a Genetic Predisposition to Postoperative Adhesion Development? Reprod Sci 2020; 28:2076-2086. [PMID: 33090376 PMCID: PMC7579853 DOI: 10.1007/s43032-020-00356-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Accepted: 10/11/2020] [Indexed: 12/11/2022]
Abstract
Adhesions are permanent fibrovascular bands between peritoneal surfaces, which develop following virtually all body cavity surgeries. The susceptibility to develop, and the severity, of adhesions following intra-abdominal surgery varies within and between individuals, suggesting that heritable factors influence adhesion development. In this manuscript, we discuss the pathophysiology of adhesion development from the perspective of genetic susceptibility. We restrict our discussion to genes and single-nucleotide polymorphisms (SNPs) that are specifically involved in, or that cause modification of, the adhesion development process. We performed a literature search using the PubMed database for all relevant English language articles up to March 2020 (n = 186). We identified and carefully reviewed all relevant articles addressing genetic mutations or single-nucleotide polymorphisms (SNPs) that impact the risk for adhesion development. We also reviewed references from these articles for additional information. We found several reported SNPs, genetic mutations, and upregulation of messenger RNAs that directly or indirectly increase the propensity for postoperative adhesion development, namely in genes for transforming growth factor beta, vascular endothelial growth factor, interferon-gamma, matrix metalloproteinase, plasminogen activator inhibitor-1, and the interleukins. An understanding of genetic variants could provide insight into the pathophysiology of adhesion development. The information presented in this review contributes to a greater understanding of adhesion development at the genetic level and may allow modification of these genetic risks, which may subsequently guide management in preventing and treating this challenging complication of abdominal surgery. In particular, the information could help identify patients at greater risk for adhesion development, which would make them candidates for anti-adhesion prophylaxis. Currently, agents to reduce postoperative adhesion development exist, and in the future, development of agents, which specifically target individual genetic profile, would be more specific in preventing intraperitoneal adhesion development.
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18
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Extraction, Quantification, and Cytokine Inhibitory Response of Bakuchiol in Psoralea coryfolia Linn. SEPARATIONS 2020. [DOI: 10.3390/separations7030048] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
(1) Background: The present investigation studies the optimization of extraction, quantification, and cytokine inhibitory effects bakuchiol (BKL) in Psoralea coryfolia Linn. (2) Methods: The seeds of Psoralea coryfolia cleaned, dried, and powdered. Different separation methods maceration, reflux, Soxhlet, and ultrasonic assisted extraction (UAE) were employed for the isolation of BKL by five pure solvents. The quantity of BKL was measured by high-performance liquid chromatography (HPLC) method to determine the highest yield percentage. The effect of optimized BKL was then tested in an animal model of sepsis induced by lipopolysaccharides (LPS). (3) Results: The UAE method was found to be the best among tested separation methods and yielded highest percentage of BKL in petroleum ether extract. Septic rats showed a significant elevation in levels of biochemical markers like AST, ALT, ALP, BIL, SCr, and BUN in plasma. Proinflammatory cytokines (TNF-α and IL-1) levels were also increased in LPS-induced animals. BKL has been found to significantly reverse these elevated levels as compared to the LPS-induced animals. (4) Conclusion: The present results suggest that BKL has positive effects when administered in animals with pathogenic shock by decreasing the circulating levels of biomarkers. Further studies are necessary to explore the clinical implications of such findings.
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19
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Wang M, Scott SR, Koniaris LG, Zimmers TA. Pathological Responses of Cardiac Mitochondria to Burn Trauma. Int J Mol Sci 2020; 21:ijms21186655. [PMID: 32932869 PMCID: PMC7554938 DOI: 10.3390/ijms21186655] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 09/04/2020] [Accepted: 09/08/2020] [Indexed: 12/18/2022] Open
Abstract
Despite advances in treatment and care, burn trauma remains the fourth most common type of traumatic injury. Burn-induced cardiac failure is a key factor for patient mortality, especially during the initial post-burn period (the first 24 to 48 h). Mitochondria, among the most important subcellular organelles in cardiomyocytes, are a central player in determining the severity of myocardial damage. Defects in mitochondrial function and structure are involved in pathogenesis of numerous myocardial injuries and cardiovascular diseases. In this article, we comprehensively review the current findings on cardiac mitochondrial pathological changes and summarize burn-impaired mitochondrial respiration capacity and energy supply, induced mitochondrial oxidative stress, and increased cell death. The molecular mechanisms underlying these alterations are discussed, along with the possible influence of other biological variables. We hope this review will provide useful information to explore potential therapeutic approaches that target mitochondria for cardiac protection following burn injury.
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Affiliation(s)
- Meijing Wang
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (S.R.S.); (L.G.K.); (T.A.Z.)
- Correspondence:
| | - Susan R. Scott
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (S.R.S.); (L.G.K.); (T.A.Z.)
| | - Leonidas G. Koniaris
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (S.R.S.); (L.G.K.); (T.A.Z.)
- Simon Cancer Center, Indiana University, Indianapolis, IN 46202, USA
- Indiana Center for Musculoskeletal Health, Indianopolis, IN 46202, USA
- Center for Cachexia Research Innovation and Therapy, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA
| | - Teresa A. Zimmers
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (S.R.S.); (L.G.K.); (T.A.Z.)
- Simon Cancer Center, Indiana University, Indianapolis, IN 46202, USA
- Indiana Center for Musculoskeletal Health, Indianopolis, IN 46202, USA
- Center for Cachexia Research Innovation and Therapy, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA
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20
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Yu H, Liu Y, Wang M, Restrepo RJ, Wang D, Kalogeris TJ, Neumann WL, Ford DA, Korthuis RJ. Myeloperoxidase instigates proinflammatory responses in a cecal ligation and puncture rat model of sepsis. Am J Physiol Heart Circ Physiol 2020; 319:H705-H721. [PMID: 32762560 DOI: 10.1152/ajpheart.00440.2020] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Myeloperoxidase (MPO)-derived hypochlorous (HOCl) reacts with membrane plasmalogens to yield α-chlorofatty aldehydes such as 2-chlorofatty aldehyde (2-ClFALD) and its metabolite 2-chlorofatty acid (2-ClFA). Recent studies showed that 2-ClFALD and 2-ClFA serve as mediators of the inflammatory responses to sepsis by as yet unknown mechanisms. Since no scavenger for chlorinated lipids is available and on the basis of the well-established role of the MPO/HOCl/chlorinated lipid axis in inflammatory responses, we hypothesized that treatment with MPO inhibitors (N-acetyl lysyltyrosylcysteine amide or 4-aminobenzoic acid hydrazide) would inhibit inflammation and proinflammatory mediator expression induced by cecal ligation and puncture (CLP). We used intravital microscopy to quantify in vivo inflammatory responses in Sham and CLP rats with or without MPO inhibition. Small intestines, mesenteries, and lungs were collected to assess changes in MPO-positive staining and lung injury, respectively, as well as free 2-ClFA and proinflammatory mediators levels. CLP caused neutrophil infiltration, 2-ClFA generation, acute lung injury, leukocyte-/platelet-endothelium interactions, mast cell activation (MCA), plasminogen activator inhibitor-1 (PAI-1) production, and the expression of several cytokines, chemokines, and vascular endothelial growth factor, changes that were reduced by MPO inhibition. Pretreatment with a PAI-1 inhibitor or MC stabilizer prevented CLP-induced leukocyte-endothelium interactions and MCA, and abrogated exogenous 2-ClFALD-induced inflammatory responses. Thus, we provide evidence that MPO instigates these inflammatory changes in CLP and that chlorinated lipids may serve as a mechanistic link between the enzymatic activity of MPO and PAI-1- and mast cell-dependent adhesive interactions, providing a rationale for new therapeutic interventions in sepsis.NEW & NOTEWORTHY Using two distinct myeloperoxidase (MPO) inhibitors, we show for the first time that MPO plays an important role in producing increases in free 2-chlorofatty aldehyde (2-ClFALD)-a powerful proinflammatory chlorinated lipid in plasma and intestine-a number of cytokines and other inflammatory mediators, leukocyte and platelet rolling and adhesion in postcapillary venules, and lung injury in a cecal ligation and puncture model of sepsis. In addition, the use of a plasminogen activator inhibitor-1 (PAI-1) inhibitor or a mast cell stabilizer prevented inflammatory responses in CLP-induced sepsis. PAI-1 inhibition also prevented the proinflammatory responses to exogenous 2-ClFALD superfusion. Thus, our study provides some of the first evidence that MPO-derived free 2-ClFA plays an important role in CLP-induced sepsis by a PAI-1- and mast cell-dependent mechanism.
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Affiliation(s)
- Hong Yu
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri
| | - Yajun Liu
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri
| | - Meifang Wang
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri
| | - Ricardo J Restrepo
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri
| | - Derek Wang
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri
| | - Theodore J Kalogeris
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri
| | - William L Neumann
- Department of Pharmaceutical Sciences, Edwardsville School of Pharmacy, Southern Illinois University, Edwardsville, Illinois
| | - David A Ford
- Department of Biochemistry and Molecular Biology, Center for Cardiovascular Research, Saint Louis University School of Medicine, Saint Louis, Missouri
| | - Ronald J Korthuis
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri.,Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri
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Gusev EY, Zotova NV. Cellular Stress and General Pathological Processes. Curr Pharm Des 2020; 25:251-297. [PMID: 31198111 DOI: 10.2174/1381612825666190319114641] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 03/13/2019] [Indexed: 02/06/2023]
Abstract
From the viewpoint of the general pathology, most of the human diseases are associated with a limited number of pathogenic processes such as inflammation, tumor growth, thrombosis, necrosis, fibrosis, atrophy, pathological hypertrophy, dysplasia and metaplasia. The phenomenon of chronic low-grade inflammation could be attributed to non-classical forms of inflammation, which include many neurodegenerative processes, pathological variants of insulin resistance, atherosclerosis, and other manifestations of the endothelial dysfunction. Individual and universal manifestations of cellular stress could be considered as a basic element of all these pathologies, which has both physiological and pathophysiological significance. The review examines the causes, main phenomena, developmental directions and outcomes of cellular stress using a phylogenetically conservative set of genes and their activation pathways, as well as tissue stress and its role in inflammatory and para-inflammatory processes. The main ways towards the realization of cellular stress and its functional blocks were outlined. The main stages of tissue stress and the classification of its typical manifestations, as well as its participation in the development of the classical and non-classical variants of the inflammatory process, were also described. The mechanisms of cellular and tissue stress are structured into the complex systems, which include networks that enable the exchange of information with multidirectional signaling pathways which together make these systems internally contradictory, and the result of their effects is often unpredictable. However, the possible solutions require new theoretical and methodological approaches, one of which includes the transition to integral criteria, which plausibly reflect the holistic image of these processes.
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Affiliation(s)
- Eugeny Yu Gusev
- Laboratory of the Immunology of Inflammation, Institute of Immunology and Physiology, Yekaterinburg, Russian Federation
| | - Natalia V Zotova
- Laboratory of the Immunology of Inflammation, Institute of Immunology and Physiology, Yekaterinburg, Russian Federation.,Department of Medical Biochemistry and Biophysics, Ural Federal University named after B.N.Yeltsin, Yekaterinburg, Russian Federation
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22
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El Gendy FM, El-Mekkawy MS, El-Naidany SS, El-torgoman ST. The role of Tumor necrosis factor alpha −308 G>A promoter polymorphism in pediatric community acquired pneumonia. EGYPTIAN PEDIATRIC ASSOCIATION GAZETTE 2020. [PMCID: PMC7149214 DOI: 10.1186/s43054-020-0019-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Background Tumor necrosis factor alpha (TNF-α) −308 G>A promoter polymorphism might be associated with excessive production of the proinflammatory cytokine TNF-α, modulating host response to pulmonary infections. Our objective was to evaluate the association of TNF-α gene −308 G>A polymorphism with susceptibility to, and severity of, community-acquired pneumonia (CAP). Results This was a cross-sectional study including 45 Egyptian children hospitalized for CAP in addition to 45 healthy children who served as a control group. Pneumonia severity was assessed on admission by the World Health Organization (WHO) guidelines; Pediatric Respiratory Severity Score (PRESS) score; Predisposition, Infection, Response and Organ failure (PIROm) score; and Respiratory Index of Severity in Children (RISC) score. Genotyping of TNF-α polymorphism was performed to all individuals by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Patients were monitored till hospital discharge. Frequency of AG genotype was lower among patients compared with control [odds ratio (OR) and 95% confidence interval (CI) = 0.13 (0.03–0.63); p = 0.012]. Prevalence of genotypes AA+AG was lower among patients compared with controls [OR and 95% CI = 0.34 (0.12–0.99); p = 0,048]. The “A” allele prevalence was higher among controls, but no significant association was found with CAP [OR and 95% CI = 0.58 (0.25–1.35); p = 0.21]. When PRESS score was used to classify patients into “severe pneumonia” and “non-severe pneumonia,” no significant association of any of the alleles or genotypes with CAP severity was found. Conclusion TNF-α −308 G>A polymorphism confers protection from pediatric CAP but is not associated with indicators of CAP severity. Larger studies are needed to confirm these findings in pediatric patients from different ethnicities.
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Wei W, Bai W, Yang Y, Li Y, Teng X, Wan Y, Zhu J. Pulmonary protection of transcutaneous electrical acupoint stimulation in gynecological laparoscopic surgery: A randomized controlled trial. Exp Ther Med 2019; 19:511-518. [PMID: 31885697 PMCID: PMC6913376 DOI: 10.3892/etm.2019.8245] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Accepted: 10/22/2019] [Indexed: 11/15/2022] Open
Abstract
Laparoscopy is performed worldwide due to its limited side effects and optimal treatment efficacy. However, it also has adverse effects, including atelectasis and ischemia-reperfusion injury, due to CO2 accumulation during ventilation in a head-down position, which may result in severe disorders and adversely affecting postoperative recovery, prolonging hospitalization. The present study was performed to assess whether transcutaneous electrical acupoint stimulation (TEAS) protects against lung injury occurring during gynecological laparoscopic surgery. Patients were randomly allocated to two groups: Control group (received no stimulation) and TEAS group (patients treated with TEAS on BL13, LI4 and LU5). The mean arterial pressure, heart rate and oxygen saturation were recorded at the time-points of arriving in the operating room (T0), immediately prior to induction of the pneumoperitoneum (T1), immediately after the end of pneumoperitoneum (T2) and on leaving the operating room (T3). Arterial blood gas analysis was performed to record the pH, determine the partial pressure of carbon dioxide and calculate the oxygenation index (OI) at T0–3. Blood samples were taken from the peripheral vein for determination of the serum concentrations of tumor necrosis factor (TNF)-α and interleukin (IL)-1β at T0 and T3. Post-operative pulmonary complications occurring during the first five days after surgery were also recorded. A total of 100 patients were initially enrolled and 80 patients were analysed. The results indicated that the OI in the control group was significantly lower than that in the TEAS group at the T2 and T3 time-points. The serum concentrations of TNF-α and IL-1β were significantly increased following surgery, while the extent of these increases was lower in the TEAS group compared with that in the control group. The incidence of post-operative pulmonary complications was significantly lower in the TEAS group. It was therefore indicated that TEAS protect against lung injury as a complication of gynecological laparoscopic surgery. The present study was registered at http://www.clinicaltrials.gov prior to enrollment of the patients (no. NCT02850471).
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Affiliation(s)
- Wei Wei
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China.,Department of Anesthesiology, Northeast International Hospital, Shenyang, Liaoning 110004, P.R. China
| | - Wenya Bai
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China.,Department of Anesthesiology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650000, P.R. China
| | - Yanchao Yang
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Yang Li
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Xiufei Teng
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Yuxiao Wan
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Junchao Zhu
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
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Han L, Ren RR, Wan KL, Yang L, Kang JQ. Plasma inflammatory factors in older people predict acute kidney injury: a case–control study. Eur Geriatr Med 2019; 10:905-911. [DOI: 10.1007/s41999-019-00250-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 10/01/2019] [Indexed: 12/13/2022]
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Cardoso-Sousa L, Aguiar EMG, Caixeta DC, Vilela DD, da Costa DP, Silva TL, Cunha TM, Faria PR, Espindola FS, Jardim AC, Vieira AA, Oliveira TL, Goulart LR, Sabino-Silva R. Effects of salbutamol and phlorizin on acute pulmonary inflammation and disease severity in experimental sepsis. PLoS One 2019; 14:e0222575. [PMID: 31536570 PMCID: PMC6752759 DOI: 10.1371/journal.pone.0222575] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 09/03/2019] [Indexed: 02/05/2023] Open
Abstract
Respiratory infection can be exacerbated by the high glucose concentration in the airway surface liquid (ASL). We investigated the effects of salbutamol and phlorizin on the pulmonary function, oxidative stress levels and SGLT1 activity in lung, pulmonary histopathological damages and survival rates of rats with sepsis. Sepsis was induced by cecal ligation and puncture surgery (CLP). Twenty-four hours after surgery, CLP rats were intranasally treated with saline, salbutamol or phlorizin. After 2 hours, animals were anesthetized and sacrificed. Sepsis promoted atelectasis and bronchial inflammation, and led to increased expression of SGLT1 on cytoplasm of pneumocytes. Salbutamol treatment reduced bronchial inflammation and promoted hyperinsuflation in CLP rats. The interferon-ɤ and Interleucin-1β concentrations in bronchoalveolar lavage (BAL) were closely related to the bronchial inflammation regulation. Salbutamol stimulated SGLT1 in plasma membrane; whereas, phlorizin promoted the increase of SGLT1 in cytoplasm. Phlorizin reduced catalase activity and induced a significant decrease in the survival rate of CLP rats. Taken together, sepsis promoted atelectasis and lung inflammation, which can be associated with SGLT1 inhibition. The loss of function of SGLT1 by phlorizin are related to the augmented disease severity, increased atelectasis, bronchial inflammation and a significant reduction of survival rate of CLP rats. Alternatively salbutamol reduced BAL inflammatory cytokines, bronchial inflammation, atelectasis, and airway damage in sepsis. These data suggest that this selective β2-adrenergic agonist may protect lung of septic acute effects.
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Affiliation(s)
- Léia Cardoso-Sousa
- Department of Physiology, Institute of Biomedical Sciences, Federal University of Uberlandia, Minas Gerais, Brazil
| | - Emilia Maria Gomes Aguiar
- Department of Physiology, Institute of Biomedical Sciences, Federal University of Uberlandia, Minas Gerais, Brazil
| | | | | | - Danilo Pereira da Costa
- Department of Physiology, Institute of Biomedical Sciences, Federal University of Uberlandia, Minas Gerais, Brazil
| | - Tamires Lopes Silva
- Institute of Biomedical Sciences, Laboratory of Immunoparasitology "Dr. Mario Endsfeldz Camargo", Federal University of Uberlandia, Minas Gerais, Brazil
| | - Thúlio Marquez Cunha
- Department of Pulmonology, School of Medicine, Federal University of Uberlandia, Minas Gerais, Brazil
| | - Paulo Rogério Faria
- Department of Morphology, Institute of Biomedical Sciences, Federal University of Uberlandia, Minas Gerais, Brazil
| | | | - Ana Carolina Jardim
- Laboratory of Virology, Institute of Biomedical Sciences, Federal University of Uberlandia, Minas Gerais, Brazil
| | - Alexandre Antônio Vieira
- Department of Physiology, Institute of Biomedical Sciences, Federal University of Uberlandia, Minas Gerais, Brazil
| | - Tales Lyra Oliveira
- Faculty of Medicine, Municipal University of Sao Caetano do Sul, Sao Paulo, Brazil
| | - Luiz Ricardo Goulart
- Institute of Biotechnology, Federal University of Uberlandia, Minas Gerais, Brazil
- Department of Medical Microbiology and Immunology, University of California Davis, California, United States of America
| | - Robinson Sabino-Silva
- Department of Physiology, Institute of Biomedical Sciences, Federal University of Uberlandia, Minas Gerais, Brazil
- * E-mail:
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26
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Munir F, Jamshed MB, Shahid N, Muhammad SA, Bhandari A, Zhang Q. Protective effects of maresin 1 against inflammation in experimentally induced acute pancreatitis and related lung injury. Am J Physiol Gastrointest Liver Physiol 2019; 317:G333-G341. [PMID: 31125268 DOI: 10.1152/ajpgi.00078.2019] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Severe acute pancreatitis (SAP) is an inflammatory disorder that progresses with local and systemic difficulties accompanied by a relatively high mortality rate. In recent years, maresin 1 (MaR1) has been shown to be a macrophage mediator with effective proresolving and anti-inflammatory properties that prevents the occurrence of various inflammatory conditions. The purpose of this study was to investigate the role of MaR1 in SAP and related lung injury. Experimental SAP was induced in mice with a combination of cerulean and lipopolysaccharide. MaR1 was administered 30 min before the primary injection of cerulean. Biochemical markers and histological injury scores were used to evaluate the severity of acute pancreatitis. To determine the degree of inflammation, serum cytokines and myeloperoxidase activity in pancreas and lung tissues were measured. Western blot analysis detected the activation of NF-κB. After MaR1 pretreatment, the activities of amylase, lipase, TNF-α, IL-1β, and IL-6 were decreased in serum, and the myeloperoxidase activity both in pancreas and in lung tissues significantly decreased, whereas the activity of anti-inflammatory cytokine IL-10 in serum was increased. MaR1-pretreated mice reduced the activation of pancreatic NF-κB and decreased the severity of pancreatic and lung-related injuries. These results confirm that MaR1 alleviated inflammation of the pancreas and lung by inhibiting the activity of NF-κB in experimentally induced acute pancreatitis and exerted anti-inflammatory effects. These findings suggest that MaR1 could be a new and useful drug in the treatment of SAP.NEW & NOTEWORTHY These results provided us evidence to confirm that maresin 1 (MaR1) can alleviate inflammation of the pancreas and lung by inhibiting the activity of NF-κB in experimental induced acute pancreatitis and exerts certain anti-inflammatory effects. These findings suggest that MaR1 could be a new and useful drug in the treatment of severe acute pancreatitis.
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Affiliation(s)
- Fahad Munir
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Muhammad Babar Jamshed
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Numan Shahid
- Department of General Surgery, The School of International Studies of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Syed Aun Muhammad
- Institute of Molecular Biology and Biotechnology, Bahaudin Zakariya University, Multan, Punjab, Pakistan
| | - Adheesh Bhandari
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - QiYu Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
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Martinez-Quinones P, Komic A, McCarthy CG, Webb RC, Wenceslau CF. Targeting Endothelial Barrier Dysfunction Caused by Circulating Bacterial and Mitochondrial N-Formyl Peptides With Deformylase. Front Immunol 2019; 10:1270. [PMID: 31244835 PMCID: PMC6563851 DOI: 10.3389/fimmu.2019.01270] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Accepted: 05/17/2019] [Indexed: 01/05/2023] Open
Abstract
Despite recent advances in our understanding of the mechanisms underlying systemic inflammatory response syndrome (SIRS) and sepsis, the current therapeutic approach to these critically ill patients is centered around supportive care including fluid resuscitation, vasopressors and source control. The incidence of SIRS and sepsis continues to increase in the United States and patients die due to failure to respond to the traditional therapies of nitric oxide blockade, adrenergic agonists, etc. Bacterial and mitochondrial N-formyl peptides (NFPs) act as damage-associated molecular patterns and activate the innate immune system through formyl peptide receptors (FPR) located in immune and non-immune cells, including the vascular endothelium. The resulting inflammatory response manifests as capillary leak, tissue hypoperfusion and vasoplegia, partially due to endothelium barrier breakdown. Potential strategies to prevent this response include decreasing NFP release, breakdown of NFPs, and blocking NFPs from binding FPR. We propose the use of deformylase, the degrading enzyme for NFPs, as potential therapeutic approach to prevent the deleterious effects of NFPs in SIRS and sepsis.
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Affiliation(s)
- Patricia Martinez-Quinones
- Department of Surgery, Medical College of Georgia, Augusta University, Augusta, GA, United States.,Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Amel Komic
- Department of Surgery, Medical College of Georgia, Augusta University, Augusta, GA, United States.,Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Cameron G McCarthy
- Department of Physiology and Pharmacology, University of Toledo, Toledo, OH, United States
| | - R Clinton Webb
- Department of Surgery, Medical College of Georgia, Augusta University, Augusta, GA, United States
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28
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Sheats MK. A Comparative Review of Equine SIRS, Sepsis, and Neutrophils. Front Vet Sci 2019; 6:69. [PMID: 30931316 PMCID: PMC6424004 DOI: 10.3389/fvets.2019.00069] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 02/15/2019] [Indexed: 12/15/2022] Open
Abstract
The most recent definition of sepsis in human medicine can be summarized as organ dysfunction caused by a dysregulated host response to infection. In equine medicine, although no consensus definition is available, sepsis is commonly described as a dysregulated host systemic inflammatory response to infection. Defense against host infection is the primary role of innate immune cells known as neutrophils. Neutrophils also contribute to host injury during sepsis, making them important potential targets for sepsis prevention, diagnosis, and treatment. This review will present both historical and updated perspectives on the systemic inflammatory response (SIRS) and sepsis; it will also discuss the impact of sepsis on neutrophils, and the impact of neutrophils during sepsis. Future identification of clinically relevant sepsis diagnosis and therapy depends on a more thorough understanding of disease pathogenesis across species. To gain this understanding, there is a critical need for research that utilizes a clearly defined, and consistently applied, classification system for patients diagnosed with, and at risk of developing, sepsis.
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Affiliation(s)
- M. Katie Sheats
- Department of Clinical Sciences, North Carolina State University College of Veterinary Medicine, Raleigh, NC, United States
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29
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Johnsen N, Hamilton ADM, Greve AS, Christensen MG, Therkildsen JR, Wehmöller J, Skals M, Praetorius HA. α-Haemolysin production, as a single factor, causes fulminant sepsis in a model of Escherichia coli-induced bacteraemia. Cell Microbiol 2019; 21:e13017. [PMID: 30761726 DOI: 10.1111/cmi.13017] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 02/08/2019] [Accepted: 02/10/2019] [Indexed: 12/14/2022]
Abstract
α-Haemolysin (HlyA) from uropathogenic Escherichia coli has been demonstrated to be a significant virulence factor for ascending urinary tract infections. Once the E. coli reach the well-vascularised kidneys, there is a high risk of bacteraemia and a subsequent septic host response. Despite this, HlyA has the potential to accelerate the host response both directly and via its ability to facilitate adenosine triphosphate release from cells. It has not been settled whether HlyA aggravates bacteraemia into a septic state. To address this, we used an E. coli strain in a model of acute urosepsis that was either transfected with a plasmid containing the full HlyA operon or one with deletion in the HlyA gene. Here, we show that HlyA accelerates the host response to E. coli in the circulation. Mice exposed to HlyA-producing E. coli showed massively increased proinflammatory cytokines, a substantial fall in circulating thrombocytes, extensive haematuria, and intravascular haemolysis. This was not seen in mice exposed to either E. coli that do not secrete HlyA or vehicle controls. Consistent with the massive host response to the bacteria, the mice exposed to HlyA-producing E. coli died exceedingly early, whereas mice exposed to E. coli without HlyA production and vehicle controls survived the entire observation period. These data allow us to conclude that HlyA is a virulence factor that accelerates a state of bacteraemia into fulminant sepsis in a mouse model.
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Affiliation(s)
- Nanna Johnsen
- Department of Biomedicine, Aarhus University, Aarhus C, Denmark
| | | | | | | | | | - Julia Wehmöller
- Department of Biomedicine, Aarhus University, Aarhus C, Denmark
| | - Marianne Skals
- Department of Biomedicine, Aarhus University, Aarhus C, Denmark
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30
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Yilmaz Y, Tumkaya L. Effects of hyperbaric oxygen and iloprost on intestinal ischemia-reperfusion induced acute lung injury. Ann Surg Treat Res 2019; 96:34-40. [PMID: 30603632 PMCID: PMC6306501 DOI: 10.4174/astr.2019.96.1.34] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 08/09/2018] [Accepted: 08/29/2018] [Indexed: 11/30/2022] Open
Abstract
Purpose To research the effects of iloprost (IL) and hyperbaric oxygen (HBO) combination treatment on lung injury and on tumor necrosis factor alpha (TNF-α), myeloperoxidase (MPO), malondialdehyde (MDA), and soluble intercellular adhesion molecule-1 (sICAM-1) levels after tissue or organ ischemia-reperfusion, and on ischemia-reperfusion induced lung neutrophil sequestration. Methods Forty white New Zealand rabbits were assigned randomly into 5 groups: HBO, IL, HBO+IL, control, and sham groups. TNF-α values were checked before ischemia, in the 1st hour of ischemia and in the 1st and 4th hours of reperfusion, also at the end of reperfusion period, plasma and tissue MPO values, MDA values, and sICAM-1 levels were detected. After sacrifice, the degree of lung injury was determined by histopathological examination. Results Compared to the control group all therapy groups showed a drastically meaningful reduction in TNF-α increase in 1, 2, and 4 hours. Plasma and lung MDA, MPO, and sICAM-1 levels were significantly lower in IL, HBO, HBO+IL, and sham groups compared with the control group. IL and/or HBO suppressed MDA and MPO increase in the lung tissue and in plasma. Additionally, histopathological score was significantly lower in HBO, IL, HBO+IL, and sham groups than that of the control group. Conclusion Both HBO and IL therapy have a beneficial effect by causing a meaningful reduction in TNF-α production, MPO, MDA, sICAM-1 levels and pulmonary neutrophil sequestration; which play a role, especially, in ischemia reperfusion induced lung damage.
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Affiliation(s)
- Yeliz Yilmaz
- Department of General Surgery, Izmir Katip Celebi University, Ataturk Training and Research Hospital, İzmir, Turkey
| | - Levent Tumkaya
- Department of Histology and Embryology, Recep Tayyip Erdogan University, Faculty of Medicine, Rize, Turkey
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31
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Ge Y, Huang M, Yao YM. Recent advances in the biology of IL-1 family cytokines and their potential roles in development of sepsis. Cytokine Growth Factor Rev 2018; 45:24-34. [PMID: 30587411 DOI: 10.1016/j.cytogfr.2018.12.004] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2018] [Revised: 12/16/2018] [Accepted: 12/19/2018] [Indexed: 12/13/2022]
Abstract
The IL-1 family comprises two anti-inflammatory cytokines (IL-37, IL-38), two receptor antagonists (IL-1ra, IL-36ra), and seven ligand agonists (IL-1α, IL-1β, IL-33, IL-36α, IL-36β, IL-36γ). The members of this family exert pleiotropic effects on intercellular signaling, leading to pro- or anti-inflammatory responses. They initiate potent inflammatory and immune responses by binding to specific receptors in the IL-1 receptor family, and their activities are repressed by naturally occurring inhibitors. Various immune cells produce and are regulated by these crucial molecules, which appear to be involved in the pathogenesis of diverse diseases including cancer as well as inflammatory and autoimmune disorders. Recent decades have seen substantial progress in understanding how the IL-1 family contributes to the development of sepsis. In this review, we will briefly introduce the IL-1 family and discuss its critical role in inflammatory and immune responses. The potential significance of IL-1 members in sepsis will also be explored, together with the clinical implications for treating this dangerous condition.
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Affiliation(s)
- Yun Ge
- Department of General Intensive Care Unit, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310052, China
| | - Man Huang
- Department of General Intensive Care Unit, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310052, China
| | - Yong-Ming Yao
- Trauma Research Center, Fourth Medical Center of the Chinese PLA General Hospital, Beijing 100048, China.
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Montgomery WG, Spinosa MD, Cullen JM, Salmon MD, Su G, Hassinger T, Sharma AK, Lu G, Fashandi A, Ailawadi G, Upchurch GR. Tamsulosin attenuates abdominal aortic aneurysm growth. Surgery 2018; 164:1087-1092. [PMID: 30174141 PMCID: PMC6459011 DOI: 10.1016/j.surg.2018.06.036] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 05/30/2018] [Accepted: 06/12/2018] [Indexed: 10/28/2022]
Abstract
BACKGROUND Tamsulosin, an α1A-adrenergic receptor inhibitor, is prescribed to treat benign prostatic hyperplasia in men >60 years of age, the same demographic most susceptible to abdominal aortic aneurysm. The goal of this study was to investigate the effect of tamsulosin on abdominal aortic aneurysm pathogenesis. METHODS Abdominal aortic aneurysms were induced in WT C57BL/6 male mice (n = 9-18/group), using an established topical elastase abdominal aortic aneurysm model. Osmotic pumps were implanted in mice 5 days before operation to create the model, administering either low dose (0.125 µg/day tamsulosin), high dose (0.250µg/day tamsulosin), or vehicle treatments with and without topical application of elastase. Blood pressures were measured preoperatively and on postoperative days 0, 3, 7, and 14. On postoperative day 14, aortic diameter was measured before harvest. Sample aortas were prepared for histology and cytokine analysis. RESULTS Measurements of systolic blood pressure did not differ between groups. Mice treated with the low dose of tamsulosin and with the high dose of tamsulosin showed decreased aortic diameter compared with vehicle-treated control (93% ± 24 versus 94% ± 30 versus 132% ± 24, respectively; P = .0003, P = .0003). Cytokine analysis demonstrated downregulation of pro-inflammatory cytokines in both treatment groups compared with the control (P < .05). Histology exhibited preservation of elastin in both low- and high-dose tamsulosin-treated groups (P = .0041 and P = .0018, respectively). CONCLUSION Tamsulosin attenuates abdominal aortic aneurysm formation with increased preservation of elastin and decreased production of pro-inflammatory cytokines. Further studies are necessary to elucidate the mechanism by which tamsulosin attenuates abdominal aortic aneurysm pathogenesis.
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Affiliation(s)
| | | | | | - Morgan D Salmon
- Department of Surgery, University of Virginia, Charlottesville
| | - Gang Su
- Department of Surgery, University of Florida, Gainesville
| | - Taryn Hassinger
- Department of Surgery, University of Virginia, Charlottesville
| | - Ashish K Sharma
- Department of Surgery, University of Virginia, Charlottesville
| | - Guanyi Lu
- Department of Surgery, University of Florida, Gainesville
| | - Anna Fashandi
- Department of Surgery, University of Virginia, Charlottesville
| | - Gorav Ailawadi
- Department of Surgery, University of Virginia, Charlottesville
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Yamada M, Hokazono C, Okutsu M. Maternal exercise training attenuates endotoxin-induced sepsis in mice offspring. Biochem Biophys Rep 2018; 15:19-24. [PMID: 29928698 PMCID: PMC6008276 DOI: 10.1016/j.bbrep.2018.06.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Revised: 05/11/2018] [Accepted: 06/02/2018] [Indexed: 12/11/2022] Open
Abstract
Regular exercise during pregnancy can prevent offspring from several diseases, such as cardiovascular diseases, obesity, and type II diabetes during adulthood. However, little information is available about whether maternal exercises during pregnancy protect the offspring from infectious diseases, such as sepsis and multiple organ dysfunction syndrome (MODS). This study aimed to investigate whether maternal exercise training protects the offspring from endotoxin-induced septic shock in mice. Female C57BL/6 mice performed voluntary wheel exercises during pregnancy. All dams and offspring were fed normal chow with sedentary activity during lactation and after weaning. At 10-week-old, mice were intraperitoneally injected a lethal (30 mg/kg) or nonlethal (15 mg/kg) dose of lipopolysaccharide (LPS), following which the survival of mice that were administered a lethal dose was monitored for 60 h. Plasma, lung, and liver samples were collected 18 h after the injection to evaluate the cytokine concentration or mRNA expression from those administered a nonlethal dose. Although maternal exercise training could not prevent lethality during an LPS-induced septic shock, it significantly inhibited the LPS-induced loss of body weight in female offspring. Regular maternal exercise significantly inhibited the mRNA expression of the LPS-induced inflammatory cytokines, such as interleukin-1β (IL-1β) and interferon-γ (IFN-γ), in the plasma and liver. Thus, maternal exercise inhibited the LPS-induced inflammatory response in female offspring, suggesting that regular exercise during pregnancy could be a potential candidate of the onset of sepsis and MODS in offspring.
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Affiliation(s)
- Mami Yamada
- Graduate School of Natural Sciences, Nagoya City University, 1 Yamanohata, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8501, Japan
| | - Chihiro Hokazono
- Graduate School of Natural Sciences, Nagoya City University, 1 Yamanohata, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8501, Japan
| | - Mitsuharu Okutsu
- Graduate School of Natural Sciences, Nagoya City University, 1 Yamanohata, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8501, Japan
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Abstract
Proinflammatory reaction by the body occurs acutely in response to injury that is considered primarily beneficial. However, sustained proinflammatory cytokines observed with chronic pathologies such as metabolic syndrome, cancer, and arthritis are detrimental and in many cases is a major cardiovascular risk factor. Proinflammatory cytokines such as interleukin-1, interleukin-6, and tumor necrosis factor α (TNFα) have long been implicated in cardiovascular risk and considered to be a major underlying cause for heart failure (HF). The failure of the anti-TNFα therapy for HF indicates our elusive understanding on the dichotomous role of proinflammatory cytokines on acutely beneficial effects versus long-term deleterious effects. Despite these well-described observations, less is known about the mechanistic underpinnings of proinflammatory cytokines especially TNFα in pathogenesis of HF. Increasing evidence suggests the existence of an active cross-talk between the TNFα receptor signaling and G-protein-coupled receptors such as β-adrenergic receptor (βAR). Given that βARs are the key regulators of cardiac function, the review will discuss the current state of understanding on the role of proinflammatory cytokine TNFα in regulating βAR function.
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Affiliation(s)
- Maradumane L Mohan
- *Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH; and †Cardiovascular Research Institute, Case Western Reserve University, Cleveland, OH
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Ahmed A, Dolasia K, Mukhopadhyay S. Mycobacterium tuberculosisPPE18 Protein Reduces Inflammation and Increases Survival in Animal Model of Sepsis. THE JOURNAL OF IMMUNOLOGY 2018; 200:3587-3598. [DOI: 10.4049/jimmunol.1602065] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Accepted: 03/14/2018] [Indexed: 12/16/2022]
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Stimulation of Interleukin 1 Production by Products of Gram–positive and Gram–negative Bacteria during Hemodialysis. Int J Artif Organs 2018. [DOI: 10.1177/039139889001300202] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Affiliation(s)
- B.J.G. Pereira
- Department of Medicine, New England Medical Center, Tufts University School of Medicine, Boston - USA
| | - C.A. Dinarello
- Department of Medicine, New England Medical Center, Tufts University School of Medicine, Boston - USA
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Sphingosine-1-Phosphate: A Potential Biomarker and Therapeutic Target for Endothelial Dysfunction and Sepsis? Shock 2018; 47:666-672. [PMID: 27922551 DOI: 10.1097/shk.0000000000000814] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Sepsis is an acute life-threatening multiple organ failure caused by a dysregulated host response to infection. Endothelial dysfunction, particularly barrier disruption leading to increased vascular permeability, edema, and insufficient tissue oxygenation, is critical to sepsis pathogenesis. Sphingosine-1-phosphate (S1P) is a signaling lipid that regulates important pathophysiological processes including vascular endothelial cell permeability, inflammation, and coagulation. It is present at high concentrations in blood and lymph and at very low concentrations in tissues due to the activity of the S1P-degrading enzyme S1P-lyase in tissue cells. Recently, four preclinical observational studies determined S1P levels in serum or plasma of sepsis patients, and all found reduced S1P levels associated with the disease. Based on these findings, this review summarizes S1P-regulated processes pertaining to endothelial functions, discusses the possible use of S1P as a marker and possibilities how to manipulate S1P levels and S1P receptor activation to restore endothelial integrity, dampens the inflammatory host response, and improves organ function in sepsis.
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Mortality Benefit of Recombinant Human Interleukin-1 Receptor Antagonist for Sepsis Varies by Initial Interleukin-1 Receptor Antagonist Plasma Concentration. Crit Care Med 2017; 46:21-28. [PMID: 28991823 DOI: 10.1097/ccm.0000000000002749] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
OBJECTIVE Plasma interleukin-1 beta may influence sepsis mortality, yet recombinant human interleukin-1 receptor antagonist did not reduce mortality in randomized trials. We tested for heterogeneity in the treatment effect of recombinant human interleukin-1 receptor antagonist by baseline plasma interleukin-1 beta or interleukin-1 receptor antagonist concentration. DESIGN Retrospective subgroup analysis of randomized controlled trial. SETTING Multicenter North American and European clinical trial. PATIENTS Five hundred twenty-nine subjects with sepsis and hypotension or hypoperfusion, representing 59% of the original trial population. INTERVENTIONS Random assignment of placebo or recombinant human interleukin-1 receptor antagonist × 72 hours. MEASUREMENTS AND MAIN RESULTS We measured prerandomization plasma interleukin-1 beta and interleukin-1 receptor antagonist and tested for statistical interaction between recombinant human interleukin-1 receptor antagonist treatment and baseline plasma interleukin-1 receptor antagonist or interleukin-1 beta concentration on 28-day mortality. There was significant heterogeneity in the effect of recombinant human interleukin-1 receptor antagonist treatment by plasma interleukin-1 receptor antagonist concentration whether plasma interleukin-1 receptor antagonist was divided into deciles (interaction p = 0.046) or dichotomized (interaction p = 0.028). Interaction remained present across different predicted mortality levels. Among subjects with baseline plasma interleukin-1 receptor antagonist above 2,071 pg/mL (n = 283), recombinant human interleukin-1 receptor antagonist therapy reduced adjusted mortality from 45.4% to 34.3% (adjusted risk difference, -0.12; 95% CI, -0.23 to -0.01), p = 0.044. Mortality in subjects with plasma interleukin-1 receptor antagonist below 2,071 pg/mL was not reduced by recombinant human interleukin-1 receptor antagonist (adjusted risk difference, +0.07; 95% CI, -0.04 to +0.17), p = 0.230. Interaction between plasma interleukin-1 beta concentration and recombinant human interleukin-1 receptor antagonist treatment was not statistically significant. CONCLUSIONS We report a heterogeneous effect of recombinant human interleukin-1 receptor antagonist on 28-day sepsis mortality that is potentially predictable by plasma interleukin-1 receptor antagonist in one trial. A precision clinical trial of recombinant human interleukin-1 receptor antagonist targeted to septic patients with high plasma interleukin-1 receptor antagonist may be worthy of consideration.
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40
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Han MS, Lee YM, Kim SW, Kim KM, Lee T, Lee W, Kwon OK, Lee S, Bae JS. Role of moesin in HMGB1-stimulated severe inflammatory responses. Thromb Haemost 2017; 114:350-63. [DOI: 10.1160/th14-11-0969] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2014] [Accepted: 02/25/2015] [Indexed: 11/05/2022]
Abstract
SummarySepsis is a life-threatening condition that arises when the body’s response to infection causes systemic inflammation. High-mobility group box 1 (HMGB1), as a late mediator of sepsis, enhances hyper-permeability, and it is therefore a therapeutic target. Despite extensive research into the underlying mechanisms of sepsis, the target molecules controlling vascular leakage remain largely unknown. Moesin is a cytoskeletal protein involved in cytoskeletal changes and para-cellular gap formation. The objectives of this study were to determine the roles of moesin in HMGB1-mediated vascular hyperpermeability and inflammatory responses and to investigate the mechanisms of action underlying these responses. Using siRNA knockdown of moesin expression in primary human umbilical vein endothelial cells (HUVECs), moesin was found to be required in HMGB1-induced F-actin rearrangement, hyperpermeability, and inflammatory responses. The mechanisms involved in moesin phosphorylation were analysed by blocking the binding of the HMGB1 receptor (RAGE) and inhibiting the Rho and MAPK pathways. HMGB1-treated HUVECs exhibited an increase in Thr558 phosphorylation of moesin. Circulating levels of moesin were measured in patients admitted to the intensive care unit with sepsis, severe sepsis, and septic shock; these patients showed significantly higher levels of moesin than healthy controls, which was strongly correlated with disease severity. High blood moesin levels were also observed in cecal ligation and puncture (CLP)-induced sepsis in mice. Administration of blocking moesin antibodies attenuated CLP-induced septic death. Collectively, our findings demonstrate that the HMGB1-RAGE-moesin axis can elicit severe inflammatory responses, suggesting it to be a potential target for the development of diagnostics and therapeutics for sepsis.
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Guo Y, Patil NK, Luan L, Bohannon JK, Sherwood ER. The biology of natural killer cells during sepsis. Immunology 2017; 153:190-202. [PMID: 29064085 DOI: 10.1111/imm.12854] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Accepted: 10/09/2017] [Indexed: 12/11/2022] Open
Abstract
Natural killer (NK) cells are large granular lymphocytes largely recognized for their importance in tumour surveillance and the host response to viral infections. However, as the major innate lymphocyte population, NK cells also coordinate early responses to bacterial infections by amplifying the antimicrobial functions of myeloid cells, especially macrophages, by production of interferon-γ (IFN-γ). Alternatively, excessive NK cell activation and IFN-γ production can amplify the systemic inflammatory response during sepsis resulting in increased physiological dysfunction and organ injury. Our understanding of NK cell biology during bacterial infections and sepsis is mostly derived from studies performed in mice. Human studies have demonstrated a correlation between altered NK cell functions and outcomes during sepsis. However, mechanistic understanding of NK cell function during human sepsis is limited. In this review, we will review the current understanding of NK cell biology during sepsis and discuss the challenges associated with modulating NK cell function during sepsis for therapeutic benefit.
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Affiliation(s)
- Yin Guo
- Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA.,Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Naeem K Patil
- Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Liming Luan
- Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Julia K Bohannon
- Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Edward R Sherwood
- Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA.,Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
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42
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Philip AM, Wang Y, Mauro A, El-Rass S, Marshall JC, Lee WL, Slutsky AS, dos Santos CC, Wen XY. Development of a zebrafish sepsis model for high-throughput drug discovery. Mol Med 2017; 23:134-148. [PMID: 28598490 PMCID: PMC5522968 DOI: 10.2119/molmed.2016.00188] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Accepted: 05/23/2017] [Indexed: 12/22/2022] Open
Abstract
Sepsis is a leading cause of death worldwide. Current treatment modalities remain largely supportive. Intervention strategies focused on inhibiting specific mediators of the inflammatory host response have been largely unsuccessful, a consequence of an inadequate understanding of the complexity and heterogeneity of the innate immune response. Moreover, the conventional drug development pipeline is time consuming and expensive and the low success rates associated with cell-based screens underline the need for whole organism screening strategies, especially for complex pathological processes. Here, we established an LPS-induced zebrafish endotoxemia model, which exhibits the major hallmarks of human sepsis including, edema and tissue/organ damage, increased vascular permeability and vascular leakage accompanied by an altered expression of cellular junction proteins, increased cytokine expression, immune cell activation and ROS production, reduced circulation and increased platelet aggregation. We tested the suitability of the model for phenotype-based drug screening using three primary readouts: mortality, vascular leakage, and ROS production. Preliminary screening identified fasudil, a drug known to protect against vascular leakage in murine models, as a lead hit thereby validating the utility of our model for sepsis drug screens. This zebrafish sepsis model has the potential to rapidly analyze sepsis associated pathologies and cellular processes in the whole organism, as well as to screen and validate large numbers of compounds that can modify sepsis pathology in vivo.
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Affiliation(s)
- Anju M Philip
- Zebrafish Centre for Advanced Drug Discovery, St. Michael’s Hospital, Toronto, Ontario, Canada
- Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Toronto, Ontario, Canada
- Department of Physiology, Toronto, Ontario, Canada
| | - Youdong Wang
- Zebrafish Centre for Advanced Drug Discovery, St. Michael’s Hospital, Toronto, Ontario, Canada
- Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Toronto, Ontario, Canada
| | - Antonio Mauro
- Zebrafish Centre for Advanced Drug Discovery, St. Michael’s Hospital, Toronto, Ontario, Canada
- Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Toronto, Ontario, Canada
- Department of Medicine and Institute of Medical Science, Toronto, Ontario, Canada
- Collaborative Program in Cardiovascular Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Suzan El-Rass
- Zebrafish Centre for Advanced Drug Discovery, St. Michael’s Hospital, Toronto, Ontario, Canada
- Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Toronto, Ontario, Canada
- Department of Medicine and Institute of Medical Science, Toronto, Ontario, Canada
- Collaborative Program in Cardiovascular Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - John C Marshall
- Zebrafish Centre for Advanced Drug Discovery, St. Michael’s Hospital, Toronto, Ontario, Canada
- Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Toronto, Ontario, Canada
- Interdepartmental Division of Critical Care, Toronto, Ontario, Canada
| | - Warren L Lee
- Zebrafish Centre for Advanced Drug Discovery, St. Michael’s Hospital, Toronto, Ontario, Canada
- Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Toronto, Ontario, Canada
- Department of Medicine and Institute of Medical Science, Toronto, Ontario, Canada
| | - Arthur S Slutsky
- Zebrafish Centre for Advanced Drug Discovery, St. Michael’s Hospital, Toronto, Ontario, Canada
- Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Toronto, Ontario, Canada
- Department of Medicine and Institute of Medical Science, Toronto, Ontario, Canada
- Interdepartmental Division of Critical Care, Toronto, Ontario, Canada
| | - Claudia C dos Santos
- Zebrafish Centre for Advanced Drug Discovery, St. Michael’s Hospital, Toronto, Ontario, Canada
- Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Toronto, Ontario, Canada
- Department of Medicine and Institute of Medical Science, Toronto, Ontario, Canada
- Interdepartmental Division of Critical Care, Toronto, Ontario, Canada
| | - Xiao-Yan Wen
- Zebrafish Centre for Advanced Drug Discovery, St. Michael’s Hospital, Toronto, Ontario, Canada
- Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Toronto, Ontario, Canada
- Department of Physiology, Toronto, Ontario, Canada
- Department of Medicine and Institute of Medical Science, Toronto, Ontario, Canada
- Collaborative Program in Cardiovascular Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
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Gomez JP, Gonçalves C, Pichon C, Midoux P. Effect of IL-1β, TNF-α and IGF-1 on trans-endothelial passage of synthetic vectors through an in vitro vascular endothelial barrier of striated muscle. Gene Ther 2017; 24:416-424. [DOI: 10.1038/gt.2017.40] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 05/09/2017] [Accepted: 05/10/2017] [Indexed: 12/12/2022]
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Jiang X, Wang Y, Qin Y, He W, Benlahrech A, Zhang Q, Jiang X, Lu Z, Ji G, Zheng Y. Micheliolide provides protection of mice against Staphylococcus aureus and MRSA infection by down-regulating inflammatory response. Sci Rep 2017; 7:41964. [PMID: 28165033 PMCID: PMC5292736 DOI: 10.1038/srep41964] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 12/30/2016] [Indexed: 12/30/2022] Open
Abstract
A major obstacle to therapy in intensive care units is sepsis caused by severe infection. In recent years gram-positive (G+) bacteria, most commonly staphylococci, are thought to be the main pathogens. Micheliolide (MCL) was demonstrated to provide a therapeutic role in rheumatoid arthritis, inflammatory intestinal disease, colitis-associated cancer, and lipopolysaccharide (LPS, the main component of G- bacterial cell wall) induced septic shock. We proved here that MCL played an anti-inflammatory role in Staphylococcus aureus (S. aureus) and methicillin-resistant S. aureus (MRSA) induced peritonitis. It inhibited the expression of inflammatory cytokines and chemokines in macrophages and dendritic cells upon stimulation with peptidoglycan (PGN, the main cell wall composition of G+ bacteria). PI3K/Akt and NF-κB pathways account for the anti-inflammatory role of MCL after PGN stimulation. MCL reduced IL-6 secretion through down-regulating NF-κB activation and improved the survival status in mice challenged with a lethal dose of S. aureus. In MRSA infection mouse model, MCL down-regulated the expression of IL-6, TNF-α, MCP-1/CCL2 and IFN-γ in sera, and ameliorated the organ damage of liver and kidney. In conclusion, MCL can help maintain immune equilibrium and decrease PGN, S. aureus and MRSA-triggered inflammatory response. These provide the rationality for the potential usage of MCL in sepsis caused by G+ bacteria (e.g., S. aureus) and antibiotic-resistant bacteria (e.g., MRSA).
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Affiliation(s)
- Xinru Jiang
- Department of Immunology and Microbiology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yuli Wang
- Department of Immunology and Microbiology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yifei Qin
- School of Clinical Medicine, Shaanxi University of Chinese Medicine, Xi xian New District, Shaanxi 712046, China
| | - Weigang He
- Department of Immunology and Microbiology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Adel Benlahrech
- MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, Nuffield Department of Medicine, University of Oxford, Oxford OX3 9DS, UK
| | - Qingwen Zhang
- Department of Immunology and Microbiology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xin Jiang
- Department of Immunology and Microbiology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Zhenhui Lu
- Department of Respiration, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Guang Ji
- Institute of Digestive Diseases, China-Canada Center of Research for Digestive Diseases (ccCRDD), Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Yuejuan Zheng
- Department of Immunology and Microbiology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, Nuffield Department of Medicine, University of Oxford, Oxford OX3 9DS, UK
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Vanoni S, Tsai YT, Waddell A, Waggoner L, Klarquist J, Divanovic S, Hoebe K, Steinbrecher KA, Hogan SP. Myeloid-derived NF-κB negative regulation of PU.1 and c/EBP-β-driven pro-inflammatory cytokine production restrains LPS-induced shock. Innate Immun 2017; 23:175-187. [PMID: 27932520 PMCID: PMC5563821 DOI: 10.1177/1753425916681444] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Sepsis is a life-threatening event predominantly caused by Gram-negative bacteria. Bacterial infection causes a pronounced macrophage (MΦ) and dendritic cell activation that leads to excessive pro-inflammatory cytokine IL-1β, IL-6 and TNF-α production (cytokine storm), resulting in endotoxic shock. Previous experimental studies have revealed that inhibiting NF-κB signaling ameliorates disease symptoms; however, the contribution of myeloid p65 in endotoxic shock remains elusive. In this study, we demonstrate increased mortality in mice lacking p65 in the myeloid lineage (p65Δmye) compared with wild type mice upon ultra-pure LPS challenge. We show that increased susceptibility to LPS-induced shock was associated with elevated serum level of IL-1β and IL-6. Mechanistic analyses revealed that LPS-induced pro-inflammatory cytokine production was ameliorated in p65-deficient bone marrow-derived MΦs; however, p65-deficient 'activated' peritoneal MΦs exhibited elevated IL-1β and IL-6. We show that the elevated pro-inflammatory cytokine secretion was due, in part, to increased accumulation of IL-1β mRNA and protein in activated inflammatory MΦs. The increased IL-1β was linked with heightened binding of PU.1 and CCAAT/enhancer binding protein-β to Il1b and Il6 promoters in activated inflammatory MΦs. Our data provide insight into a role for NF-κB in the negative regulation of pro-inflammatory cytokines in myeloid cells.
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Affiliation(s)
- Simone Vanoni
- Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229
| | - Yi Ting Tsai
- Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229
| | - Amanda Waddell
- Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229
| | - Lisa Waggoner
- Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229
| | - Jared Klarquist
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229
| | - Senad Divanovic
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229
| | - Kasper Hoebe
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229
| | - Kris A. Steinbrecher
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229
| | - Simon P. Hogan
- Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229
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Fujishima S. Organ dysfunction as a new standard for defining sepsis. Inflamm Regen 2016; 36:24. [PMID: 29259697 PMCID: PMC5725936 DOI: 10.1186/s41232-016-0029-y] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Accepted: 11/01/2016] [Indexed: 01/20/2023] Open
Abstract
Despite advances in intensive care and the widespread use of standardized care included in the Surviving Sepsis Campaign Guidelines, sepsis remains a leading cause of death, and the prevalence of sepsis increases concurrent with the aging process. The diagnosis of sepsis was originally based on the evidence of persistent bacteremia (septicemia) but was modified in 1992 to incorporate systemic inflammatory response syndrome (SIRS). Since then, SIRS has become the gold standard for the diagnosis of sepsis. In 2016, the Society of Critical Care Medicine and the European Society of Intensive Care Medicine published a new clinical definition of sepsis that is called Sepsis-3. In contrast to previous definitions, Sepsis-3 is based on organ dysfunctions and uses a sequential organ failure (SOFA) score as an index. Thus, patients diagnosed with respect to Sepsis-3 will inevitably represent a different population than those previously diagnosed. We assume that this drastic change in clinical definition will affect not only clinical practice but also the viewpoint and focus of basic research. This review intends to summarize the pathophysiology of sepsis and organ dysfunction and discusses potential directions for future research.
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Affiliation(s)
- Seitaro Fujishima
- Center for General Medicine Education, Keio University School of Medicine, Tokyo, Japan
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Abstract
Interleukin-1 (IL-1) is a polypeptide which possesses a broad spectrum of biological activities, many of which are associated with disease. It has been studied for its ability to induce fever, sleep and anorexia, elevate prostaglandins and nitric oxide, stimulate the release of pituitary hormones, elevate hepatic acute phase proteins, increase gene expression for other cytokines and augment the proliferation of T and B lymphocytes. In addition, IL-1 increases the synthesis of collagenases and decreases the synthesis of proteoglycans, resulting in joint destruction. More recently, IL-1 has been shown to induce hypotension and upregulate endothelial cell adhesion molecules, both important parameters of the septic shock syndrome. IL-1 also possesses host defense properties. For example, pretreatment with IL-1 non-specifically reduces lethality to bacterial and fungal infections, even in the absence of circulating neutrophils. IL-1 has been given to humans in clinical trials; as increasing doses are given, IL-1 is toxic, producing gastrointestinal disturbances and hypotension. It appears that low doses of exogenously administered IL-1 may prove useful as a therapy. On the other hand, blocking the toxic effects of IL-1 may be necessary in the treatment of certain diseases. IL-1 receptor blockade has been studied in human disease including sepsis. Similar to other studies using corticosteroids, antibodies to tumor necrosis factor, bradykinin antagonists and inhibitors of platelet activating factor, clear-cut beneficial effects of IL-1 receptor blockade have not matched those demonstrated in animals.
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Affiliation(s)
- C.A. Dinarello
- Department of Medicine, Tufts University School of Medicine and New England Medical Center Hospital, Boston, MA, USA
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48
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Veloso D, Denny S, Cosgriff T, Hochstein H. Differential susceptibility of rhesus monkeys to high doses of endotoxin. ACTA ACUST UNITED AC 2016. [DOI: 10.1177/096805199600200604] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
We investigated susceptibility of rhesus monkeys ( Macaca mulatta) to Escherichia coli endotoxin (ETX) in two ways. We infused 8 monkeys (group A) with various doses of ETX (1.0-7.5 mg/kg) to assess the effect of dose on shock severity; and we infused 6 monkeys (group B) with 1.0 mg ETX/kg to test biological variability to ETX challenge. Controls were 7 saline-infused monkeys. Systolic pressure, heart rate (HR), temperature, plasma ETX and inflammatory markers — tumor necrosis factor-α (TNF), interleukin-1 (IL-1) and IL-6 — were quantified before and at 1.5, 2.5, 6 and 26 h after infusion. The highest plasma concentrations of ETX (at 1.5 h) — < 8% that infused — correlated well with the infused doses. ETX elicited hypotension and increases in HR in all monkeys. Fever did not occur. The degree of hypotension and increase in HR and death did not correlate with ETX dose (or plasma ETX concentrations). The response of inflammatory cytokines to ETX was greater in nonsurvivors than in survivors. The observed low mortality rate (4/14) suggests that rhesus monkeys are rather resistant to high endotoxin concentrations similar to baboons but unlike humans or chimpanzees. The lack of correlation between ETX dose and shock severity suggests that there is a critical ETX concentration in each animal that leads to controllable or uncontrollable cytokine elevation in plasma, with reversible or irreversible shock, and resulting survival or death.
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Affiliation(s)
- D. Veloso
- Division of Medicine, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland, Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center, Houston, Texas, Center for Biologics Evaluation and Research, FDA, Bethesda, Maryland, USA
| | - S. Denny
- Division of Medicine, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland, Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center, Houston, Texas, Center for Biologics Evaluation and Research, FDA, Bethesda, Maryland, USA
| | - T.M. Cosgriff
- Division of Medicine, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland, Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center, Houston, Texas, Center for Biologics Evaluation and Research, FDA, Bethesda, Maryland, USA
| | - H.D. Hochstein
- Division of Medicine, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland, Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center, Houston, Texas, Center for Biologics Evaluation and Research, FDA, Bethesda, Maryland, USA
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49
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Morrison D, Danner R, Dinarello C, Munford R, Natanson C, Pollack M, Spitzer J, Ulevitch R, Vogel S, McSweegan E. Bacterial endotoxins and pathogenesis of Gram-negative infections: current status and future direction. ACTA ACUST UNITED AC 2016. [DOI: 10.1177/096805199400100201] [Citation(s) in RCA: 88] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
100 years after the discovery of a bacterial 'endotoxin', 50 years after the introduction of antibiotics and 25 years after the routine use of intensive care units to support septic shock patients, Gram-negative infections continue to account for significant morbidity and mortality. In the coming decade, basic research on the structure/function of LPS, the cytokine cascade, and receptor-mediated intracellular signalling responses to LPS and cytokines will provide a greater understanding of the molecular, cellular and systemic responses to endotoxin and infection. New therapeutic agents now emerging from research, and better designed clinical trials to assess those agents will contribute to the next significant decline in sepsis- and shock-related morbidity and mortality. This article summarizes the findings of a workshop convened at the National Institutes of Health (NIH) to examine current research on endotoxin and Gram-negative septic shock.
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Affiliation(s)
- D.C. Morrison
- Sponsored by National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - R.L. Danner
- Sponsored by National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - C.A. Dinarello
- Sponsored by National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - R.S. Munford
- Sponsored by National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - C. Natanson
- Sponsored by National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - M. Pollack
- Sponsored by National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - J.J. Spitzer
- Sponsored by National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - R.J. Ulevitch
- Sponsored by National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - S.N. Vogel
- Sponsored by National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - E. McSweegan
- Sponsored by National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
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Misra B, Ferranti T, Donnelly L, Erickson J, Schaub R, Keith J. Recombinant human interleukin-11 prevents hypotension in LPS-treated anesthetized rabbits. ACTA ACUST UNITED AC 2016. [DOI: 10.1177/096805199600300403] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Recombinant human interleukin-11 (rhlL-11) was evaluated in a New Zealand White rabbit model of endotoxemia. Animals received Escherichia coli LPS (150 μg/kg i.v.) via a femoral venous catheter. 30 min later, animals were treated with rhlL-11 (100 μg/kg i.v., n = 7), or rhlL-11 formulation buffer (n = 6). Arterial pressures were monitored for 6 h following rhlL-11. Approximately 5 h after LPS treatment, mean arterial pressure in vehicle-treated control animals was 46.7 mmHg, or 55% of group mean baseline, while that of rhlL-11-treated animals was 74.8 mmHg, or 94% of group mean baseline (P < 0.0005). Histologic evaluation of ileum, cecum and colon from rhlL-11-treated rabbits showed decreased hemorrhage, edema, and mucosal damage (P < 0.02), compared to the vehicle-treated controls. Intravenous LPS evokes hypotension mediated by the induction of inducible nitric oxide synthase (iNOS) and subsequent production of NO. Maintenance of blood pressure by rhIL-11 in LPS-treated rabbits in addition to the concurrent significant decrease in NO levels compared to vehicle-treated animals ( P < 0.04) suggests that rhlL-11 interferes with the production of NO by iNOS and or the physiologic effects of NO on vascular smooth muscle.
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Affiliation(s)
- B.R. Misra
- Preclinical R & D, Genetics Institute, Inc., Cambridge, Massachusetts, USA,
| | - T.J. Ferranti
- Preclinical R & D, Genetics Institute, Inc., Cambridge, Massachusetts, USA
| | - L.H. Donnelly
- Preclinical R & D, Genetics Institute, Inc., Cambridge, Massachusetts, USA
| | - J.E. Erickson
- Preclinical R & D, Genetics Institute, Inc., Cambridge, Massachusetts, USA
| | - R.G. Schaub
- Preclinical R & D, Genetics Institute, Inc., Cambridge, Massachusetts, USA
| | - J.C. Keith
- Preclinical R & D, Genetics Institute, Inc., Cambridge, Massachusetts, USA
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