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Ozuygur Ermis SS, Ercan S, Malmhäll C, Adesoba H, Salisu M, Bossios A, Rådinger M, Kankaanranta H, Nwaru BI. Sex steroid hormones and asthma in males: a state-of-the-art review. Expert Rev Respir Med 2025:1-22. [PMID: 40322957 DOI: 10.1080/17476348.2025.2501276] [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: 02/18/2025] [Accepted: 04/29/2025] [Indexed: 05/14/2025]
Abstract
INTRODUCTION The incidence, prevalence, and disease prognosis of asthma differ between males and females throughout the life course. However, the underlying mechanisms are not known. Sex hormones might have a potential role in asthma pathogenesis. But most studies on the role of sex hormones in asthma have focused on females, with a paucity of evidence in males. AREAS COVERED This paper provides a comprehensive review of the state-of-the-art on sex steroids in asthma, focusing on males, covering mechanistic, clinical, and epidemiological studies. Literature search was conducted in PubMed in September 2024. EXPERT OPINION Androgen signaling has a protective role in asthma by reducing airway smooth muscle (ASM) contractility and decreasing airway inflammation. In contrast, estrogens appear to promote type 2 (T2) airway inflammation, while the effect on ASM remains controversial. To date, suggested mechanisms have not fully clarify the underlying pathways through which sex steroids modulate ASM and T2 inflammation in asthma. The balance between androgen and estrogen signaling might also play a role. While epidemiological studies support a protective role for androgens, the evidence on onset of puberty and asthma is inconclusive. Larger longitudinal population samples and stratification based on age and obesity are needed to resolve these questions.
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Affiliation(s)
- Saliha Selin Ozuygur Ermis
- Krefting Research Centre, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Selin Ercan
- Krefting Research Centre, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Carina Malmhäll
- Krefting Research Centre, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Helen Adesoba
- Krefting Research Centre, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Michael Salisu
- Krefting Research Centre, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Apostolos Bossios
- Division of Lung and Airway Research, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- Karolinska Severe Asthma Center, Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden
| | - Madeleine Rådinger
- Krefting Research Centre, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Hannu Kankaanranta
- Krefting Research Centre, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Tampere University Respiratory Research Group, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Department of Respiratory Medicine, Seinäjoki Central Hospital, Seinäjoki, Finland
| | - Bright I Nwaru
- Krefting Research Centre, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
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Boucher M, Henry C, Gélinas L, Packwood R, Rojas-Ruiz A, Fereydoonzad L, Graham P, Bossé Y. High throughput screening of airway constriction in mouse lung slices. Sci Rep 2024; 14:20133. [PMID: 39210022 PMCID: PMC11362152 DOI: 10.1038/s41598-024-71170-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 08/26/2024] [Indexed: 09/04/2024] Open
Abstract
The level of airway constriction in thin slices of lung tissue is highly variable. Owing to the labor-intensive nature of these experiments, determining the number of airways to be analyzed in order to allocate a reliable value of constriction in one mouse is challenging. Herein, a new automated device for physiology and image analysis was used to facilitate high throughput screening of airway constriction in lung slices. Airway constriction was first quantified in slices of lungs from male BALB/c mice with and without experimental asthma that were inflated with agarose through the trachea or trans-parenchymal injections. Random sampling simulations were then conducted to determine the number of airways required per mouse to quantify maximal constriction. The constriction of 45 ± 12 airways per mouse in 32 mice were analyzed. Mean maximal constriction was 37.4 ± 32.0%. The agarose inflating technique did not affect the methacholine response. However, the methacholine constriction was affected by experimental asthma (p = 0.003), shifting the methacholine concentration-response curve to the right, indicating a decreased sensitivity. Simulations then predicted that approximately 35, 16 and 29 airways per mouse are needed to quantify the maximal constriction mean, standard deviation and coefficient of variation, respectively; these numbers varying between mice and with experimental asthma.
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Affiliation(s)
- Magali Boucher
- Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ)-Université Laval, Pavillon M, room 2687, 2725, chemin Sainte-Foy, Quebec, Qc, G1V 4G5, Canada
| | - Cyndi Henry
- Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ)-Université Laval, Pavillon M, room 2687, 2725, chemin Sainte-Foy, Quebec, Qc, G1V 4G5, Canada
| | - Louis Gélinas
- Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ)-Université Laval, Pavillon M, room 2687, 2725, chemin Sainte-Foy, Quebec, Qc, G1V 4G5, Canada
| | - Rosalie Packwood
- Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ)-Université Laval, Pavillon M, room 2687, 2725, chemin Sainte-Foy, Quebec, Qc, G1V 4G5, Canada
| | - Andrés Rojas-Ruiz
- Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ)-Université Laval, Pavillon M, room 2687, 2725, chemin Sainte-Foy, Quebec, Qc, G1V 4G5, Canada
| | | | | | - Ynuk Bossé
- Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ)-Université Laval, Pavillon M, room 2687, 2725, chemin Sainte-Foy, Quebec, Qc, G1V 4G5, Canada.
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Gill R, Rojas‐Ruiz A, Boucher M, Henry C, Bossé Y. More airway smooth muscle in males versus females in a mouse model of asthma: A blessing in disguise? Exp Physiol 2023; 108:1080-1091. [PMID: 37341687 PMCID: PMC10988431 DOI: 10.1113/ep091236] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 06/06/2023] [Indexed: 06/22/2023]
Abstract
NEW FINDINGS What is the central question of this study? The lung response to inhaled methacholine is reputed to be greater in male than in female mice. The underpinnings of this sex disparity are ill defined. What is the main finding and its importance? We demonstrated that male airways exhibit a greater content of airway smooth muscle than female airways. We also found that, although a more muscular airway tree in males might contribute to their greater responsiveness to inhaled methacholine than females, it might also curb the heterogeneity in small airway narrowing. ABSTRACT Mouse models are helpful in unveiling the mechanisms underlying sex disparities in asthma. In comparison to their female counterparts, male mice are hyperresponsive to inhaled methacholine, a cardinal feature of asthma that contributes to its symptoms. The physiological details and the structural underpinnings of this hyperresponsiveness in males are currently unknown. Herein, BALB/c mice were exposed intranasally to either saline or house dust mite once daily for 10 consecutive days to induce experimental asthma. Twenty-four hours after the last exposure, respiratory mechanics were measured at baseline and after a single dose of inhaled methacholine that was adjusted to trigger the same degree of bronchoconstriction in both sexes (it was twice as high in females). Bronchoalveolar lavages were then collected, and the lungs were processed for histology. House dust mite increased the number of inflammatory cells in bronchoalveolar lavages to the same extent in both sexes (asthma, P = 0.0005; sex, P = 0.96). The methacholine response was also markedly increased by asthma in both sexes (e.g., P = 0.0002 for asthma on the methacholine-induced bronchoconstriction). However, for a well-matched bronchoconstriction between sexes, the increase in hysteresivity, an indicator of airway narrowing heterogeneity, was attenuated in males for both control and asthmatic mice (sex, P = 0.002). The content of airway smooth muscle was not affected by asthma but was greater in males (asthma, P = 0.31; sex, P < 0.0001). These results provide further insights regarding an important sex disparity in mouse models of asthma. The increased amount of airway smooth muscle in males might contribute functionally to their greater methacholine response and, possibly, to their decreased propensity for airway narrowing heterogeneity.
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Affiliation(s)
- Rebecka Gill
- Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Université LavalDépartement de médecineQuébecCanada
| | - Andrés Rojas‐Ruiz
- Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Université LavalDépartement de médecineQuébecCanada
| | - Magali Boucher
- Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Université LavalDépartement de médecineQuébecCanada
| | - Cyndi Henry
- Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Université LavalDépartement de médecineQuébecCanada
| | - Ynuk Bossé
- Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Université LavalDépartement de médecineQuébecCanada
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Boucher M, Dufour-Mailhot A, Tremblay-Pitre S, Khadangi F, Rojas-Ruiz A, Henry C, Bossé Y. In mice of both sexes, repeated contractions of smooth muscle in vivo greatly enhance the response of peripheral airways to methacholine. Respir Physiol Neurobiol 2022; 304:103938. [PMID: 35716869 DOI: 10.1016/j.resp.2022.103938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 05/10/2022] [Accepted: 06/12/2022] [Indexed: 10/18/2022]
Abstract
BALB/c mice from both sexes underwent one of two nebulized methacholine challenges that were preceded by a period of 20 min either with or without tone induced by repeated contractions of the airway smooth muscle. Impedance was monitored throughout and the constant phase model was used to dissociate the impact of tone on conducting airways (RN - Newtonian resistance) versus the lung periphery (G and H - tissue resistance and elastance). The effect of tone on smooth muscle contractility was also tested on excised tracheas. While tone markedly potentiated the methacholine-induced gains in H and G in both sexes, the gain in RN was only potentiated in males. The contractility of female and male tracheas was also potentiated by tone. Inversely, the methacholine-induced gain in hysteresivity (G/H) was mitigated by tone in both sexes. Therefore, the tone-induced muscle hypercontractility impacts predominantly the lung periphery in vivo, but also promotes further airway narrowing in males while protecting against narrowing heterogeneity in both sexes.
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Affiliation(s)
- Magali Boucher
- Institut Universitaire de Cardiologie et de Pneumologie de Québec - Université Laval, Québec, Canada
| | - Alexis Dufour-Mailhot
- Institut Universitaire de Cardiologie et de Pneumologie de Québec - Université Laval, Québec, Canada
| | - Sophie Tremblay-Pitre
- Institut Universitaire de Cardiologie et de Pneumologie de Québec - Université Laval, Québec, Canada
| | - Fatemeh Khadangi
- Institut Universitaire de Cardiologie et de Pneumologie de Québec - Université Laval, Québec, Canada
| | - Andrés Rojas-Ruiz
- Institut Universitaire de Cardiologie et de Pneumologie de Québec - Université Laval, Québec, Canada
| | - Cyndi Henry
- Institut Universitaire de Cardiologie et de Pneumologie de Québec - Université Laval, Québec, Canada
| | - Ynuk Bossé
- Institut Universitaire de Cardiologie et de Pneumologie de Québec - Université Laval, Québec, Canada.
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Somayaji R, Chalmers JD. Just breathe: a review of sex and gender in chronic lung disease. Eur Respir Rev 2022; 31:31/163/210111. [PMID: 35022256 DOI: 10.1183/16000617.0111-2021] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Accepted: 08/20/2021] [Indexed: 01/08/2023] Open
Abstract
Chronic lung diseases are the third leading cause of death worldwide and are increasing in prevalence over time. Although much of our traditional understanding of health and disease is derived from study of the male of the species - be it animal or human - there is increasing evidence that sex and gender contribute to differences in disease risk, prevalence, presentation, severity, treatment approach, response and outcomes. Chronic obstructive pulmonary disease, asthma and bronchiectasis represent the most prevalent and studied chronic lung diseases and have key sex- and gender-based differences which are critical to consider and incorporate into clinical and research approaches. Mechanistic differences present opportunities for therapeutic development whereas behavioural and clinical differences on the part of patients and providers present opportunities for greater education and understanding at multiple levels. In this review, we seek to summarise the sex- and gender-based differences in key chronic lung diseases and outline the clinical and research implications for stakeholders.
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Affiliation(s)
- Ranjani Somayaji
- Dept of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Canada .,Dept of Microbiology, Immunology and Infectious Disease, University of Calgary, Calgary, Canada.,Dept of Community Health Sciences, University of Calgary, Calgary, Canada
| | - James D Chalmers
- Division of Molecular and Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK
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Ganouna-Cohen G, Khadangi F, Marcouiller F, Bossé Y, Joseph V. Additive effects of orchiectomy and intermittent hypoxia on lung mechanics and inflammation in C57BL/6J male mice. Exp Physiol 2021; 107:68-81. [PMID: 34761830 DOI: 10.1113/ep090050] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 11/05/2021] [Indexed: 01/01/2023]
Abstract
NEW FINDINGS What is the central question of this study? Does endogenous testosterone modulate the consequences of intermittent hypoxia (IH) in the lungs of male mice? What is the main finding and its importance? Orchiectomized mice exposed to IH develop a pattern that is similar to emphysema or obstructive lung disease with elevated lung volumes, low pulmonary elastance during a methacholine challenge test and high counts of lymphocytes in bronchoalveolar lavages. Since low testosterone levels and other respiratory diseases are common in sleep apnoea, there is a clear clinical relevance to these results. ABSTRACT We tested the hypothesis that low testosterone levels modulate the pulmonary responses to intermittent hypoxia (IH; used as a model of sleep apnoea (SA)) in male mice. We used intact (SHAM) or orchiectomized (ORX) mice exposed to IH for 14 days (12 h/day, 10 cycles/h, 6% oxygen) or to normoxia (Nx). We first measured ventilation and metabolic rates in freely behaving mice (whole-body plethysmography) and then respiratory mechanics in tracheotomized mice (flexiVent). We assessed the respiratory system resistance and elastance (Ers ), Newtonian resistance (resistance of the large airways), tissue damping and tissue elastance (H) under baseline conditions and during a methacholine challenge test. We also measured the quasi-static compliance and inspiratory capacity with partial pressure-volume loops. Finally, inflammatory cells were counted in the broncho-alveolar lavage (BAL) and we measured lung volume by water displacement. ORX-IH mice had higher tidal volume, inspiratory capacity and lung volume compared to the other groups, but showed signs of low efficiency of O2 exchange rate relative to minute ventilation. During the methacholine challenge, orchiectomy decreased the values of most mechanical parameters and IH reduced Ers and H leading to very low values in ORX-IH mice. Finally, the total number of cells and the number of lymphocytes in BAL were both increased by IH in ORX mice. Since reduced lung elasticity, low O2 extraction, increased lung volumes and inflammation are signs of emphysematous lung disease, we conclude that testosterone might prevent lung emphysema during IH exposures.
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Affiliation(s)
- Gauthier Ganouna-Cohen
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie du Québec, Université Laval, Québec, QC, Canada
| | - Fatemeh Khadangi
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie du Québec, Université Laval, Québec, QC, Canada
| | - François Marcouiller
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie du Québec, Université Laval, Québec, QC, Canada
| | - Ynuk Bossé
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie du Québec, Université Laval, Québec, QC, Canada
| | - Vincent Joseph
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie du Québec, Université Laval, Québec, QC, Canada
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7
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Chiarella SE, Cardet JC, Prakash YS. Sex, Cells, and Asthma. Mayo Clin Proc 2021; 96:1955-1969. [PMID: 34218868 PMCID: PMC8262071 DOI: 10.1016/j.mayocp.2020.12.007] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 11/19/2020] [Accepted: 12/17/2020] [Indexed: 12/15/2022]
Abstract
There are marked sex differences in asthma prevalence and severity. Sex hormones play a central role in these sex biases and directly interact with multiple key cells involved in the pathogenesis of asthma. Here we review the known effects of estrogen, progesterone, and testosterone on airway epithelial cells, airway smooth muscle cells, the mononuclear phagocyte system, innate lymphoid cells, eosinophils, mast cells, T cells, and B cells, all in the context of asthma. Furthermore, we explore unresolved clinical questions, such as the role of sex hormones in the link between asthma and obesity.
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Affiliation(s)
- Sergio E Chiarella
- Division of Allergic Diseases, Department of Medicine, Mayo Clinic, Rochester, MN
| | - Juan Carlos Cardet
- Division of Allergy and Immunology, Department of Internal Medicine, University of South Florida, Tampa
| | - Y S Prakash
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN.
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Tiwari D, Gupta P. Nuclear Receptors in Asthma: Empowering Classical Molecules Against a Contemporary Ailment. Front Immunol 2021; 11:594433. [PMID: 33574813 PMCID: PMC7870687 DOI: 10.3389/fimmu.2020.594433] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 12/09/2020] [Indexed: 02/06/2023] Open
Abstract
The escalation in living standards and adoption of 'Western lifestyle' has an allied effect on the increased allergy and asthma burden in both developed and developing countries. Current scientific reports bespeak an association between allergic diseases and metabolic dysfunction; hinting toward the critical requirement of organized lifestyle and dietary habits. The ubiquitous nuclear receptors (NRs) translate metabolic stimuli into gene regulatory signals, integrating diet inflences to overall developmental and physiological processes. As a consequence of such promising attributes, nuclear receptors have historically been at the cutting edge of pharmacy world. This review discusses the recent findings that feature the cardinal importance of nuclear receptors and how they can be instrumental in modulating current asthma pharmacology. Further, it highlights a possible future employment of therapy involving dietary supplements and synthetic ligands that would engage NRs and aid in eliminating both asthma and linked comorbidities. Therefore, uncovering new and evolving roles through analysis of genomic changes would represent a feasible approach in both prevention and alleviation of asthma.
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Affiliation(s)
| | - Pawan Gupta
- Department of Molecular Biology, Council of Scientific and Industrial Research, Institute of Microbial Technology, Chandigarh, India
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9
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Increased risk of subsequent benign prostatic hyperplasia in non-Helicobacter pylori-infected peptic ulcer patients: a population-based cohort study. Sci Rep 2020; 10:21719. [PMID: 33303936 PMCID: PMC7728766 DOI: 10.1038/s41598-020-78913-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Accepted: 12/01/2020] [Indexed: 11/08/2022] Open
Abstract
The vagus nerve plays an essential role in homeostasis and inflammation. Clinically, peptic ulcer patients without helicobacter pylori (HP) infection may provide a population for studying the effect of vagal hyperactivity. There were interests in the association of gastrointestinal disease and urogenital disorders. Herein, we try to investigate subsequent risk of benign prostatic hyperplasia (BPH) in non-HP infected peptic ulcer patients. We identified 17,672 peptic ulcer admission male patients newly diagnosed in 1998-2007 from Taiwan Health Insurance Database, and 17,672 male comparison without peptic ulcer, frequency matched by age, and index-year. We assessed subsequent incidence of BPH in each cohort by the end of 2013, and then compared the risk of developing BPH between individuals with and without peptic ulcer. In addition, peptic ulcer patients underwent surgery were also examined. There were 2954 peptic ulcer patients and 2291 comparisons noted with the occurrence of BPH (25.35 and 16.70 per 1000 person-years, respectively). Compared to comparisons, peptic ulcer patients had a 1.45- and 1.26-fold BPH risk in multivariable Cox model and Fine and Gray model (95% CI 1.37-1.54 and 1.19-1.34). In age-stratified analysis, the highest risk of BPH was in 45-59 years (interaction p < 0.05). Regarding surgery types, peptic ulcer patients who underwent simple suture surgery (i.e.: with integrated vagus nerve) had a significant higher BPH risk than comparison (HR 1.50 and 95% CI 1.33-1.74; SHR 1.26 and 95% CI 1.07-1.48), while patients underwent truncal vagotomy/pyloroplasty showed a lower incidence of BPH. In this study, non-HP-infected male peptic ulcer patients were found to have an increased risk of subsequent BPH. Indicating that there might be a role of vagus nerve. Based on the limitations of retrospective nature, further studies are required.
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10
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Osgood RS, Tashiro H, Kasahara DI, Yeliseyev V, Bry L, Shore SA. Gut microbiota from androgen-altered donors alter pulmonary responses to ozone in female mice. Physiol Rep 2020; 8:e14584. [PMID: 33052618 PMCID: PMC7556311 DOI: 10.14814/phy2.14584] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 08/19/2020] [Accepted: 08/24/2020] [Indexed: 12/18/2022] Open
Abstract
In mice, both androgens and the gut microbiota modify pulmonary responses to ozone. We hypothesized that androgens affect gut microbiota and thereby impact pulmonary responses to ozone. To address this hypothesis, we transferred cecal microbiota from male castrated or sham castrated C57BL/6J mice into female germ-free recipient C57BL/6J mice. Four weeks later mice were exposed to ozone (2 ppm) or room air for 3 hr. The gut microbiomes of castrated versus sham castrated donors differed, as did those of recipients of microbiota from castrated versus sham castrated donors. In recipients, ozone-induced airway hyperresponsiveness was not affected by donor castration status. However, compared to mice receiving microbiota from sham castrated donors, mice receiving microbiota from castrated donors had elevated numbers of bronchoalveolar lavage (BAL) neutrophils despite evidence of reduced lung injury as measured by BAL protein. Serum concentrations of IL-17A and G-CSF were significantly greater in recipients of castrated versus sham castrated microbiota. Furthermore, BAL neutrophils correlated with both serum IL-17A and serum G-CSF. Our data indicate that androgen-mediated effects on the gut microbiota modulate pulmonary inflammatory responses to ozone and suggest a role for circulating IL-17A and G-CSF in these events.
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Affiliation(s)
- Ross S. Osgood
- Department of Environmental HealthHarvard T.H. Chan School of Public HealthBostonMAUSA
| | - Hiroki Tashiro
- Department of Environmental HealthHarvard T.H. Chan School of Public HealthBostonMAUSA
| | - David I. Kasahara
- Department of Environmental HealthHarvard T.H. Chan School of Public HealthBostonMAUSA
| | - Vladimir Yeliseyev
- Massachusetts Host‐Microbiome CenterDepartment of Pathology, Brigham & Women’s HospitalBostonMAUSA
| | - Lynn Bry
- Massachusetts Host‐Microbiome CenterDepartment of Pathology, Brigham & Women’s HospitalBostonMAUSA
| | - Stephanie A. Shore
- Department of Environmental HealthHarvard T.H. Chan School of Public HealthBostonMAUSA
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11
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Fuentes N, Nicoleau M, Cabello N, Montes D, Zomorodi N, Chroneos ZC, Silveyra P. 17β-Estradiol affects lung function and inflammation following ozone exposure in a sex-specific manner. Am J Physiol Lung Cell Mol Physiol 2019; 317:L702-L716. [PMID: 31553636 DOI: 10.1152/ajplung.00176.2019] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Inflammatory lung diseases affect men and women disproportionately, suggesting that fluctuations of circulating hormone levels mediate inflammatory responses. Studies have shown that ozone exposure contributes to lung injury and impairment of innate immunity with differential effects in men and women. Here, we hypothesized that 17β-estradiol enhances inflammation and airway hyperresponsiveness (AHR), triggered by ozone exposure, in the female lung. We performed gonadectomy and hormone treatment (17β-estradiol, 2 wk) in C57BL/6J female and male mice and exposed animals to 1 ppm of ozone or filtered air for 3 h. Twenty-four hours later, we tested lung function, inflammatory gene expression, and changes in bronchoalveolar lavage fluid (BALF). We found increased AHR and expression of inflammatory genes after ozone exposure. These changes were higher in females and were affected by gonadectomy and 17β-estradiol treatment in a sex-specific manner. Gonadectomized male mice displayed higher AHR and inflammatory gene expression than controls exposed to ozone; 17β-estradiol treatment did not affect this response. In females, ovariectomy reduced ozone-induced AHR, which was restored by 17β-estradiol treatment. Ozone exposure also increased BALF lipocalin-2, which was reduced in both male and female gonadectomized mice. Treatment with 17β-estradiol increased lipocalin-2 levels in females but lowered them in males. Gonadectomy also reduced ozone-induced expression of lung IL-6 and macrophage inflammatory protein-3 in females, which was restored by treatment with 17β-estradiol. Together, these results indicate that 17β-estradiol increases ozone-induced inflammation and AHR in females but not in males. Future studies examining diseases associated with air pollution exposure should consider the patient's sex and hormonal status.
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Affiliation(s)
- Nathalie Fuentes
- Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania
| | - Marvin Nicoleau
- Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania
| | - Noe Cabello
- Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania
| | - Deborah Montes
- Biobehavioral Laboratory, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Naseem Zomorodi
- Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania
| | - Zissis C Chroneos
- Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania
| | - Patricia Silveyra
- Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania.,Biobehavioral Laboratory, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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Birukova A, Cyphert-Daly J, Cumming RI, Yu YR, Gowdy KM, Que LG, Tighe RM. Sex Modifies Acute Ozone-Mediated Airway Physiologic Responses. Toxicol Sci 2019; 169:499-510. [PMID: 30825310 PMCID: PMC6542336 DOI: 10.1093/toxsci/kfz056] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Sex differences clearly exist in incidence, susceptibility, and severity of airway disease and in pulmonary responses to air pollutants such as ozone (O3). Prior rodent O3 exposure studies demonstrate sex-related differences in the expression of lung inflammatory mediators and signaling. However, whether or not sex modifies O3-induced airway physiologic responses remains less explored. To address this, we exposed 8- to 10-week-old male and female C57BL/6 mice to either 1 or 2 ppm O3 or filtered air (FA) for 3 h. At 12, 24, 48, and 72 h following exposure, we assessed airway hyperresponsiveness to methacholine (MCh), bronchoalveolar lavage fluid cellularity, cytokines and total protein/albumin, serum progesterone, and whole lung immune cells by flow cytometry. Male mice generated consistent airway hyperresponsiveness to MCh at all time points following exposure. Alternatively, females had less consistent airway physiologic responses to MCh, which were more variable between individual experiments and did not correlate with serum progesterone levels. Bronchoalveolar lavage fluid total cells peaked at 12 h and were persistently elevated through 72 h. At 48 h, bronchoalveolar lavage cells were greater in females versus males. Bronchoalveolar lavage fluid cytokines and total protein/albumin increased following O3 exposure without sex differences. Flow cytometry of whole lung tissue identified dynamic O3-induced immune cell changes also independent of sex. Our results indicate sex differences in acute O3-induced airway physiology responses and airspace influx without significant difference in other injury and inflammation measures. This study highlights the importance of considering sex as a biological variable in acute O3-induced airway physiology responses.
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Affiliation(s)
| | | | | | - Yen-Rei Yu
- Department of Medicine, Duke University, Durham, North Carolina 27710
| | - Kymberly M Gowdy
- Department of Pharmacology and Toxicology, East Carolina University, Greenville, North Carolina 27858
| | - Loretta G Que
- Department of Medicine, Duke University, Durham, North Carolina 27710
| | - Robert M Tighe
- Department of Medicine, Duke University, Durham, North Carolina 27710
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Gauderman WJ, Kim A, Conti DV, Morrison J, Thomas DC, Vora H, Lewinger JP. A Unified Model for the Analysis of Gene-Environment Interaction. Am J Epidemiol 2019; 188:760-767. [PMID: 30649161 DOI: 10.1093/aje/kwy278] [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: 07/18/2018] [Revised: 12/13/2018] [Accepted: 12/17/2018] [Indexed: 11/14/2022] Open
Abstract
Gene-environment (G × E) interaction is important for many complex traits. In a case-control study of a disease trait, logistic regression is the standard approach used to model disease as a function of a gene (G), an environmental factor (E), G × E interaction, and adjustment covariates. We propose an alternative model with G as the outcome and show how it provides a unified framework for obtaining results from all of the common G × E tests. These include the 1-degree-of-freedom (df) test of G × E interaction, the 2-df joint test of G and G × E, the case-only and empirical Bayes tests, and several 2-step tests. In the context of this unified model, we propose a novel 3-df test and demonstrate that it provides robust power across a wide range of underlying G × E interaction models. We demonstrate the 3-df test in a genome-wide scan of G × sex interaction for childhood asthma using data from the Children's Health Study (Southern California, 1993-2001). This scan identified a strong G × sex interaction at the phosphodiesterase gene 4D locus (PDE4D), a known asthma-related locus, with a strong effect in males (per-allele odds ratio = 1.70; P = 3.8 × 10-8) and virtually no effect in females. We describe a software program, G×EScan (University of Southern California, Los Angeles, California), which can be used to fit standard and unified models for genome-wide G × E studies.
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Affiliation(s)
- W James Gauderman
- Division of Biostatistics, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Andre Kim
- Division of Biostatistics, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - David V Conti
- Division of Biostatistics, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - John Morrison
- Division of Biostatistics, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Duncan C Thomas
- Division of Biostatistics, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Hita Vora
- Division of Biostatistics, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Juan Pablo Lewinger
- Division of Biostatistics, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
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14
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Wang KCW, Chang AY, Pillow JJ, Suki B, Noble PB. Transition From Phasic to Tonic Contractility in Airway Smooth Muscle After Birth: An Experimental and Computational Modeling Study. ACTA ACUST UNITED AC 2019; 2. [PMID: 31001605 DOI: 10.1115/1.4042312] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Fetal airway smooth muscle (ASM) exhibits phasic contractile behavior, which transitions to a more sustained "tonic" contraction after birth. The timing and underlying mechanisms of ASM transition from a phasic to a tonic contractile phenotype are yet to be established. We characterized phasic ASM contraction in preterm (128 day gestation), term (~150 day gestation), 1-4 month, 1 yr, and adult sheep (5yr). Spontaneous phasic activity was measured in bronchial segments as amplitude, frequency, and intensity. The mechanism of phasic ASM contraction was investigated further with a computational model of ASM force development and lumen narrowing. The computational model comprised a two-dimensional cylindrical geometry of a network of contractile units and the activation of neighboring cells was dependent on the strength of coupling between cells. As expected, phasic contractions were most prominent in fetal airways and decreased with advancing age, to a level similar to the level in the 1-4 month lambs. Computational predictions demonstrated phasic contraction through the generation of a wave of activation events, the magnitude of which is determined by the number of active cells and the strength of cell-cell interactions. Decreases in phasic contraction with advancing age were simulated by reducing cell-cell coupling. Results show that phasic activity is suppressed rapidly after birth, then sustained at a lower intensity from the preweaning phase until adulthood in an ovine developmental model. Cell-cell coupling is proposed as a key determinant of phasic ASM contraction and if reduced could explain the observed maturational changes.
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Affiliation(s)
- Kimberley C W Wang
- School of Human Sciences, The University of Western Australia, Crawley 6009, Western Australia, Australia
| | - Amy Y Chang
- School of Human Sciences, The University of Western Australia, Crawley 6009, Western Australia, Australia
| | - J Jane Pillow
- School of Human Sciences, The University of Western Australia, Crawley 6009, Western Australia, Australia
| | - Béla Suki
- Department of Biomedical Engineering, Boston University, Boston, MA 02215
| | - Peter B Noble
- School of Human Sciences, The University of Western Australia, Crawley 6009, Western Australia, Australia
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15
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Wang Y, Zu Y, Huang L, Zhang H, Wang C, Hu J. Associations between daily outpatient visits for respiratory diseases and ambient fine particulate matter and ozone levels in Shanghai, China. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2018; 240:754-763. [PMID: 29778811 DOI: 10.1016/j.envpol.2018.05.029] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 05/06/2018] [Accepted: 05/09/2018] [Indexed: 05/26/2023]
Abstract
Air pollution in China has been very serious during the recent decades. However, few studies have investigated the effects of short-term exposure to PM2.5 and O3 on daily outpatient visits for respiratory diseases. We examined the effects of PM2.5 and O3 on the daily outpatient visits for respiratory diseases, explored the sensitivities of different population subgroups and analyzed the relative risk (RR) of PM2.5 and O3 in different seasons in Shanghai during 2013-2016. The generalized linear model (GLM) was applied to analyze the exposure-response relationship between air pollutants (daily average PM2.5 and daily maximum 8-h average O3), and daily outpatient visits due to respiratory diseases. The sensitivities of males and females at the ages of 15-60 yr-old and 60+ yr-old to the pollutants were also studied for the whole year and for the cold and warm months, respectively. Finally, the results of the single-day lagged model were compared with that of the moving average lag model. At lag 0 day, the RR of respiratory outpatients increased by 0.37% with a 10 μg/m3 increase in PM2.5. Exposure to PM2.5 (RR, 1.0047, 95% CI, 1.0032-1.0062) was more sensitive for females than for males (RR, 1.0025, 95% CI, 1.0008-1.0041), and was more sensitive for the 15-60 yr-old (RR, 1.0041, 95% CI, 1.0027-1.0055) than the 60+ yr-old age group (RR, 1.0031, 95% CI, 1.0014-1.0049). O3 was not significantly associated with respiratory outpatient visits during the warm periods, but was negatively associated during the cold periods. PM2.5 was more significantly in the cold periods than that in the warm periods. The results indicated that control of PM2.5, compared to O3, in the cold periods would be more beneficial to the respiratory health in Shanghai. In addition, the single-day lagged model underestimated the relationship between PM2.5 and O3 and outpatient visits for respiratory diseases compared to the moving average lag model.
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Affiliation(s)
- Yiyi Wang
- Jiangsu Collaborative Innovation Center of Atmospheric Environment and Equipment Technology, Jiangsu Key Laboratory of Atmospheric Environment Monitoring and Pollution Control, Nanjing University of Information Science & Technology, 219 Ningliu Road, Nanjing, 210044, China
| | - Yaqun Zu
- Jiangsu Collaborative Innovation Center of Atmospheric Environment and Equipment Technology, Jiangsu Key Laboratory of Atmospheric Environment Monitoring and Pollution Control, Nanjing University of Information Science & Technology, 219 Ningliu Road, Nanjing, 210044, China
| | - Lin Huang
- Jiangsu Collaborative Innovation Center of Atmospheric Environment and Equipment Technology, Jiangsu Key Laboratory of Atmospheric Environment Monitoring and Pollution Control, Nanjing University of Information Science & Technology, 219 Ningliu Road, Nanjing, 210044, China
| | - Hongliang Zhang
- Department of Civil and Environmental Engineering, Louisiana State University, Baton Rouge, 77803, LA, USA.
| | - Changhui Wang
- Department of Respiratory Medicine, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, China
| | - Jianlin Hu
- Jiangsu Collaborative Innovation Center of Atmospheric Environment and Equipment Technology, Jiangsu Key Laboratory of Atmospheric Environment Monitoring and Pollution Control, Nanjing University of Information Science & Technology, 219 Ningliu Road, Nanjing, 210044, China.
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16
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Han MM, Xue FS, Kang F, Huang X, Li J. Male requires a higher median target effect-site concentration of propofol for I-gel placement when combined with dexmedetomidine. Anaesth Crit Care Pain Med 2018; 38:57-61. [PMID: 29452333 DOI: 10.1016/j.accpm.2018.01.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Revised: 12/10/2017] [Accepted: 01/21/2018] [Indexed: 11/28/2022]
Abstract
OBJECTIVE The supraglottic airway device (SAD) can be used for airway management of spontaneous breathing patients, and propofol is commonly applied for the SAD placement. This study was designed to assess the effect of gender on median target effect-site concentration (Ce50) of propofol for I-gel placement when combined with dexmedetomidine. MATERIAL AND METHOD 19 males and 18 females, aged 18 to 59 and undergoing elective surgery, were enrolled. After intravenous infusion of dexmedetomidine 1.0μg/kg over 10min followed by continuous infusion of 0.4μg/kg/h, target-controlled infusion of propofol under Marsh model was started and the initial Ce of propofol was set at 4.79μg/mL and 4.35μg/mL in the male and female patients, respectively. The I-gel was inserted when the Ce of propofol reached the pre-set concentration and bispectral index value was less than 60. The Ce of propofol required for I-gel placement was determined by the Dixon up-and-down method. RESULTS The Ce50 (95% confidence interval) of propofol required for I-gel placement were 4.082μg/mL (3.798-4.332μg/mL) and 3.509μg/mL (3.266-3.749μg/mL) in male and female patients, respectively, with a significantly higher Ce50 in males. CONCLUSION When combined with dexmedetomidine, males require a higher Ce50 of propofol for I-gel placement compared to females.
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Affiliation(s)
- M-M Han
- Department of Anaesthesiology, Anhui Provincial Hospital, Anhui Medical University, Hefei, China.
| | - F-S Xue
- Department of Anaesthesiology, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - F Kang
- Department of Anaesthesiology, Anhui Provincial Hospital, Anhui Medical University, Hefei, China.
| | - X Huang
- Department of Anaesthesiology, Anhui Provincial Hospital, Anhui Medical University, Hefei, China.
| | - J Li
- Department of Anaesthesiology, Anhui Provincial Hospital, Anhui Medical University, Hefei, China.
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17
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Yung JA, Fuseini H, Newcomb DC. Hormones, sex, and asthma. Ann Allergy Asthma Immunol 2018; 120:488-494. [PMID: 29410216 DOI: 10.1016/j.anai.2018.01.016] [Citation(s) in RCA: 135] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 12/22/2017] [Accepted: 01/12/2018] [Indexed: 11/24/2022]
Abstract
OBJECTIVE To summarize the current literature on the sex disparity in asthma and the role of sex hormone signaling in allergic and neutrophilic airway inflammation. DATA SOURCES PubMed and Centers for Disease Control and Prevention health surveys were searched. STUDY SELECTIONS Clinical and epidemiologic studies in children and adults as well as animal models of asthma were included in this review. RESULTS Compared with males, females have an increase in asthma prevalence starting around puberty, and fluctuations in hormones during menstruation, pregnancy, and menopause are associated with changes in asthma symptoms. Animal studies using genetic deletions of estrogen receptors or androgen receptors have shown that estrogen signaling promotes and androgen signaling attenuates allergen-mediated type 2 airway inflammation. Furthermore, animal studies have found that ovarian hormones are important for interleukin 17A-mediated airway inflammation. CONCLUSION Sex hormones are important in regulating asthma pathogenesis. However, additional studies need to be conducted to further elucidate how sex hormones are initiating and driving the inflammatory response(s) in asthma. Determining these pathways will provide the foundation necessary for the development of treatment strategies and potentially new therapeutics for patients, in particular females, with asthma.
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Affiliation(s)
- Jeffrey A Yung
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Hubaida Fuseini
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Dawn C Newcomb
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
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18
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Abstract
PURPOSE OF REVIEW Many phenotypes of asthma exist, ranging from mild asthma with onset during childhood to severe asthma with later onset, making asthma a broad disease with different pathologies. A gender disparity exists in asthma prevalence. As adults, women have an increased asthma prevalence compared to men. Further, women are more likely to have severe asthma and a later onset of asthma compared to men. Here, we review clinical and animal studies that have defined the role of sex hormones in airway inflammation, smooth muscle contraction, mucus production, and airway mechanics associated with asthma pathogenesis. RECENT FINDINGS Clinical evidence shows that increased asthma symptoms occur in females starting at puberty compared to those in boys. However, after puberty, the role for sex hormones in regulating asthma symptoms during menstruation, pregnancy, and menopause is not as clear. Animal studies have shown that estrogen increases and testosterone decreases Th2-mediated airway inflammation, and that females have increased IL-17A-mediated airway inflammation compared to males. Further, females had increased DC and Mϕ function compared to males. However, the mechanisms driving the types of allergic inflammation are not fully elucidated. Overall, ovarian hormones increased and testosterone decreased airway inflammation in asthma, but the mechanisms remain unclear. Delineating these pathways using animal models as well as women and men with various phenotypes of asthma will help determine if women with asthma should take (or avoid) hormonal contraceptives as well as predict changes in asthma symptoms during life phases, including pregnancy and menopause, when sex hormones are dramatically changing.
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19
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Lin TY, Lin PY, Su TP, Li CT, Lin WC, Chang WH, Chen TJ, Bai YM, Chen MH. Risk of developing obstructive sleep apnea among women with polycystic ovarian syndrome: a nationwide longitudinal follow-up study. Sleep Med 2017; 36:165-169. [PMID: 28599952 DOI: 10.1016/j.sleep.2016.12.029] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Revised: 12/22/2016] [Accepted: 12/23/2016] [Indexed: 01/22/2023]
Abstract
BACKGROUND Previous cross-sectional studies have suggested a comorbid relationship between polycystic ovarian syndrome (PCOS) and obstructive sleep apnea (OSA). However, the temporal association between these two distinct diseases has not yet been investigated. METHODS Using the Taiwan National Health Insurance Research Database, 4595 women with PCOS and 4595 (1:1) age-/sex-matched controls were enrolled into the present study between 1998 and 2009, and followed to the end of 2011. Those who developed OSA during the follow-up were identified. RESULTS Women with PCOS had a greater incidence of developing OSA (1.71 vs 0.63 1000 person-years, p < 0.001) than those without PCOS. The Cox regression analysis after adjusting for demographic data and medical comorbidities showed that women with PCOS had an elevated likelihood of subsequent OSA (hazard ratio: 2.63, 95% CI 1.57-4.04) during the follow-up compared to the controls. DISCUSSION Women with PCOS were associated with an increased risk of developing OSA in later life. Further studies would be required to investigate the underlying pathophysiology between PCOS and OSA, and to clarify whether prompt intervention for PCOS would reduce the risk of OSA.
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Affiliation(s)
- Ting-Yang Lin
- Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Pei-Yin Lin
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Tung-Ping Su
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Psychiatry, College of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Cheng-Ta Li
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Psychiatry, College of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Wei-Chen Lin
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Psychiatry, College of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Wen-Hang Chang
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Tzeng-Ji Chen
- Department of Family Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Hospital and Health Care Administration, National Yang-Ming University, Taipei, Taiwan
| | - Ya-Mei Bai
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Psychiatry, College of Medicine, National Yang-Ming University, Taipei, Taiwan.
| | - Mu-Hong Chen
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Psychiatry, College of Medicine, National Yang-Ming University, Taipei, Taiwan.
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20
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House JS, Nichols CE, Li H, Brandenberger C, Virgincar RS, DeGraff LM, Driehuys B, Zeldin DC, London SJ. Vagal innervation is required for pulmonary function phenotype in Htr4-/- mice. Am J Physiol Lung Cell Mol Physiol 2017; 312:L520-L530. [PMID: 28130264 PMCID: PMC5407097 DOI: 10.1152/ajplung.00495.2016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Revised: 01/19/2017] [Accepted: 01/25/2017] [Indexed: 11/22/2022] Open
Abstract
Human genome-wide association studies have identified over 50 loci associated with pulmonary function and related phenotypes, yet follow-up studies to determine causal genes or variants are rare. Single nucleotide polymorphisms in serotonin receptor 4 (HTR4) are associated with human pulmonary function in genome-wide association studies and follow-up animal work has demonstrated that Htr4 is causally associated with pulmonary function in mice, although the precise mechanisms were not identified. We sought to elucidate the role of neural innervation and pulmonary architecture in the lung phenotype of Htr4-/- animals. We report here that the Htr4-/- phenotype in mouse is dependent on vagal innervation to the lung. Both ex vivo tracheal ring reactivity and in vivo flexiVent pulmonary functional analyses demonstrate that vagotomy abrogates the Htr4-/- airway hyperresponsiveness phenotype. Hyperpolarized 3He gas magnetic resonance imaging and stereological assessment of wild-type and Htr4-/- mice reveal no observable differences in lung volume, inflation characteristics, or pulmonary microarchitecture. Finally, control of breathing experiments reveal substantive differences in baseline breathing characteristics between mice with/without functional HTR4 in breathing frequency, relaxation time, flow rate, minute volume, time of inspiration and expiration and breathing pauses. These results suggest that HTR4's role in pulmonary function likely relates to neural innervation and control of breathing.
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Affiliation(s)
- John S House
- Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
| | - Cody E Nichols
- Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
| | - Huiling Li
- Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
| | | | - Rohan S Virgincar
- Center for In Vivo Microscopy, Duke University Medical Center, Durham, North Carolina.,Biomedical Engineering, Duke University, Durham, North Carolina
| | - Laura M DeGraff
- Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
| | - Bastiaan Driehuys
- Center for In Vivo Microscopy, Duke University Medical Center, Durham, North Carolina.,Biomedical Engineering, Duke University, Durham, North Carolina.,Radiology, Duke University Medical Center, Durham, North Carolina; and
| | - Darryl C Zeldin
- Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
| | - Stephanie J London
- Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina; .,Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
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21
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Prakash YS. Emerging concepts in smooth muscle contributions to airway structure and function: implications for health and disease. Am J Physiol Lung Cell Mol Physiol 2016; 311:L1113-L1140. [PMID: 27742732 DOI: 10.1152/ajplung.00370.2016] [Citation(s) in RCA: 104] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Accepted: 10/06/2016] [Indexed: 12/15/2022] Open
Abstract
Airway structure and function are key aspects of normal lung development, growth, and aging, as well as of lung responses to the environment and the pathophysiology of important diseases such as asthma, chronic obstructive pulmonary disease, and fibrosis. In this regard, the contributions of airway smooth muscle (ASM) are both functional, in the context of airway contractility and relaxation, as well as synthetic, involving production and modulation of extracellular components, modulation of the local immune environment, cellular contribution to airway structure, and, finally, interactions with other airway cell types such as epithelium, fibroblasts, and nerves. These ASM contributions are now found to be critical in airway hyperresponsiveness and remodeling that occur in lung diseases. This review emphasizes established and recent discoveries that underline the central role of ASM and sets the stage for future research toward understanding how ASM plays a central role by being both upstream and downstream in the many interactive processes that determine airway structure and function in health and disease.
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Affiliation(s)
- Y S Prakash
- Departments of Anesthesiology, and Physiology & Biomedical Engineering, Mayo Clinic, Rochester, Minnesota
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22
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Joe HB, Kim JY, Kwak HJ, Oh SE, Lee SY, Park SY. Effect of sex differences in remifentanil requirements for the insertion of a laryngeal mask airway during propofol anesthesia: A prospective randomized trial. Medicine (Baltimore) 2016; 95:e5032. [PMID: 27684878 PMCID: PMC5265971 DOI: 10.1097/md.0000000000005032] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Remifentanil can improve insertion of a laryngeal mask airway (LMA) during induction with propofol. Recently, it has been suggested that there is a sex difference in opioid requirements for this procedure. The purposes of this study were to determine the effective effect-site concentration (Ce) of remifentanil for the facilitation of LMA insertion in male and female patients during propofol anesthesia without neuromuscular blockade and to evaluate whether there are sex differences in the Ce of remifentanil required for successful LMA insertion. METHODS Forty-eight patients (24 male, 24 female) with American Society of Anesthesiologists physical status 1 or 2, aged 20 to 60 years, scheduled for minor orthopedic surgery under general anesthesia were enrolled. Anesthesia was induced by target-controlled infusion (TCI) of propofol and remifentanil. The target Ce of propofol was 5 μg/mL initially and was reduced to 3.5 μg/mL after loss of consciousness. The Ce of remifentanil given to each patient was determined by the response of the previously tested patient using 0.5 ng/mL as a step size. The 1st patient was tested at a Ce of 3.0 ng/mL of remifentanil. Successful LMA insertion was defined as smooth insertion without patient movement or significant resistance to mouth opening. RESULTS The effective Ce of remifentanil required for successful LMA insertion on 50% of occasions (effective effect-site concentration for 50% [EC50]) as estimated by Dixon method was significantly lower in women (2.18 ± 0.35 ng/mL) than in men (2.82 ± 0.53 ng/mL) (P = 0.02). Using the isotonic regression method, the effective Ce of remifentanil required for successful LMA insertion on 95% of occasions (EC95) (95% confidence interval [CI]) was significantly lower in women (3.38 [3.0-3.48] ng/mL) than in men (3.94 [3.80-3.98] ng/mL). CONCLUSION The Ce of remifentanil required to facilitate successful LMA insertion is higher during propofol induction by TCI in men than in women. When using remifentanil for LMA insertion, patient sex should be taken into account for appropriate dosing.
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Affiliation(s)
- Han Bum Joe
- Department of Anesthesiology and Pain Medicine, Ajou University School of Medicine, World Cup-ro, Yeongtong-gu, Suwon
| | - Jong Yeop Kim
- Department of Anesthesiology and Pain Medicine, Ajou University School of Medicine, World Cup-ro, Yeongtong-gu, Suwon
| | - Hyun Jeong Kwak
- Department of Anesthesiology and Pain Medicine, Gachon University, Gil Medical Center, Namdong-gu, Incheon, Republic of Korea
| | - Sang Eon Oh
- Department of Anesthesiology and Pain Medicine, Ajou University School of Medicine, World Cup-ro, Yeongtong-gu, Suwon
| | - Sook Young Lee
- Department of Anesthesiology and Pain Medicine, Ajou University School of Medicine, World Cup-ro, Yeongtong-gu, Suwon
| | - Sung Yong Park
- Department of Anesthesiology and Pain Medicine, Ajou University School of Medicine, World Cup-ro, Yeongtong-gu, Suwon
- Correspondence: Sung Yong Park, Department of Anesthesiology and Pain Medicine, Ajou University School of Medicine, 164, World Cup-ro, Yeongtong-gu, Suwon 16499, Republic of Korea (e-mail: )
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23
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Choi JJ, Kim JY, Lee D, Chang YJ, Cho NR, Kwak HJ. Male patients require higher optimal effect-site concentrations of propofol during i-gel insertion with dexmedetomidine 0.5 μg/kg. BMC Anesthesiol 2016; 16:20. [PMID: 27004426 PMCID: PMC4804608 DOI: 10.1186/s12871-016-0186-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 03/18/2016] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The pharmacokinetics and pharmacodynamics of an anesthetic drug may be influenced by gender. The purpose of this study was to compare effect-site half maximal effective concentrations (EC50) of propofol in male and female patients during i-gel insertion with dexmedetomidine 0.5 μg/kg without muscle relaxants. METHODS Forty patients, aged 20-46 years of ASA physical status I or II, were allocated to one of two groups by gender (20 patients per group). After the infusion of dexmedetomidine 0.5 μg/kg over 2 min, anesthesia was induced with a pre-determined effect-site concentration of propofol by target controlled infusion. Effect-site EC50 values of propofol for successful i-gel insertion were determined using the modified Dixon's up-and-down method. RESULTS Mean effect-site EC50 ± SD of propofol for successful i-gel insertion was significantly higher for men than women (5.46 ± 0.26 μg/ml vs. 3.82 ± 0.34 μg/ml, p < 0.01). The EC50 of propofol in men was approximately 40% higher than in women. Using isotonic regression with a bootstrapping approach, the estimated EC50 (95% confidence interval) of propofol was also higher in men [5.32 (4.45-6.20) μg/ml vs. 3.75 (3.05-4.43) μg/ml]. The estimated EC95 (95% confidence interval) of propofol in men and women were 5.93 (4.72-6.88) μg/ml and 4.52 (3.02-5.70) μg/ml, respectively. CONCLUSIONS During i-gel insertion with dexmedetomidine 0.5 μg/kg without muscle relaxant, male patients had higher effect-site EC50 for propofol using Schnider's model. Based on the results of this study, patient gender should be considered when determining the optimal dose of propofol during supraglottic airway insertion. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02268656. Registered August 26, 2014.
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Affiliation(s)
- Jung Ju Choi
- Department of Anesthesiology and Pain Medicine, Gachon University, Gil Medical Center, 1198 Guwol-dong, Namdong-gu, Incheon, 405-760, Republic of Korea
| | - Ji Young Kim
- Department of Anesthesiology and Pain Medicine, Anesthesiology and Pain Research Institute, Yonsei University College of Medicine, Seoul, South Korea
| | - Dongchul Lee
- Department of Anesthesiology and Pain Medicine, Gachon University, Gil Medical Center, 1198 Guwol-dong, Namdong-gu, Incheon, 405-760, Republic of Korea
| | - Young Jin Chang
- Department of Anesthesiology and Pain Medicine, Gachon University, Gil Medical Center, 1198 Guwol-dong, Namdong-gu, Incheon, 405-760, Republic of Korea
| | - Noo Ree Cho
- Department of Anesthesiology and Pain Medicine, Gachon University, Gil Medical Center, 1198 Guwol-dong, Namdong-gu, Incheon, 405-760, Republic of Korea
| | - Hyun Jeong Kwak
- Department of Anesthesiology and Pain Medicine, Gachon University, Gil Medical Center, 1198 Guwol-dong, Namdong-gu, Incheon, 405-760, Republic of Korea.
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Mukudai S, Ichi Matsuda K, Bando H, Takanami K, Nishio T, Sugiyama Y, Hisa Y, Kawata M. Expression of Sex Steroid Hormone Receptors in Vagal Motor Neurons Innervating the Trachea and Esophagus in Mouse. Acta Histochem Cytochem 2016; 49:37-46. [PMID: 27006520 PMCID: PMC4794553 DOI: 10.1267/ahc.15037] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Accepted: 01/22/2016] [Indexed: 12/11/2022] Open
Abstract
The medullary vagal motor nuclei, the nucleus ambiguus (NA) and dorsal motor nucleus of the vagus (DMV), innervate the respiratory and gastrointestinal tracts. We conducted immunohistochemical analysis of expression of the androgen receptor (AR) and estrogen receptor α (ERα), in relation to innervation of the trachea and esophagus via vagal motor nuclei in mice. AR and ERα were expressed in the rostral NA and in part of the DMV. Tracing experiments using cholera toxin B subunit demonstrated that neurons of vagal motor nuclei that innervate the trachea and esophagus express AR and ERα. There was no difference in expression of sex steroid hormone receptors between trachea- and esophagus-innervating neurons. These results suggest that sex steroid hormones may act on vagal motor nuclei via their receptors, thereby regulating functions of the trachea and esophagus.
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Affiliation(s)
- Shigeyuki Mukudai
- Department of Anatomy and Neurobiology, Kyoto Prefectural University of Medicine
- Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine
- Department of Otolaryngology-Bronchoesophagology, Kyoto Second Red Cross Hospital
| | - Ken Ichi Matsuda
- Department of Anatomy and Neurobiology, Kyoto Prefectural University of Medicine
| | - Hideki Bando
- Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine
| | - Keiko Takanami
- Department of Anatomy and Neurobiology, Kyoto Prefectural University of Medicine
- Ushimado Marine Institute, Graduate School of Natural Science and Technology, Okayama University
| | - Takeshi Nishio
- Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine
| | - Yoichiro Sugiyama
- Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine
| | - Yasuo Hisa
- Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine
- Faculty of Health and Medical Sciences, Kyoto Gakuen University
| | - Mitsuhiro Kawata
- Department of Anatomy and Neurobiology, Kyoto Prefectural University of Medicine
- School of Health Sciences, Bukkyo University
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Sathish V, Prakash Y. Sex Differences in Pulmonary Anatomy and Physiology. SEX DIFFERENCES IN PHYSIOLOGY 2016:89-103. [DOI: 10.1016/b978-0-12-802388-4.00006-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
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Carroll WW, O'Connell BP, Schlosser RJ, Gudis DA, Karnezis TT, Lawrence LA, Soler ZM, Mulligan JK. Fibroblast levels are increased in chronic rhinosinusitis with nasal polyps and are associated with worse subjective disease severity. Int Forum Allergy Rhinol 2015; 6:162-8. [DOI: 10.1002/alr.21636] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Revised: 07/24/2015] [Accepted: 08/04/2015] [Indexed: 12/18/2022]
Affiliation(s)
- William W. Carroll
- Department of Otolaryngology-Head and Neck Surgery; Medical University of South Carolina; Charleston SC
| | - Brendan P. O'Connell
- Department of Otolaryngology-Head and Neck Surgery; Medical University of South Carolina; Charleston SC
| | - Rodney J. Schlosser
- Department of Otolaryngology-Head and Neck Surgery; Medical University of South Carolina; Charleston SC
- Ralph H. Johnson VA Medical Center; Charleston SC
| | - David A. Gudis
- Department of Otolaryngology-Head and Neck Surgery; Medical University of South Carolina; Charleston SC
| | - Tom T. Karnezis
- Department of Otolaryngology-Head and Neck Surgery; Medical University of South Carolina; Charleston SC
| | - Lauren A. Lawrence
- Department of Otolaryngology-Head and Neck Surgery; Medical University of South Carolina; Charleston SC
| | - Zachary M. Soler
- Department of Otolaryngology-Head and Neck Surgery; Medical University of South Carolina; Charleston SC
| | - Jennifer K. Mulligan
- Department of Otolaryngology-Head and Neck Surgery; Medical University of South Carolina; Charleston SC
- Ralph H. Johnson VA Medical Center; Charleston SC
- Department of Pediatrics; Medical University of South Carolina; Charleston SC
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Mendes PR, Kiyota TA, Cipolli JA, Schreiber R, Paim LR, Bellinazzi VR, Matos-Souza JR, Sposito AC, Nadruz W. Gender influences the relationship between lung function and cardiac remodeling in hypertensive subjects. Hypertens Res 2014; 38:264-8. [PMID: 25427680 DOI: 10.1038/hr.2014.168] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2014] [Revised: 10/01/2014] [Accepted: 10/10/2014] [Indexed: 11/10/2022]
Abstract
Hypertensive patients are predisposed to left ventricular (LV) remodeling and frequently exhibit decline in lung function as compared with the general population. Here, we investigated the association between spirometric and echocardiographic data in non-smoking hypertensive subjects and the role of gender in this regard. In a cross-sectional study, 107 hypertensive patients (60 women) enrolled from a university outpatient clinic were evaluated by clinical, hemodynamic, laboratory and echocardiographic analysis. Vital capacity, forced vital capacity (FVC), forced expired volume in 1 s (FEV1) and in 6 s (FEV6), FEV1/FVC ratio and FEV1/FEV6 ratio were estimated by spirometry. In women, higher LV mass index and E/Em ratio correlated with markers of restrictive lung alterations, such as reduced FVC (r=-044; P<0.001; r=-0.42; P<0.001, respectively) and FEV6 (r=-0.43; P<0.001; r=-0.39; P<0.01, respectively), while higher left atrial volume index correlated with markers of obstructive lung alterations, such as reduced FEV1/FVC (r=-055; P<0.001) and FEV1/FEV6 (r=-0.45; P<0.001) ratios. These relationships were further confirmed by stepwise regression analysis adjusted for potential confounders. In men, LV mass index correlated with FVC and FEV6, but these associations did not remain statistically significant after adjustment for confounding variables. Furthermore, inflammatory markers such as plasma C-reactive protein and matrix-metalloproteinases-2 and -9 levels did not influence the association between spirometric and cardiac parameters. In conclusion, these results indicate that LV remodeling is related to restrictive lung alterations while left atrial remodeling is associated with obstructive lung alterations in hypertensive women.
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Affiliation(s)
- Paulo R Mendes
- Department of Internal Medicine, School of Medical Sciences, University of Campinas, São Paulo, Brazil
| | - Tatiana A Kiyota
- Department of Internal Medicine, School of Medical Sciences, University of Campinas, São Paulo, Brazil
| | - José A Cipolli
- Department of Internal Medicine, School of Medical Sciences, University of Campinas, São Paulo, Brazil
| | - Roberto Schreiber
- Department of Internal Medicine, School of Medical Sciences, University of Campinas, São Paulo, Brazil
| | - Layde R Paim
- Department of Internal Medicine, School of Medical Sciences, University of Campinas, São Paulo, Brazil
| | - Vera R Bellinazzi
- Department of Internal Medicine, School of Medical Sciences, University of Campinas, São Paulo, Brazil
| | - José R Matos-Souza
- Department of Internal Medicine, School of Medical Sciences, University of Campinas, São Paulo, Brazil
| | - Andrei C Sposito
- Department of Internal Medicine, School of Medical Sciences, University of Campinas, São Paulo, Brazil
| | - Wilson Nadruz
- Department of Internal Medicine, School of Medical Sciences, University of Campinas, São Paulo, Brazil
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Abstract
Asthma is a prevalent respiratory disorder triggered by a variety of inhaled environmental factors, such as allergens, viruses, and pollutants. Asthma is characterized by an elevated activation of the smooth muscle surrounding the airways, as well as a propensity of the airways to narrow excessively in response to a spasmogen (i.e. contractile agonist), a feature called airway hyperresponsiveness. The level of airway smooth muscle (ASM) activation is putatively controlled by mediators released in its vicinity. In asthma, many mediators that affect ASM contractility originate from inflammatory cells that are mobilized into the airways, such as eosinophils. However, mounting evidence indicates that mediators released by remote organs can also influence the level of activation of ASM, as well as its level of responsiveness to spasmogens and relaxant agonists. These remote mediators are transported through circulating blood to act either directly on ASM or indirectly via the nervous system by tuning the level of cholinergic activation of ASM. Indeed, mediators generated from diverse organs, including the adrenals, pancreas, adipose tissue, gonads, heart, intestines, and stomach, affect the contractility of ASM. Together, these results suggest that, apart from a paracrine mode of regulation, ASM is subjected to an endocrine mode of regulation. The results also imply that defects in organs other than the lungs can contribute to asthma symptoms and severity. In this review, I suggest that the endocrine mode of regulation of ASM contractility is overlooked.
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Affiliation(s)
- Ynuk Bossé
- Institut Universitaire de Cardiologie et de Pneumologie de QuébecUniversité Laval, Québec, Québec, Canada G1V 4G5
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Taillé C, Raherison C, Sobaszek A, Thumerelle C, Prudhomme A, Biron E, Nocent C, Tillie-Leblond I. [Features of asthma in women: what is the relationship with hormonal status?]. Rev Mal Respir 2014; 31:469-77. [PMID: 25012033 DOI: 10.1016/j.rmr.2014.02.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2013] [Accepted: 12/31/2013] [Indexed: 11/29/2022]
Abstract
INTRODUCTION The prevalence and control of asthma are modulated by hormonal changes in women, suggesting an influence of sex hormones on the airways. BACKGROUND The blood levels of both oestrogens and progesterone can modulate airway tone and inflammation. Asthma prevalence changes at puberty and the menopause, events also associated with modifications of adipose tissue and behaviour. Changes in lung function and asthma control are well documented during the menstrual cycle. However, an effect of hormone therapy on asthma control has not been demonstrated. PERSPECTIVE The effect of a targeted hormonal therapeutic intervention in menopausal asthma, a phenotype, which is frequently particularly severe, or in premenstrual asthma, should be evaluated by randomized trials. CONCLUSION Involvement of sex hormones and their cyclical variations in the characteristics of asthma in women is probable, despite lack of convincing data. However, no definitive protective or deleterious effect can be assigned. Complex interactions with adipose tissue, airways anatomy and the domestic or working environment must be taken into account to explain these differences.
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Affiliation(s)
- C Taillé
- Inserm U700, service de pneumologie, département hospitalo-universitaire FIRE, centre de compétence des maladies pulmonaires rares, hôpital Bichat, université Paris Diderot, AP-HP, 46, rue Henri-Huchard, 75877 Paris cedex, France.
| | - C Raherison
- U897 ISPED, service des maladies respiratoires, CHU de Bordeaux, université Bordeaux Segalen, 33076 Bordeaux, France
| | - A Sobaszek
- Service de médecine du travail et pathologies professionnelles, CHRU de Lille, 59000 Lille, France
| | - C Thumerelle
- Unité de pneumologie pédiatrique, hôpital Jeanne-de-Flandre, CHRU de Lille, 59000 Lille, France
| | - A Prudhomme
- Service de pneumologie, CHG de Bigorre, 65000 Tarbes, France
| | - E Biron
- Hôpital privé Jean-Mermoz, 69008 Lyon, France
| | - C Nocent
- Service de pneumologie, centre hospitalier de la Côte Basque, 64100 Bayonne, France
| | - I Tillie-Leblond
- Inserm U1019, service de pneumologie et d'immuno-allergologie, institut Pasteur de Lille, hôpital Calmette, université de Lille-2, CHRU, 59000 Lille, France
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Prakash YS. Airway smooth muscle in airway reactivity and remodeling: what have we learned? Am J Physiol Lung Cell Mol Physiol 2013; 305:L912-33. [PMID: 24142517 PMCID: PMC3882535 DOI: 10.1152/ajplung.00259.2013] [Citation(s) in RCA: 159] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2013] [Accepted: 10/12/2013] [Indexed: 12/12/2022] Open
Abstract
It is now established that airway smooth muscle (ASM) has roles in determining airway structure and function, well beyond that as the major contractile element. Indeed, changes in ASM function are central to the manifestation of allergic, inflammatory, and fibrotic airway diseases in both children and adults, as well as to airway responses to local and environmental exposures. Emerging evidence points to novel signaling mechanisms within ASM cells of different species that serve to control diverse features, including 1) [Ca(2+)]i contractility and relaxation, 2) cell proliferation and apoptosis, 3) production and modulation of extracellular components, and 4) release of pro- vs. anti-inflammatory mediators and factors that regulate immunity as well as the function of other airway cell types, such as epithelium, fibroblasts, and nerves. These diverse effects of ASM "activity" result in modulation of bronchoconstriction vs. bronchodilation relevant to airway hyperresponsiveness, airway thickening, and fibrosis that influence compliance. This perspective highlights recent discoveries that reveal the central role of ASM in this regard and helps set the stage for future research toward understanding the pathways regulating ASM and, in turn, the influence of ASM on airway structure and function. Such exploration is key to development of novel therapeutic strategies that influence the pathophysiology of diseases such as asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis.
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Affiliation(s)
- Y S Prakash
- Dept. of Anesthesiology, Mayo Clinic, 4-184 W Jos SMH, 200 First St. SW, Rochester, MN 55905.
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Zhuang J, Bailet D, Curtis R, Xu F. High-frequency electrical stimulation of cervical vagi reduces airway response to methacholine. World J Respirol 2013; 3:11-19. [DOI: 10.5320/wjr.v3.i2.11] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2013] [Revised: 05/15/2013] [Accepted: 06/19/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To test whether high-frequency electrical stimulation (HES) of the bilateral cervical vagus nerves reduces the airway responses to methacholine (MCh).
METHODS: Guinea pigs were pretreated with saline (Sal, n = 9) or ovalbumin (Ova, n = 10) aerosol for two weeks (5 min/d, 5 d/wk) and subsequently anesthetized, paralyzed, tracheotomized and artificially ventilated. Both total lung resistance (RL) and dynamic pulmonary compliance (Cdyn) were recorded. In addition, the effects of vagal low-frequency electrical stimulation (LES, monophasic, 50 Hz) and HES (monophasic and biphasic, 1 and 2.5 kHz) for about 10 s or 2 min on the responses of RL and Cdyn to MCh aerosol-induced bronchoconstriction were compared in both groups of guinea pigs. In a few guinea pigs, the impact of bivagotomy on the RL responses to MCh was assessed.
RESULTS: Before MCh challenge, LES, but not HES, significantly increased RL by about 30% (P < 0.01) and decreased Cdyn by about 20% (P < 0.01) similarly in both groups. MCh aerosol for 2 min elevated RL and diminished Cdyn more in Ova- than Sal-treated animals (RL: 313% ± 52% vs 113% ± 17%, P < 0.01; Cdyn: -56% ± 7% vs -21% ± 3%, P < 0.01). During MCh-induced airway constriction, LES further enhanced, but HES decreased RL and this decrease was greater in Ova- (about 45%) than Sal-treated animals (about 34%, P < 0.01) with little change in cardiovascular activity. On the other hand, LES further reduced whereas HES increased Cdyn more in Ova- (about 20%) than Sal-treated animals (about 13%, P < 0.01). In addition, bivagotomy almost eliminated the RL and Cdyn responses to MCh.
CONCLUSION: We conclude that vagal HES is able to alleviate the bronchoconstriction induced by MCh in anesthetized guinea pigs, likely via reversible inhibition/blockade of vagal conduction.
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Abstract
Sex differences in the biology of different organ systems and the influence of sex hormones in modulating health and disease are increasingly relevant in clinical and research areas. Although work has focused on sex differences and sex hormones in cardiovascular, musculoskeletal, and neuronal systems, there is now increasing clinical evidence for sex differences in incidence, morbidity, and mortality of lung diseases including allergic diseases (such as asthma), chronic obstructive pulmonary disease, pulmonary fibrosis, lung cancer, as well as pulmonary hypertension. Whether such differences are inherent and/or whether sex steroids play a role in modulating these differences is currently under investigation. The purpose of this review is to define sex differences in lung structure/function under normal and specific disease states, with exploration of whether and how sex hormone signaling mechanisms may explain these clinical observations. Focusing on adult age groups, the review addresses the following: 1) inherent sex differences in lung anatomy and physiology; 2) the importance of certain time points in life such as puberty, pregnancy, menopause, and aging; 3) expression and signaling of sex steroid receptors under normal vs. disease states; 4) potential interplay between different sex steroids; 5) the question of whether sex steroids are beneficial or detrimental to the lung; and 6) the potential use of sex steroid signaling as biomarkers and therapeutic avenues in lung diseases. The importance of focusing on sex differences and sex steroids in the lung lies in the increasing incidence of lung diseases in women and the need to address lung diseases across the life span.
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Affiliation(s)
- Elizabeth A Townsend
- Department of Physiology and Biomedical Engineering, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
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Larcombe AN, Foong RE, Bozanich EM, Berry LJ, Garratt LW, Gualano RC, Jones JE, Dousha LF, Zosky GR, Sly PD. Sexual dimorphism in lung function responses to acute influenza A infection. Influenza Other Respir Viruses 2011; 5:334-42. [PMID: 21668688 PMCID: PMC4942045 DOI: 10.1111/j.1750-2659.2011.00236.x] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Please cite this paper as: Larcombe et al. (2011) Sexual dimorphism in lung function responses to acute influenza A infection. Influenza and Other Respiratory Viruses 5(5), 334–342. Background Males are generally more susceptible to respiratory infections; however, there are few data on the physiological responses to such infections in males and females. Objectives To determine whether sexual dimorphism exists in the physiological/inflammatory responses of weanling and adult BALB/c mice to influenza. Methods Weanling and adult mice of both sexes were inoculated with influenza A or appropriate control solution. Respiratory mechanics, responsiveness to methacholine (MCh), viral titre and bronchoalveolar lavage (BAL) cellular inflammation/cytokines were measured 4 (acute) and 21 (resolution) days post‐inoculation. Results Acute infection impaired lung function and induced hyperresponsiveness and cellular inflammation in both sexes at both ages. Males and females responded differently with female mice developing greater abnormalities in tissue damping and elastance and greater MCh responsiveness at both ages. BAL inflammation, cytokines and lung viral titres were similar between the sexes. At resolution, all parameters had returned to baseline levels in adults and weanling males; however, female weanlings had persisting hyperresponsiveness. Conclusions We identified significant differences in the physiological responses of male and female mice to infection with influenza A, which occurred in the absence of variation in viral titre and cellular inflammation.
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Affiliation(s)
- Alexander N Larcombe
- Division of Clinical Sciences, Telethon Institute for Child Health Research, Centre for Child Health Research, University of Western Australia, West Perth, WA, Australia.
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Antunes MA, Abreu SC, Silva AL, Parra-Cuentas ER, Ab'Saber AM, Capelozzi VL, Ferreira TPT, Martins MA, Silva PMR, Rocco PRM. Sex-specific lung remodeling and inflammation changes in experimental allergic asthma. J Appl Physiol (1985) 2010; 109:855-63. [PMID: 20634353 DOI: 10.1152/japplphysiol.00333.2010] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
There is evidence that sex and sex hormones influence the severity of asthma. Airway and lung parenchyma remodeling and the relationship of ultrastructural changes to airway responsiveness and inflammation in male, female, and oophorectomized mice (OVX) were analyzed in experimental chronic allergic asthma. Seventy-two BALB/c mice were randomly divided into three groups (n=24/each): male, female, and OVX mice, whose ovaries were removed 7 days before the start of sensitization. Each group was further randomized to be sensitized and challenged with ovalbumin (OVA) or saline. Twenty-four hours after the last challenge, collagen fiber content in airways and lung parenchyma, the volume proportion of smooth muscle-specific actin in alveolar ducts and terminal bronchiole, the amount of matrix metalloproteinase (MMP)-2 and MMP-9, and the number of eosinophils and interleukin (IL)-4, IL-5, and transforming growth factor (TGF)-β levels in bronchoalveolar lavage fluid were higher in female than male OVA mice. The response of OVX mice was similar to that of males, except that IL-5 remained higher. Nevertheless, after OVA provocation, airway responsiveness to methacholine was higher in males compared with females and OVX mice. In conclusion, sex influenced the remodeling process, but the mechanisms responsible for airway hyperresponsiveness seemed to differ from those related to remodeling.
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Affiliation(s)
- Mariana A Antunes
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Centro de Ciências da Saúde, Avenida Carlos Chagas Filho, s/n, Bloco G-014, Ilha do Fundão 21941-902, Rio de Janeiro, RJ, Brazil
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Hormonal influences on lung function and response to environmental agents: lessons from animal models of respiratory disease. Ann Am Thorac Soc 2010; 6:588-95. [PMID: 19934354 DOI: 10.1513/pats.200904-020rm] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Numerous studies in humans and experimental animals have identified considerable sex differences in respiratory physiology and in the response of the lung to environmental agents. These differences appear to be mediated, at least in part, by sex hormones and their nuclear receptors. Moreover, animal models are increasingly used to study pathogenic mechanisms and test potential therapies for a variety of human lung diseases, many of which appear to be influenced by sex and sex hormones. In this article, data are summarized from studies of lung function and disease in which sex differences have been observed. Specific attention is paid to animal models of acute lung injury, nonallergic and allergic lung inflammation, and lung fibrosis. It is anticipated that continued investigation of the role of sex and sex hormones in animal models will provide valuable insight into the pathogenesis and potential treatments for a variety of acute and chronic human lung diseases.
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Modulatory role of endogenous androgens on airway smooth muscle tone in isolated guinea-pig and bovine trachea; involvement of beta2-adrenoceptors, the polyamine system and external calcium. Eur J Pharmacol 2008; 601:154-62. [PMID: 18983840 DOI: 10.1016/j.ejphar.2008.10.039] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2008] [Revised: 10/17/2008] [Accepted: 10/20/2008] [Indexed: 11/20/2022]
Abstract
Androgens relax several smooth muscles, including the airways. They also contract ileum and myocardium via nongenomic mechanisms. To find out whether androgens modulate airway smooth muscles in different species and further assess their mechanism of action, regarding the role of beta-adrenoceptors, polyamines and extracellular Ca(2+), and the modulation of contraction, 5 alpha-dihydrotestosterone, testosterone and 5 beta-dihydrotestosterone were used. A preliminary study was performed to evaluate the effect of 5 alpha-dihydrotestosterone, a non-aromatisable derivate of testosterone, in isolated guinea-pig trachea and a more exhaustive characterisation was followed in bovine trachea, to also characterise the effect of testosterone and 5 beta-dihydrotestosterone. The androgens elicited a nongenomic epithelium-independent relaxation of the trachea which had been precontracted. In the bovine trachea, the order of potency was: testosterone>5 alpha-dihydrotestosterone=5 beta-dihydrotestosterone. This effect was inversely proportional to the magnitude of carbachol-raised tone and was independent of beta(2)-adrenoceptors, since the beta-blockers, propranolol and ICI-118,551, and beta(2)-adrenoceptor desensitisation did not modify 5 alpha-dihydrotestosterone-elicited relaxation. 5 alpha-Dihydrotestosterone was unable to displace the radiolabel, [(3)H]dihydroalprenolol, from these receptors in the binding assay. Polyamine synthesis was not involved in this androgen effect, since an ornithine decarboxylase inhibitor, alpha-difluoromethylornithine, was ineffective. The androgens were more effective relaxing bovine trachea precontracted by KCl (80 mM), suggesting a calcium entry blockade, as reported for several smooth muscles. This mechanism might be involved in the observed 5 alpha-dihydrotestosterone facilitation of salbutamol-relaxation. Androgens facilitated carbachol-elicited contraction independently of polyamine synthesis, contrary to what has been reported in the ileum. Therefore, androgens modulate tracheal smooth muscle tone which might be of importance in the regulation of airway reactivity.
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Proskocil BJ, Bruun DA, Lorton JK, Blensly KC, Jacoby DB, Lein PJ, Fryer AD. Antigen sensitization influences organophosphorus pesticide-induced airway hyperreactivity. ENVIRONMENTAL HEALTH PERSPECTIVES 2008; 116:381-8. [PMID: 18335107 PMCID: PMC2265045 DOI: 10.1289/ehp.10694] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/19/2007] [Accepted: 01/02/2008] [Indexed: 05/11/2023]
Abstract
BACKGROUND Recent epidemiologic studies have identified organophosphorus pesticides (OPs) as environmental factors potentially contributing to the increase in asthma prevalence over the last 25 years. In support of this hypothesis, we have demonstrated that environmentally relevant concentrations of OPs induce airway hyperreactivity in guinea pigs. OBJECTIVES Sensitization to allergen is a significant contributing factor in asthma, and we have shown that sensitization changes virus-induced airway hyperreactivity from an eosinophil-independent mechanism to one mediated by eosinophils. Here, we determine whether sensitization similarly influences OP-induced airway hyperreactivity. METHODS Nonsensitized and ovalbumin-sensitized guinea pigs were injected subcutaneously with the OP parathion (0.001-1.0 mg/kg). Twenty-four hours later, animals were anesthetized and ventilated, and bronchoconstriction was measured in response to either vagal stimulation or intravenous acetylcholine. Inflammatory cells and acetylcholinesterase activity were assessed in tissues collected immediately after physiologic measurements. RESULTS Ovalbumin sensitization decreased the threshold dose for parathion-induced airway hyperreactivity and exacerbated parathion effects on vagally induced bronchoconstriction. Pretreatment with antibody to interleukin (IL)-5 prevented parathion-induced hyperreactivity in sensitized but not in nonsensitized guinea pigs. Parathion did not increase the number of eosinophils in airways or the number of eosinophils associated with airway nerves nor did it alter eosinophil activation as assessed by major basic protein deposition. CONCLUSIONS Antigen sensitization increases vulnerability to parathion-induced airway hyperreactivity and changes the mechanism to one that is dependent on IL-5. Because sensitization to allergens is characteristic of 50% of the general population and 80% of asthmatics (including children), these findings have significant implications for OP risk assessment, intervention, and treatment strategies.
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Affiliation(s)
- Becky J Proskocil
- Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, Oregon 97239, USA.
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Mikerov AN, Gan X, Umstead TM, Miller L, Chinchilli VM, Phelps DS, Floros J. Sex differences in the impact of ozone on survival and alveolar macrophage function of mice after Klebsiella pneumoniae infection. Respir Res 2008; 9:24. [PMID: 18307797 PMCID: PMC2268931 DOI: 10.1186/1465-9921-9-24] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2007] [Accepted: 02/28/2008] [Indexed: 11/10/2022] Open
Abstract
Background Sex differences have been described in a number of pulmonary diseases. However, the impact of ozone exposure followed by pneumonia infection on sex-related survival and macrophage function have not been reported. The purpose of this study was to determine whether ozone exposure differentially affects: 1) survival of male and female mice infected with Klebsiella pneumoniae, and 2) the phagocytic ability of macrophages from these mice. Methods Male and female C57BL/6 mice were exposed to O3 or to filtered air (FA) (control) and then infected intratracheally with K. pneumoniae bacteria. Survival was monitored over a 14-day period, and the ability of alveolar macrophages to phagocytize the pathogen in vivo was investigated after 1 h. Results 1) Both male and female mice exposed to O3 are significantly more susceptible to K. pneumoniae infection than mice treated with FA; 2) although females appeared to be more resistant to K. pneumoniae than males, O3 exposure significantly increased the susceptibility of females to K. pneumoniae infection to a greater degree than males; 3) alveolar macrophages from O3-exposed male and female mice have impaired phagocytic ability compared to macrophages from FA-exposed mice; and 4) the O3-dependent reduction in phagocytic ability is greater in female mice. Conclusion O3 exposure reduces the ability of mice to survive K. pneumoniae infection and the reduced phagocytic ability of alveolar macrophages may be one of the contributing factors. Both events are significantly more pronounced in female mice following exposure to the environmental pollutant, ozone.
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Affiliation(s)
- Anatoly N Mikerov
- The Penn State Center for Host defense, Inflammation, and Lung Disease (CHILD) Research, Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
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Voltz JW, Card JW, Carey MA, Degraff LM, Ferguson CD, Flake GP, Bonner JC, Korach KS, Zeldin DC. Male sex hormones exacerbate lung function impairment after bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol 2008; 39:45-52. [PMID: 18276795 DOI: 10.1165/rcmb.2007-0340oc] [Citation(s) in RCA: 87] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
The roles of sex hormones as modulators of lung function and disease have received significant attention as differential sex responses to various lung insults have been recently reported. The present study used a bleomycin-induced pulmonary fibrosis model in C57BL/6 mice to examine potential sex differences in physiological and pathological outcomes. Endpoints measured included invasive lung function assessment, immunological response, lung collagen deposition, and a quantitative histological analysis of pulmonary fibrosis. Male mice had significantly higher basal static lung compliance than female mice (P < 0.05) and a more pronounced decline in static compliance after bleomycin administration when expressed as overall change or percentage of baseline change (P < 0.05). In contrast, there were no significant differences between the sexes in immune cell infiltration into the lung or in total lung collagen content after bleomycin. Total lung histopathology scores measured using the Ashcroft method did not differ between the sexes, while a quantitative histopathology scoring system designed to determine where within the lung the fibrosis occurred indicated a tendency toward more fibrosis immediately adjacent to airways in bleomycin-treated male versus female mice. Furthermore, castrated male mice exhibited a female-like response to bleomycin while female mice given exogenous androgen exhibited a male-like response. These data indicate that androgens play an exacerbating role in decreased lung function after bleomycin administration, and traditional measures of fibrosis may miss critical differences in lung function between the sexes. Sex differences should be carefully considered when designing and interpreting experimental models of pulmonary fibrosis in mice.
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Affiliation(s)
- James W Voltz
- Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA
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Carey MA, Card JW, Voltz JW, Arbes SJ, Germolec DR, Korach KS, Zeldin DC. It's all about sex: gender, lung development and lung disease. Trends Endocrinol Metab 2007; 18:308-13. [PMID: 17764971 PMCID: PMC2391086 DOI: 10.1016/j.tem.2007.08.003] [Citation(s) in RCA: 283] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2007] [Revised: 07/13/2007] [Accepted: 08/15/2007] [Indexed: 10/22/2022]
Abstract
Accumulating evidence suggests that gender affects the incidence, susceptibility and severity of several lung diseases. Gender also influences lung development and physiology. Data from both human and animal studies indicate that sex hormones might contribute to disease pathogenesis or serve as protective factors, depending on the disease involved. In this review, the influence of gender and sex hormones on lung development and pathology will be discussed, with specific emphasis on pulmonary fibrosis, asthma and cancer.
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Affiliation(s)
- Michelle A Carey
- National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA
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Carey MA, Card JW, Voltz JW, Germolec DR, Korach KS, Zeldin DC. The impact of sex and sex hormones on lung physiology and disease: lessons from animal studies. Am J Physiol Lung Cell Mol Physiol 2007; 293:L272-8. [PMID: 17575008 DOI: 10.1152/ajplung.00174.2007] [Citation(s) in RCA: 162] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Numerous animal studies have revealed significant effects of sex and sex hormones on normal lung development, lung physiology, and various lung diseases. The primary goal of this review is to summarize knowledge to date on the effects of sex and sex hormones on lung development, physiology, and disease in animals. Specific emphasis will be placed on fibrosis, allergic airway disease, acute lung injury models, respiratory infection, and lung toxicology studies.
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Affiliation(s)
- Michelle A Carey
- National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA
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