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Calcaterra V, Nappi RE, Farolfi A, Tiranini L, Rossi V, Regalbuto C, Zuccotti G. Perimenstrual Asthma in Adolescents: A Shared Condition in Pediatric and Gynecological Endocrinology. CHILDREN 2022; 9:children9020233. [PMID: 35204953 PMCID: PMC8870409 DOI: 10.3390/children9020233] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 02/04/2022] [Accepted: 02/07/2022] [Indexed: 12/12/2022]
Abstract
Asthma is a frequent medical condition in adolescence. The worsening of the most common symptoms perimenstrually is defined as perimenstrual asthma (PMA). The cause of PMA remains unclear, but a role for hormonal milieu is plausible. Data on PMA in adolescents are limited, and its management is not fully established. We aimed to discuss the PMA phenomenon in young females from pathophysiology to preventive strategies, focusing on the relationship with the hormonal pattern. The fluctuation of estrogens at ovulation and before menstruation and the progesterone secretion during the luteal phase and its subsequent withdrawal seem to be the culprits, because the deterioration of asthma is cyclical during the luteal phase and/or during the first days of the menstrual cycle. Conventional asthma therapies are not always effective for PMA. Preventive strategies may include innovative hormonal contraception. Even a possible beneficial effect of other hormonal treatments, including estrogens, progestogens, and androgens, as well as leukotriene receptor antagonists and explorative approach using microbial-directed therapy, is considered. The underlying mechanisms, through which sex-hormone fluctuations influence asthma symptoms, represent a challenge in the clinical management of such a distressing condition. Further studies focused on young females are mandatory to promote adolescent health.
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Affiliation(s)
- Valeria Calcaterra
- Pediatric and Adolescent Unit, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
- Department of Pediatrics, “Vittore Buzzi” Children’s Hospital, 20154 Milano, Italy; (A.F.); (V.R.); (G.Z.)
- Correspondence:
| | - Rossella Elena Nappi
- Research Center for Reproductive Medicine, Gynecological Endocrinology and Menopause, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (R.E.N.); (L.T.)
- Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, 27100 Pavia, Italy
| | - Andrea Farolfi
- Department of Pediatrics, “Vittore Buzzi” Children’s Hospital, 20154 Milano, Italy; (A.F.); (V.R.); (G.Z.)
| | - Lara Tiranini
- Research Center for Reproductive Medicine, Gynecological Endocrinology and Menopause, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (R.E.N.); (L.T.)
- Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, 27100 Pavia, Italy
| | - Virginia Rossi
- Department of Pediatrics, “Vittore Buzzi” Children’s Hospital, 20154 Milano, Italy; (A.F.); (V.R.); (G.Z.)
| | - Corrado Regalbuto
- Pediatric Unit, Fondazione IRCCS Policlinico San Matteo, University of Pavia, 27100 Pavia, Italy;
| | - Gianvincenzo Zuccotti
- Department of Pediatrics, “Vittore Buzzi” Children’s Hospital, 20154 Milano, Italy; (A.F.); (V.R.); (G.Z.)
- Department of Biomedical and Clinical Science “L. Sacco”, University of Milano, 20157 Milano, Italy
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Aravamudan B, Goorhouse KJ, Unnikrishnan G, Thompson MA, Pabelick CM, Hawse JR, Prakash YS, Sathish V. Differential Expression of Estrogen Receptor Variants in Response to Inflammation Signals in Human Airway Smooth Muscle. J Cell Physiol 2017; 232:1754-1760. [PMID: 27808402 DOI: 10.1002/jcp.25674] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Accepted: 11/01/2016] [Indexed: 12/16/2022]
Abstract
The prevalence of asthma is higher in pre-pubescent and aging males, and in post-pubertal females, strongly indicating that sex steroids (especially estrogen) may be an important modulator in lung disease. We recently demonstrated that airway smooth muscle (ASM) expresses both alpha and beta forms of the estrogen receptor (ERα and ERβ) in males and females, and that these receptors regulate intracellular [Ca2+ ] and ASM contractility. Although both ERα and ERβ have multiple splice variants, it is unclear if and how the expression of these variants is modulated under conditions such as chronic inflammation/asthma. In order to test the hypothesis that the differential expression of ERα and ERβ variants contributes to the pathogenesis of asthma, we profiled the expression of various ERα and ERβ genes in asthmatic and inflamed (TNFα- or IL-13-treated) ASM. Gene expression was assessed at both the mRNA and protein levels in asthmatic ASM cells or non-asthmatic cells treated with TNFα (20 ng/ml) or IL-13 (50 ng/ml). We observed marked variation in the expression of ER isoforms in response to inflammatory stimuli, and in non-asthmatic versus asthmatic ASM. Changes in protein levels of ERα and ERβ corresponded with the observed differential mRNA patterns. Pharmacological studies implicate cytosolic (p42/44 MAPK and PI3 K) and nuclear (NFκB, STAT6, and AP-1) signaling pathways as putative mechanisms that mediate and/or regulate effects of inflammation on ER expression. We conclude that variations in ASM ER expression profiles occur with inflammation and that ER variants could contribute to estrogen signaling in airway diseases such as asthma. J. Cell. Physiol. 232: 1754-1760, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Bharathi Aravamudan
- Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota.,Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota
| | | | | | - Michael A Thompson
- Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota.,Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota
| | - Christina M Pabelick
- Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota.,Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota
| | - John R Hawse
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota
| | - Y S Prakash
- Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota.,Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota
| | - Venkatachalem Sathish
- Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota.,Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.,Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota
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Pereira-Vega A, Sánchez-Ramos JL. Questions relating to premenstrual asthma. World J Respirol 2015; 5:180-187. [DOI: 10.5320/wjr.v5.i3.180] [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: 07/03/2015] [Revised: 08/05/2015] [Accepted: 10/13/2015] [Indexed: 02/06/2023] Open
Abstract
The study of asthma in fertile women needs to consider its potentially recurrent exacerbation in a specific phase of the menstrual cycle. Premenstrual asthma (PMA) refers to the deterioration of asthma in some women of fertile age during the premenstrual phase. Prevalence varies considerably according to studies (11%-47.44%) mainly because there is no standardized definition of the illness. There is a possible link between PMA and premenstrual syndrome, which is a set of physical and psychic manifestations that occur in some fertile women during the same premenstrual phase. This relation has been widely studied but there are still several unknowns. PMA etiopathogeny is not known. It involves possible causes such as hormonal variations in the premenstrual phase, the coexistence of atopy, variations during the cycle in substances related to inflammation, like LTC4 leukotrienes, catecholamines, E2 and F2α prostaglandins and certain cytokines. Also considered are psychological factors related to this phase of the menstrual cycle, a high susceptibility to infection or increased bronchial hyperreactivity prior to menstruation. Yet no factor fully explains its etiology, consequently no specific treatment exists. Researchers have investigated hormones, anti-leukotrienes, prostaglandin synthesis inhibitors, diuretics, phytoestrogens and alternative therapies, but none has been shown to be effective.
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Itoga M, Konno Y, Moritoki Y, Saito Y, Ito W, Tamaki M, Kobayashi Y, Kayaba H, Kikuchi Y, Chihara J, Takeda M, Ueki S, Hirokawa M. G-protein-coupled estrogen receptor agonist suppresses airway inflammation in a mouse model of asthma through IL-10. PLoS One 2015; 10:e0123210. [PMID: 25826377 PMCID: PMC4380451 DOI: 10.1371/journal.pone.0123210] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Accepted: 02/28/2015] [Indexed: 02/06/2023] Open
Abstract
Estrogen influences the disease severity and sexual dimorphism in asthma, which is caused by complex mechanisms. Besides classical nuclear estrogen receptors (ERαβ), G-protein-coupled estrogen receptor (GPER) was recently established as an estrogen receptor on the cell membrane. Although GPER is associated with immunoregulatory functions of estrogen, the pathophysiological role of GPER in allergic inflammatory lung disease has not been examined. We investigated the effect of GPER-specific agonist G-1 in asthmatic mice. GPER expression in asthmatic lung was confirmed by immunofluorescent staining. OVA-sensitized BALB/c and C57BL/6 mice were treated with G-1 by daily subcutaneous injections during an airway challenge phase, followed by histological and biochemical examination. Strikingly, administration of G-1 attenuated airway hyperresponsiveness, accumulation of inflammatory cells, and levels of Th2 cytokines (IL-5 and IL-13) in BAL fluid. G-1 treatment also decreased serum levels of anti-OVA IgE antibodies. The frequency of splenic Foxp3+CD4+ regulatory T cells and IL-10-producing GPER+CD4+ T cells was significantly increased in G-1-treated mice. Additionally, splenocytes isolated from G-1-treated mice showed greater IL-10 production. G-1-induced amelioration of airway inflammation and IgE production were abolished in IL-10-deficient mice. Taken together, these results indicate that extended GPER activation negatively regulates the acute asthmatic condition by altering the IL-10-producing lymphocyte population. The current results have potential importance for understanding the mechanistic aspects of function of estrogen in allergic inflammatory response.
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Affiliation(s)
- Masamichi Itoga
- Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010–8543, Japan
- Department of Clinical Laboratory Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036–8562, Japan
| | - Yasunori Konno
- Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010–8543, Japan
- Division of Dentistry and Oral Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010–8543, Japan
| | - Yuki Moritoki
- Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010–8543, Japan
| | - Yukiko Saito
- Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010–8543, Japan
| | - Wataru Ito
- Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010–8543, Japan
- Nagareyama Tobu Clinic, 909–1 Nazukari, Nagareyama City, Chiba, 270–0145, Japan
| | - Mami Tamaki
- Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010–8543, Japan
| | - Yoshiki Kobayashi
- Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010–8543, Japan
- Department of Otolaryngology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata City, Osaka, 573–1010, Japan
| | - Hiroyuki Kayaba
- Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010–8543, Japan
- Department of Clinical Laboratory Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036–8562, Japan
| | - Yuta Kikuchi
- Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010–8543, Japan
| | - Junichi Chihara
- Soseikai General Hospital, 101 Shimotoba Hiroosacho, Fushimi-ku, Kyoto City, Kyoto, 612–8473, Japan
| | - Masahide Takeda
- Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010–8543, Japan
- Department of Cardiovascular and Respiratory Medicine, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010–8543, Japan
- * E-mail: (SU); (MT)
| | - Shigeharu Ueki
- Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010–8543, Japan
- * E-mail: (SU); (MT)
| | - Makoto Hirokawa
- Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010–8543, Japan
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Payne AS, Freishtat RJ. Conserved steroid hormone homology converges on nuclear factor κB to modulate inflammation in asthma. J Investig Med 2013; 60:13-7. [PMID: 22183120 DOI: 10.2310/jim.0b013e31823d7989] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Asthma is a complex, multifactorial disease comprising multiple different subtypes, rather than a single disease entity, yet it has a consistent clinical phenotype: recurring episodes of chest tightness, wheezing, and difficulty breathing (Pediatr Pulmonol Suppl. 1997;15:9-12). Despite the complex pathogenesis of asthma, steroid hormones (eg, glucocorticoids) are ubiquitous in the short-term and long-term management of all types of asthma. Overall, steroid hormones are a class of widely relevant, biologically active compounds originating from cholesterol and altered in a stepwise fashion, but maintain a basic 17-carbon, 4-ring structure. Steroids are lipophilic molecules that diffuse readily through cell membranes to directly and/or indirectly affect gene transcription. In addition, they use rapid, nongenomic actions to affect cellular products. Steroid hormones comprise several groups (including glucocorticoids, sex steroid hormones, and secosteroids) with critical divergent biological and physiological functions relevant to health and disease. However, the conserved homology of steroid hormone molecules, receptors, and signaling pathways suggests that each of these is part of a dynamic system of hormone interaction, likely involving an overlap of downstream signaling mechanisms. Therefore, we will review the similarities and differences of these 3 groups of steroid hormones (ie, glucocorticoids, sex steroid hormones, and secosteroids), identifying nuclear factor κB as a common inflammatory mediator. Despite our understanding of the impact of individual steroids (eg, glucocorticoids, sex steroids and secosteroids) on asthma, research has yet to explain the interplay of the dynamic system in which these hormones function. To do so, there needs to be a better understanding of the interplay of classic, nonclassic, and nongenomic steroid hormone functions. However, clues from the conserved homology steroid hormone structure and function and signaling pathways offer insight into a possible model of steroid hormone regulation of inflammation in asthma through common nuclear factor κB-mediated downstream events.
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Affiliation(s)
- Asha S Payne
- Division of Emergency Medicine, Children's National Medical Center, Washington, DC, USA
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Premenstrual asthma and leukotriene variations in the menstrual cycle. Allergol Immunopathol (Madr) 2012; 40:368-73. [PMID: 22115570 DOI: 10.1016/j.aller.2011.09.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2011] [Accepted: 09/06/2011] [Indexed: 12/24/2022]
Abstract
BACKGROUND Several authors have reported an increase in leukotriene C4 in the premenstrual phase in women with severe premenstrual asthma, indicating that antileukotrienes could be used in treatment. OBJECTIVE To analyse the role of leukotrienes in premenstrual asthma. METHODS A questionnaire on respiratory symptoms and peak flow during one complete menstrual cycle was given to women of fertile age to define them as asthmatics who suffered from premenstrual asthma or not. Premenstrual asthma (PMA) was defined as a clinical or functional deterioration (≥20%) in the premenstrual phase compared with the preovulatory phase. Blood samples to measure leukotriene C4 were taken during the preovulatory and premenstrual phases. RESULTS Blood samples were taken in 62 asthmatic women, 34 of whom (54.3%) presented PMA criteria, all with a premenstrual deterioration of between 20 and 40%. There was no difference in leukotriene C4 levels between the preovulatory and premenstrual phases in the women who suffered from PMA (1.50ng/mL vs. 1.31ng/mL; p=0.32) and those who did not (1.40ng/mL vs. 1.29ng/mL; p=0.62). Neither were there any differences in leukotriene levels between women with or without PMA. The results were similar for each category of asthma severity. CONCLUSIONS Our data show that leukotriene C4 does not appear to be involved in the pathogenesis of premenstrual asthma, or support the use of anti-leukotrienes in the specific treatment of premenstrual asthma, at least in women with a moderate premenstrual deterioration. No differences appeared in any of the categories of asthma severity.
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Chauhan BF, Ducharme FM, Cochrane Airways Group. Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and children. Cochrane Database Syst Rev 2012; 2012:CD002314. [PMID: 22592685 PMCID: PMC4164381 DOI: 10.1002/14651858.cd002314.pub3] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND Anti-leukotrienes (5-lipoxygenase inhibitors and leukotriene receptors antagonists) serve as alternative monotherapy to inhaled corticosteroids (ICS) in the management of recurrent and/or chronic asthma in adults and children. OBJECTIVES To determine the safety and efficacy of anti-leukotrienes compared to inhaled corticosteroids as monotherapy in adults and children with asthma and to provide better insight into the influence of patient and treatment characteristics on the magnitude of effects. SEARCH METHODS We searched MEDLINE (1966 to Dec 2010), EMBASE (1980 to Dec 2010), CINAHL (1982 to Dec 2010), the Cochrane Airways Group trials register, and the Cochrane Central Register of Controlled Trials (Dec 2010), abstract books, and reference lists of review articles and trials. We contacted colleagues and the international headquarters of anti-leukotrienes producers. SELECTION CRITERIA We included randomised trials that compared anti-leukotrienes with inhaled corticosteroids as monotherapy for a minimum period of four weeks in patients with asthma aged two years and older. DATA COLLECTION AND ANALYSIS Two review authors independently assessed the methodological quality of trials and extracted data. The primary outcome was the number of patients with at least one exacerbation requiring systemic corticosteroids. Secondary outcomes included patients with at least one exacerbation requiring hospital admission, lung function tests, indices of chronic asthma control, adverse effects, withdrawal rates and biological inflammatory markers. MAIN RESULTS Sixty-five trials met the inclusion criteria for this review. Fifty-six trials (19 paediatric trials) contributed data (representing total of 10,005 adults and 3,333 children); 21 trials were of high methodological quality; 44 were published in full-text. All trials pertained to patients with mild or moderate persistent asthma. Trial durations varied from four to 52 weeks. The median dose of inhaled corticosteroids was quite homogeneous at 200 µg/day of microfine hydrofluoroalkane-propelled beclomethasone or equivalent (HFA-BDP eq). Patients treated with anti-leukotrienes were more likely to suffer an exacerbation requiring systemic corticosteroids (N = 6077 participants; risk ratio (RR) 1.51, 95% confidence interval (CI) 1.17, 1.96). For every 28 (95% CI 15 to 82) patients treated with anti-leukotrienes instead of inhaled corticosteroids, there was one additional patient with an exacerbation requiring rescue systemic corticosteroids. The magnitude of effect was significantly greater in patients with moderate compared with those with mild airway obstruction (RR 2.03, 95% CI 1.41, 2.91 versus RR 1.25, 95% CI 0.97, 1.61), but was not significantly influenced by age group (children representing 23% of the weight versus adults), anti-leukotriene used, duration of intervention, methodological quality, and funding source. Significant group differences favouring inhaled corticosteroids were noted in most secondary outcomes including patients with at least one exacerbation requiring hospital admission (N = 2715 participants; RR 3.33; 95% CI 1.02 to 10.94), the change from baseline FEV(1) (N = 7128 participants; mean group difference (MD) 110 mL, 95% CI 140 to 80) as well as other lung function parameters, asthma symptoms, nocturnal awakenings, rescue medication use, symptom-free days, the quality of life, parents' and physicians' satisfaction. Anti-leukotriene therapy was associated with increased risk of withdrawals due to poor asthma control (N = 7669 participants; RR 2.56; 95% CI 2.01 to 3.27). For every thirty one (95% CI 22 to 47) patients treated with anti-leukotrienes instead of inhaled corticosteroids, there was one additional withdrawal due to poor control. Risk of side effects was not significantly different between both groups. AUTHORS' CONCLUSIONS As monotherapy, inhaled corticosteroids display superior efficacy to anti-leukotrienes in adults and children with persistent asthma; the superiority is particularly marked in patients with moderate airway obstruction. On the basis of efficacy, the results support the current guidelines' recommendation that inhaled corticosteroids remain the preferred monotherapy.
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Affiliation(s)
- Bhupendrasinh F Chauhan
- Research Centre, CHU Sainte‐JustineClinical Research Unit on Childhood Asthma3175, Cote Sainte‐CatherineMontrealQCCanada
| | - Francine M Ducharme
- University of MontrealDepartment of PaediatricsMontrealQCCanada
- CHU Sainte‐JustineResearch CentreMontrealCanada
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[Exacerbations of asthma--precipitating factors: drugs]. Rev Mal Respir 2011; 28:1059-70. [PMID: 22099411 DOI: 10.1016/j.rmr.2011.02.015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2010] [Accepted: 02/01/2011] [Indexed: 11/24/2022]
Abstract
Asthmatic exacerbations are sometimes triggered by medications, primarily the non-steroidal anti-inflammatory agents (NSAIDS) and beta-blockers. Asthma attacks induced by NSAIDS occur rapidly and can be severe. Widal syndrome is a specific disease entity whose physiopathology remains incompletely explained. Asthma is characteristically severe and steroid dependent; desensitisation with aspirin has been proposed, but this remains controversial. Beta-blockers are contra-indicated in asthma; the β1 "cardioselectivity" of some agents is not absolute, disappearing at high doses and the "partial agonists" are not better tolerated. However, certain authors have called into question the harmful effect of beta-blockade in moderate and stable asthma. More studies are needed, but the current data suggest that in some cases beta-blockers may be safe but their use requires close supervision. Other molecules can pose problems in asthmatics (dipyridamole, synthetic sex hormones and certain excipients). On the whole, there has been little innovation concerning the hazard that drugs can pose for some asthmatics. The task for the future will be to specify the physiopathology of Widal syndrome, and to clarify the categories of patients in whom beta-blockers can be safely employed as the public health consequences of cardiovascular pathologies make this an important issue for lung specialists.
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de Oliveira APL, Peron JPS, Damazo AS, Franco ALDS, Domingos HV, Oliani SM, Oliveira-Filho RM, Vargaftig BB, Tavares-de-Lima W. Female sex hormones mediate the allergic lung reaction by regulating the release of inflammatory mediators and the expression of lung E-selectin in rats. Respir Res 2010; 11:115. [PMID: 20735828 PMCID: PMC2936382 DOI: 10.1186/1465-9921-11-115] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2009] [Accepted: 08/24/2010] [Indexed: 12/19/2022] Open
Abstract
Background Fluctuations of estradiol and progesterone levels caused by the menstrual cycle worsen asthma symptoms. Conflicting data are reported in literature regarding pro and anti-inflammatory properties of estradiol and progesterone. Methods Female Wistar rats were ovalbumin (OVA) sensitized 1 day after resection of the ovaries (OVx). Control group consisted of sensitized-rats with intact ovaries (Sham-OVx). Allergic challenge was performed by aerosol (OVA 1%, 15 min) two weeks later. Twenty four hours after challenge, BAL, bone marrow and total blood cells were counted. Lung tissues were used as explants, for expontaneous cytokine secretion in vitro or for immunostaining of E-selectin. Results We observed an exacerbated cell recruitment into the lungs of OVx rats, reduced blood leukocytes counting and increased the number of bone marrow cells. Estradiol-treated OVx allergic rats reduced, and those treated with progesterone increased, respectively, the number of cells in the BAL and bone marrow. Lungs of OVx allergic rats significantly increased the E-selectin expression, an effect prevented by estradiol but not by progesterone treatment. Systemically, estradiol treatment increased the number of peripheral blood leukocytes in OVx allergic rats when compared to non treated-OVx allergic rats. Cultured-BAL cells of OVx allergic rats released elevated amounts of LTB4 and nitrites while bone marrow cells increased the release of TNF-α and nitrites. Estradiol treatment of OVx allergic rats was associated with a decreased release of TNF-α, IL-10, LTB4 and nitrites by bone marrow cells incubates. In contrast, estradiol caused an increase in IL-10 and NO release by cultured-BAL cells. Progesterone significantly increased TNF- α by cultured BAL cells and bone marrow cells. Conclusions Data presented here suggest that upon hormonal oscillations the immune sensitization might trigger an allergic lung inflammation whose phenotype is under control of estradiol. Our data could contribute to the understanding of the protective role of estradiol in some cases of asthma symptoms in fertile ans post-menopausal women clinically observed.
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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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Dratva J, Schindler C, Curjuric I, Stolz D, Macsali F, Gomez FR, Zemp E. Perimenstrual increase in bronchial hyperreactivity in premenopausal women: results from the population-based SAPALDIA 2 cohort. J Allergy Clin Immunol 2010; 125:823-9. [PMID: 20227756 DOI: 10.1016/j.jaci.2009.12.938] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2009] [Revised: 12/08/2009] [Accepted: 12/15/2009] [Indexed: 02/08/2023]
Abstract
BACKGROUND Studies on perimenstrual asthma are inconsistent, and different methodologies limit comparisons. OBJECTIVE To investigate cyclic variations in bronchial hyperreactivity (BHR) to methacholine in premenopausal women in a population-based cohort and assess effect modification by oral contraceptives (OCs). METHODS Day of menstruation cycle at the time of methacholine challenge was calculated in 571 menstruating women without hormonal treatment, age 28 to 58 years, on the basis of questionnaire data from the Swiss cohort study on Air Pollution And Lung Disease In Adults (SAPALDIA) cohort 2001/2002. A window of risk was defined 3 days before and after the first day of menstruation. Logistic and linear regression analyses were performed adjusting for main predictors of BHR and stratifying for asthma status. The impact of OCs was studied in the same sample enlarged by 130 women taking OCs. RESULTS The prevalence of BHR was 13% (fall of > or =20% in FEV(1) up to a maximal cumulative dose of 2 mg), and 6% had asthma. A total of 143 women had undergone methacholine challenge within the risk window. We observed a significant increase in BHR within the window of risk (odds ratio [OR], 2.3; 95% CI, 1.27-4.29). A cyclic association pattern was confirmed by trigonometric functions. Effect modification by asthma status and oral contraceptive use was found, with lower OR in subjects without asthma and OR <1 in women using OCs. CONCLUSION The data provide evidence of a systematic variation in BHR during the menstruation cycle, supporting the hypothesis of a hormonal influence. OCs appear to have a protective effect. Cyclicity of BHR could be of clinical importance in view of future medication recommendations and timing of respiratory function tests in women.
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Affiliation(s)
- Julia Dratva
- Institute of Social and Preventive Medicine at the Swiss Tropical Institute, Basel, Switzerland.
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Baroffio M, Barisione G, Crimi E, Brusasco V. Noninflammatory mechanisms of airway hyper-responsiveness in bronchial asthma: an overview. Ther Adv Respir Dis 2009; 3:163-74. [PMID: 19661157 DOI: 10.1177/1753465809343595] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Airway hyper-responsiveness (AHR) is a cardinal feature of asthma. Its absence has been considered useful in excluding asthma, whereas it may be present in other diseases such as atopic rhinitis and chronic obstructive pulmonary disease. AHR is often considered an epiphenomenon of airway inflammation. Actually, the response of airways to constrictor stimuli is modulated by a complex array of factors, some facilitating and others opposing airway narrowing. Thus, it has been suggested that AHR, and perhaps asthma, might be present even without or before the development of airway inflammation. We begin this review by highlighting some terminological and methodological issues concerning the measurement of AHR. Then we describe the neurohumoral mechanisms controlling airway tone. Finally, the pivotal role of airway smooth muscle and internal and external modulation of airway caliber in vivo are discussed in detail.
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Affiliation(s)
- Michele Baroffio
- Dipartimento di Medicina Interna, Università di Genova, Genova, Italy.
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Murphy VE, Gibson PG. Premenstrual asthma: prevalence, cycle-to-cycle variability and relationship to oral contraceptive use and menstrual symptoms. J Asthma 2008; 45:696-704. [PMID: 18951263 DOI: 10.1080/02770900802207279] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The prevalence of asthma is higher in women than men of reproductive age and almost half of all hospitalisations for asthma in women occur during the perimenstrual phase of the cycle. The mechanisms of premenstrual asthma (PMA) are unknown and a definition of PMA has not been clearly presented in the literature. The objective of this study was to determine the prevalence of PMA using a variety of definitions, to investigate the cycle-to-cycle variation in PMA, the effects of oral contraceptive use and the relationship between PMA and premenstrual symptoms. Premenopausal women with asthma (n = 28) were prospectively followed for at least 12 weeks over 2-4 consecutive menstrual cycles. Asthma symptoms, beta(2)-agonist and inhaled corticosteroid use and morning and evening peak expiratory flow were recorded daily. The following types of PMA definitions were investigated: self-reported PMA, increased symptoms, increased medication use, decreased peak flow or a combination of changes in symptoms, medication and peak flow. Changes of more than 20%, for at least 2 consecutive days of the luteal phase (last 14 days of the cycle prior to menstruation) compared to the early follicular phase average (first 7 days after menstruation) were considered PMA. Using a composite definition where subjects experienced increased symptoms and medication use with or without a change in peak flow, 16 subjects were classified as having PMA (57%), while 12 did not have PMA. Only 4 subjects (25%) had PMA in every cycle examined. Fifty-five percent of subjects who used oral contraceptives had PMA, while 59% of subjects who did not use oral contraceptives had PMA. Women who were defined PMA using the composite definition were more likely than those without PMA to experience a 20% decrease in peak flow during the luteal phase. There was no relationship between asthma symptoms and premenstrual symptoms on day 1 of the menstrual cycle in women with PMA. PMA resulting in increased symptoms and medication use occurred in 57% of subjects studied for 2-4 menstrual cycles. The use of oral contraceptives is not protective and further work is required to elucidate the mechanisms of PMA.
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Affiliation(s)
- Vanessa E Murphy
- Centre for Asthma and Respiratory Diseases, University of Newcastle and Hunter Medical Research Institute, Newcastle, NSW, Australia.
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Lim RH, Kobzik L. Sexual tension in the airways: the puzzling duality of estrogen in asthma. Am J Respir Cell Mol Biol 2008; 38:499-500. [PMID: 18417757 DOI: 10.1165/rcmb.2008-0002ed] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
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Matsubara S, Swasey CH, Loader JE, Dakhama A, Joetham A, Ohnishi H, Balhorn A, Miyahara N, Takeda K, Gelfand EW. Estrogen determines sex differences in airway responsiveness after allergen exposure. Am J Respir Cell Mol Biol 2008; 38:501-8. [PMID: 18063836 PMCID: PMC2335333 DOI: 10.1165/rcmb.2007-0298oc] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2007] [Accepted: 11/21/2007] [Indexed: 11/24/2022] Open
Abstract
The female hormone estrogen is an important factor in the regulation of airway function and inflammation, and sex differences in the prevalence of asthma are well described. Using an animal model, we determined how sex differences may underlie the development of altered airway function in response to allergen exposure. We compared sex differences in the development of airway hyperresponsiveness (AHR) after allergen exposure exclusively via the airways. Ovalbumin (OVA) was administered by nebulization on 10 consecutive days in BALB/c mice. After methacholine challenge, significant AHR developed in male mice but not in female mice. Ovariectomized female mice showed significant AHR after 10-day OVA inhalation. ICI182,780, an estrogen antagonist, similarly enhanced airway responsiveness even when administered 1 hour before assay. In contrast, 17beta-estradiol dose-dependently suppressed AHR in male mice. In all cases, airway responsiveness was inhibited by the administration of a neurokinin 1 receptor antagonist. These results demonstrate that sex differences in 10-day OVA-induced AHR are due to endogenous estrogen, which negatively regulates airway responsiveness in female mice. Cumulatively, the results suggest that endogenous estrogen may regulate the neurokinin 1-dependent prejunctional activation of airway smooth muscle in allergen-exposed mice.
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Affiliation(s)
- Shigeki Matsubara
- National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206, USA
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Pasaoglu G, Mungan D, Abadoglu O, Misirligil Z. Leukotriene receptor antagonists: a good choice in the treatment of premenstrual asthma? J Asthma 2008; 45:95-9. [PMID: 18350399 DOI: 10.1080/02770900701751799] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The aim of this study was to investigate the effects of leukotriene receptor antagonists (LTRAs) on the premenstrual exacerbation of asthma (PMA). Twenty-four female patients with mild asthma were enrolled in the study. Patients were followed for three menstrual cycles and separated into two groups based on whether they exhibit premenstrual worsening of asthma symptoms (n = 11) or not (n = 13). During the first month all were treated with only inhaled steroids (IS) (run-in period); during the second month they received IS plus placebo; and during the third month they were given IS plus montelukast. Furthermore, they were advised to use beta(2)-agonists as needed. Peak expiratory flow rate (PEFR) and symptom scores were recorded during the 3 months. Pulmonary function tests (PFT) and the levels of oestrogen, progesterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were measured a week before the beginning of the menstrual period. At the end of the 3-month period, it was observed that following therapy with montelukast, the patients with PMA showed significant improvement in PEFR variability and symptom scores when compared with the placebo group. Baseline FSH levels were higher, but FSH and other hormone levels and PFTs did not change in these groups. However, in the group without PMA there was no difference between the montelukast or placebo groups in PEFR variability, symptom scores, PFTs, and hormone levels. Based on the data in hand, it could be stated that LTRAs have ensured the control of symptoms and improved PEFR variability in patients with PMA by suppressing inflammation. We are of the view that LTRAs would be a right choice in the treatment of patients with PMA.
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Affiliation(s)
- Gulden Pasaoglu
- Department of Cheast Disease and Allergy, Acibadem Health Care, Istanbul, Turkey.
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A multi-hit endocrine model of intrinsic adult-onset asthma. Ageing Res Rev 2008; 7:114-25. [PMID: 18373959 DOI: 10.1016/j.arr.2007.12.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2007] [Accepted: 12/19/2007] [Indexed: 11/21/2022]
Abstract
Epidemiological studies indicate that adult-onset asthma is initiated by stress (anxiety and depression), obesity and menopause. Ironically, despite our understanding of the various stressors that promote chronic adult-onset asthma, most of which are known to elevate cortisol production via the hypothalamic-pituitary-adrenal (HPA) axis, inhaled and systemic corticosteroids are the mainstay for the treatment of chronic asthma. This implicates other endocrine or cellular changes independent of cortisol synthesis in non-allergic adult-onset asthma. The mechanism by which corticosteroids are thought to modulate bronchial tone in relieving asthma is via corticosteroid-responsive genes that increase PGE(2) and cAMP production which promote muscle relaxation. Therefore, any physiological condition that suppresses intracellular PGE(2) and cAMP production would counter cortisol-induced muscle relaxation and potentially trigger non-allergic adult-onset asthma. Stress, obesity and menopause act on three interrelated endocrine pathways, the serotonergic, leptinergic and hypothalamic pathways, all of which operate through receptors to modulate cAMP and Ca(2+) metabolism in smooth muscle cells (SMCs). We propose that the level of SMC cAMP, as determined by overall signaling through corticosteroid receptors, leptin receptors and the GPCRs of the HPG and serotonergic pathways, will regulate bronchial tone (i.e. the 'Multi-Hit Endocrine Model of Adult-Onset Asthma'). Thus, decreases in HPG (menopause) and serotonergic (depression) signaling and increases in leptinergic (obesity) signaling relative to HPA signaling would decrease cellular SMC cAMP and promote muscle contraction. This model can explain the discrepant epidemiological data associating stress, obesity, depression and menopause with adult-onset asthma and is supported by basic and clinical data. Treatment of depressed or menopausal asthmatics with selective serotonin reuptake inhibitors or hormone replacement therapy, respectively, alleviates bronchoconstriction. Future therapeutic strategies might therefore target the serotonergic, leptinergic and hypothalamic pathways in regulating cellular cAMP production and bronchoconstriction for the treatment of adult-onset asthma.
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Salam MT, Wenten M, Gilliland FD. Endogenous and exogenous sex steroid hormones and asthma and wheeze in young women. J Allergy Clin Immunol 2006; 117:1001-7. [PMID: 16675325 DOI: 10.1016/j.jaci.2006.02.004] [Citation(s) in RCA: 105] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2005] [Revised: 01/30/2006] [Accepted: 02/01/2006] [Indexed: 11/29/2022]
Abstract
BACKGROUND Emerging evidence suggests that both endogenous and exogenous sex steroid hormones may influence the occurrence of asthma and wheeze among women. OBJECTIVE We investigated the associations between exogenous sex hormone (oral contraceptive [OC]) use and wheezing in young women with and without asthma history. To investigate the role of endogenous sex hormones, we examined the association between age at menarche and the development of asthma after puberty. METHODS We conducted a study among 905 women who had undergone menarche. Subjects were between 13 and 28 years of age and had participated in the Children's Health Study. RESULTS In women without asthma, OC use was associated with higher risk of current wheeze (odds ratio [OR], 1.75; 95% CI, 1.15-2.65). In contrast, OC use was associated with a markedly reduced prevalence of current wheeze in women with a history of asthma (OR, 0.18; 95% CI, 0.06-0.56; P value for interaction = .003). These associations showed significant trends with duration of OC use. Age at menarche was associated with new-onset asthma after puberty. Compared with women who had menarche after age 12 years, women with menarche before age 12 years had a 2.08-fold (95% CI, 1.05-4.12) higher risk of asthma after puberty. CONCLUSION Both endogenous and exogenous sex steroid hormones affect asthma and wheeze occurrences in young women. CLINICAL IMPLICATIONS Because women have higher asthma risk after puberty, and OC use is common among young women, clinicians may inform women with asthma about the potential effects of OC on asthma-related respiratory symptoms.
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Affiliation(s)
- Muhammad T Salam
- Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles 90033, USA
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Haxhiu MA, Kc P, Moore CT, Acquah SS, Wilson CG, Zaidi SI, Massari VJ, Ferguson DG. Brain stem excitatory and inhibitory signaling pathways regulating bronchoconstrictive responses. J Appl Physiol (1985) 2005; 98:1961-82. [PMID: 15894534 DOI: 10.1152/japplphysiol.01340.2004] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
This review summarizes recent work on two basic processes of central nervous system (CNS) control of cholinergic outflow to the airways: 1) transmission of bronchoconstrictive signals from the airways to the airway-related vagal preganglionic neurons (AVPNs) and 2) regulation of AVPN responses to excitatory inputs by central GABAergic inhibitory pathways. In addition, the autocrine-paracrine modulation of AVPNs is briefly discussed. CNS influences on the tracheobronchopulmonary system are transmitted via AVPNs, whose discharge depends on the balance between excitatory and inhibitory impulses that they receive. Alterations in this equilibrium may lead to dramatic functional changes. Recent findings indicate that excitatory signals arising from bronchopulmonary afferents and/or the peripheral chemosensory system activate second-order neurons within the nucleus of the solitary tract (NTS), via a glutamate-AMPA signaling pathway. These neurons, using the same neurotransmitter-receptor unit, transmit information to the AVPNs, which in turn convey the central command to airway effector organs: smooth muscle, submucosal secretory glands, and the vasculature, through intramural ganglionic neurons. The strength and duration of reflex-induced bronchoconstriction is modulated by GABAergic-inhibitory inputs and autocrine-paracrine controlling mechanisms. Downregulation of GABAergic inhibitory influences may result in a shift from inhibitory to excitatory drive that may lead to increased excitability of AVPNs, heightened airway responsiveness, and sustained narrowing of the airways. Hence a better understanding of these normal and altered central neural circuits and mechanisms could potentially improve the design of therapeutic interventions and the treatment of airway obstructive diseases.
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Affiliation(s)
- Musa A Haxhiu
- Dept. of Physiology and Biophysics, Howard University College of Medicine, 520 W St. NW, Washington, DC 20059, USA.
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