Role of MUC5AC in the pathogenesis of exercise-induced bronchoconstriction

Hallstrand, Teal S.; Debley, Jason S.; Farin, Federico M.; Henderson, William R.

doi:10.1016/j.jaci.2007.01.005

Cited by 56 publications

(39 citation statements)

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“…The average time between baseline and post-exercise-induced sputum visits was 9.3 days (range, 4-18 d) in the asthma group, and 10.0 days (range, 5-19 d) in the control group. The levels of the eicosanoids (CysLTs, 15S-HETE, and PGE 2 ) were previously reported in the asthma group (8,29), and are compared with levels of eicosanoids in the control group in Figures E1 and E2 of the online supplement.…”

Section: Subject Characteristics and Eicosanoid Levelsmentioning

confidence: 99%

Secreted Phospholipase A₂Group X Overexpression in Asthma and Bronchial Hyperresponsiveness

Hallstrand

Emil

Singer

et al. 2007

Am J Respir Crit Care Med

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103

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Rationale: Secreted phospholipase A 2 enzymes (sPLA 2 s) play key regulatory roles in the biosynthesis of eicosanoids, such as the cysteinyl leukotrienes, but the role of these enzymes in the pathogenesis of asthma is not known. Objectives: To establish if sPLA 2 s are overexpressed in the airways of patients with asthma, and to determine if these enzymes may play a role in the generation of eicosanoids in exercise-induced bronchoconstriction. Methods: Induced sputum samples were obtained from subjects with asthma with exercise-induced bronchoconstriction and nonasthmatic control subjects at baseline, and on a separate day 30 minutes after exercise challenge. The expression of the PLA 2 s in induced sputum cells and supernatant was determined by quantitative polymerase chain reaction, immunocytochemistry, and Western blot. Measurements and Main Results: The sPLA 2 s expressed at the highest levels in airway cells of subjects with asthma were groups X and XIIA. Group X sPLA 2 (sPLA 2 -X) was differentially overexpressed in asthma and localized to airway epithelial cells and bronchial macrophages. The gene expression, immunostaining in airway epithelial cells and bronchial macrophages, and the level of the extracellular sPLA 2 -X protein in the airways increased in response to exercise challenge in the asthma group, whereas the levels were lower and unchanged after challenge in nonasthmatic control subjects. Conclusions: Increased expression of sPLA 2 -X may play a key role in the dysregulated eicosanoid synthesis in asthma.

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Section: Subject Characteristics and Eicosanoid Levelsmentioning

confidence: 99%

Secreted Phospholipase A₂Group X Overexpression in Asthma and Bronchial Hyperresponsiveness

Hallstrand

Emil

Singer

et al. 2007

Am J Respir Crit Care Med

Self Cite

103

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“…Exercise-induced bronchoconstriction (EIB) is a prototypical feature of indirect AHR in asthma that occurs in about 30 to 50% of subjects with asthma in cross-sectional studies (2,3). Prior studies have identified epithelial shedding into the airway lumen and increased production of inflammatory eicosanoids such as leukotrienes in the airways of patients with EIB (4)(5)(6)(7)(8). The basis for the dysregulation of eicosanoids in asthma is incompletely understood.…”

mentioning

confidence: 99%

Regulation and Function of Epithelial Secreted Phospholipase A₂ Group X in Asthma

Hallstrand

Lü

Altemeier

et al. 2013

Am J Respir Crit Care Med

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Rationale: Indirect airway hyperresponsiveness (AHR) is a fundamental feature of asthma that is manifest as exercise-induced bronchoconstriction (EIB). Secreted phospholipase A 2 group X (sPLA 2 -X) plays a key role in regulating eicosanoid formation and the development of inflammation and AHR in murine models. Objectives: We sought to examine sPLA 2 -X in the airway epithelium and airway wall of patients with asthma, the relationship to AHR in humans, and the regulation and function of sPLA 2 -X within the epithelium. Methods: We precisely phenotyped 34 patients with asthma (19 with and 15 without EIB) and 10 normal control subjects to examine in vivo differences in epithelial gene expression, quantitative morphometry of endobronchial biopsies, and levels of secreted protein. The regulation of sPLA 2 -X gene (PLA2G10) expression was examined in primary airway epithelial cell cultures. The function of epithelial sPLA 2 -X in eicosanoid formation was examined using PLA 2 inhibitors and murine tracheal epithelial cells with Pla2g10 deletion. Measurements and Main Results: We found that sPLA 2 -X protein is increased in the airways of patients with asthma and that epithelial-derived sPLA 2 -X may be increased in association with indirect AHR. The expression of sPLA 2 -X increases during in vitro epithelial differentiation; is regulated by inflammatory signals including tumor necrosis factor, IL-13, and IL-17; and is both secreted from the epithelium and directly participates in the release of arachidonic acid by epithelial cells. Conclusions: These data reveal a relationship between epithelialderived sPLA 2 -X and indirect AHR in asthma and that sPLA 2 -X serves as an epithelial regulator of inflammatory eicosanoid formation. Therapies targeting epithelial sPLA 2 -X may be useful in asthma.Keywords: airway hyperresponsiveness; asthma; eicosanoid; epithelial cell; secretory phospholipase A 2Indirect airway hyperresponsiveness (AHR) refers to the propensity to develop airway narrowing in response to stimuli such as exercise, osmotic challenge, or adenosine that cause airflow obstruction via inflammatory or neuronal cells that release mediators (1). Exercise-induced bronchoconstriction (EIB) is a prototypical feature of indirect AHR in asthma that occurs in about 30 to 50% of subjects with asthma in cross-sectional studies (2, 3). Prior studies have identified epithelial shedding into the airway lumen and increased production of inflammatory eicosanoids such as leukotrienes in the airways of patients with EIB (4-8). The basis for the dysregulation of eicosanoids in asthma is incompletely understood. The rate-limiting step in eicosanoid biosynthesis is the release of unesterified arachidonic acid (AA) from the sn-2 position of membrane phospholipids by phospholipase A 2 (PLA 2 ) (9). Recent work has uncovered 10 mammalian secreted PLA 2 s (sPLA 2 s) that may coordinate eicosanoid synthesis with the well-described cytosolic PLA 2 -a (i.e., cPLA 2 a) (10-12). sPLA 2 s have several other inflammatory functions, including ...

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“…Two polymeric mucins (MUC5AC and MUC5B) are normally expressed and secreted in the lungs by secretory cells in the conducting airway epithelium and submucosal glands, respectively. Increased production of MUC5AC mRNA and protein occurs in the airway epithelium and secretions of patients with asthma (7)(8)(9)(10), and MUC5B concentrations are increased in the secretions of patients with chronic obstructive diseases (11). Studies from several laboratories have shown that secretory mucin gene expression is up-regulated in lung epithelial cells in vitro by inflammatory/immune response mediators that are activated in the respiratory tract in response to airborne challenges and mechanisms whereby mediators up-regulating mucin gene expression have been identified (6,12,13).…”

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confidence: 99%

Glucocorticoid Receptor and Histone Deacetylase–2 Mediate Dexamethasone-Induced Repression of MUC5AC Gene Expression

Chen

Watson

Williamson³

et al. 2012

Am J Respir Cell Mol Biol

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Airway occlusion in obstructive airway diseases is caused in part by the overproduction of secretory mucin glycoproteins through the up-regulation of mucin (MUC) genes by inflammatory mediators. Some pharmacological agents, including the glucocorticoid dexamethasone (Dex), repress mucin concentrations in lung epithelial cancer cells. Here, we show that Dex reduces the expression of MUC5AC, a major airway mucin gene, in primary differentiated normal human bronchial epithelial (NHBE) cells in a dose-dependent and time-dependent manner, and that the Dex-induced repression is mediated by the glucocorticoid receptor (GR) and two glucocorticoid response elements (GREs) in the MUC5AC promoter. The preexposure of cells to RU486, a GR antagonist, and mutations in either the GRE3 or GRE5 cis-sites abolished the Dex-induced repression. Chromatin immunoprecipitation (ChIP) assays showed a rapid temporal recruitment of GR to the GRE3 and GRE5 cis-elements in the MUC5AC promoter in NHBE and in A549 cells. Immunofluorescence showed nuclear colocalization of GR and histone deacetylase-2 (HDAC2) in MUC5AC-expressing NHBE cells. ChIP also showed a rapid temporal recruitment of HDAC2 to the GRE3 and GRE5 cis-elements in the MUC5AC promoter in both cell types. The knockdown of HDAC2 by HDAC2-specific short interfering RNA prevented the Dex-induced repression of MUC5AC in NHBE and A549 cells. These data demonstrate that GR and HDAC2 are recruited to the GRE3 and GRE5 cis-sites in the MUC5AC promoter and mediate the Dexinduced cis repression of MUC5AC gene expression. A better understanding of the mechanisms whereby glucocorticoids repress MUC5AC gene expression may be useful in formulating therapeutic interventions in chronic lung diseases.Keywords: MUC5AC; HDAC2; dexamethasone; gene repression; glucocorticoid receptor Mucus covers and protects the epithelium in the mammalian respiratory, gastrointestinal, and reproductive tracts, and contributes to the mucosal defense barrier (1, 2). In the respiratory tract, secreted mucin glycoproteins (mucins), the major macromolecular components of lung mucus, are part of the innate immune defense system and mucociliary escalator that protect the airways against airborne challenges (3). Mucin production is increased in chronic lung diseases and contributes to the occlusion of the conducting airways by mucus, thereby significantly affecting disease morbidity and mortality in patients with asthma, cystic fibrosis, bronchopulmonary dysplasia, and chronic obstructive pulmonary diseases (4).Mucin (MUC) genes encode the protein backbone of human mucins, and exhibit a selective tissue and cell specificity that is frequently altered in inflammatory diseases and in cancer (5, 6). Two polymeric mucins (MUC5AC and MUC5B) are normally expressed and secreted in the lungs by secretory cells in the conducting airway epithelium and submucosal glands, respectively. Increased production of MUC5AC mRNA and protein occurs in the airway epithelium and secretions of patients with asthma (7-10), and MUC5B concentrati...

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Role of MUC5AC in the pathogenesis of exercise-induced bronchoconstriction

Abstract: Background: The pathogenesis of exercise-induced bronchoconstriction (EIB) involves the release of mediators from several airway cells in response to exercise challenge, but the mechanism leading to airflow obstruction during EIB is incompletely understood.

Cited by 56 publications

References 44 publications

Secreted Phospholipase A₂Group X Overexpression in Asthma and Bronchial Hyperresponsiveness

Secreted Phospholipase A₂Group X Overexpression in Asthma and Bronchial Hyperresponsiveness

Regulation and Function of Epithelial Secreted Phospholipase A₂ Group X in Asthma

Glucocorticoid Receptor and Histone Deacetylase–2 Mediate Dexamethasone-Induced Repression of MUC5AC Gene Expression

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Role of MUC5AC in the pathogenesis of exercise-induced bronchoconstriction

Abstract: Background: The pathogenesis of exercise-induced bronchoconstriction (EIB) involves the release of mediators from several airway cells in response to exercise challenge, but the mechanism leading to airflow obstruction during EIB is incompletely understood.

Cited by 56 publications

References 44 publications

Secreted Phospholipase A2Group X Overexpression in Asthma and Bronchial Hyperresponsiveness

Secreted Phospholipase A2Group X Overexpression in Asthma and Bronchial Hyperresponsiveness

Regulation and Function of Epithelial Secreted Phospholipase A2 Group X in Asthma

Glucocorticoid Receptor and Histone Deacetylase–2 Mediate Dexamethasone-Induced Repression of MUC5AC Gene Expression

Contact Info

Product

Resources

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Secreted Phospholipase A₂Group X Overexpression in Asthma and Bronchial Hyperresponsiveness

Secreted Phospholipase A₂Group X Overexpression in Asthma and Bronchial Hyperresponsiveness

Regulation and Function of Epithelial Secreted Phospholipase A₂ Group X in Asthma