Michel Aubier1, Gabriel Thabut2, Fatima Hamidi3, Noëlline Guillou3, Julien Brard3, Marie-Christine Dombret1, Keren Borensztajn3, Brahim Aitilalne4, Isabelle Poirier3, Pascale Roland-Nicaise5, Camille Taillé1, Marina Pretolani6. 1. Inserm UMR1152, Physiopathologie et Epidémiologie des Maladies Respiratoires, Paris, France; Université Paris Diderot, Faculté de Médecine, site Bichat, Paris, France; Départment de Pneumologie A, Groupement Hospitalier Universitaire Nord Bichat-Claude Bernard, Paris, France; Départment de Hématologie-Immunologie, Groupement Hospitalier Universitaire Nord Bichat-Claude Bernard, Paris, France; Assistance Publique des Hopitaux de Paris, Paris, France; Laboratory of Excellence INFLAMEX, Université Sorbonne Paris-Cité, Paris, France; Département Hospitalo-Universitaire FIRE, Paris, France. 2. Inserm UMR1152, Physiopathologie et Epidémiologie des Maladies Respiratoires, Paris, France; Université Paris Diderot, Faculté de Médecine, site Bichat, Paris, France; Départment de Pneumologie B, Groupement Hospitalier Universitaire Nord Bichat-Claude Bernard, Paris, France; Assistance Publique des Hopitaux de Paris, Paris, France; Laboratory of Excellence INFLAMEX, Université Sorbonne Paris-Cité, Paris, France; Département Hospitalo-Universitaire FIRE, Paris, France. 3. Inserm UMR1152, Physiopathologie et Epidémiologie des Maladies Respiratoires, Paris, France; Université Paris Diderot, Faculté de Médecine, site Bichat, Paris, France; Laboratory of Excellence INFLAMEX, Université Sorbonne Paris-Cité, Paris, France; Département Hospitalo-Universitaire FIRE, Paris, France. 4. Inserm UMR1152, Physiopathologie et Epidémiologie des Maladies Respiratoires, Paris, France; Université Paris Diderot, Faculté de Médecine, site Bichat, Paris, France; Centre d'Investigation Clinique, Groupement Hospitalier Universitaire Nord Bichat-Claude Bernard, Paris, France; Laboratory of Excellence INFLAMEX, Université Sorbonne Paris-Cité, Paris, France; Département Hospitalo-Universitaire FIRE, Paris, France. 5. Université Paris Diderot, Faculté de Médecine, site Bichat, Paris, France; Départment de Pneumologie A, Groupement Hospitalier Universitaire Nord Bichat-Claude Bernard, Paris, France; Assistance Publique des Hopitaux de Paris, Paris, France. 6. Inserm UMR1152, Physiopathologie et Epidémiologie des Maladies Respiratoires, Paris, France; Université Paris Diderot, Faculté de Médecine, site Bichat, Paris, France; Laboratory of Excellence INFLAMEX, Université Sorbonne Paris-Cité, Paris, France; Département Hospitalo-Universitaire FIRE, Paris, France. Electronic address: marina.pretolani@inserm.fr.
Abstract
BACKGROUND: Asthma is a complex disease with heterogeneous features of airway inflammation and remodeling. The increase in airway smooth muscle (ASM) mass is an essential component of airway remodeling in patients with severe asthma, yet the pathobiological mechanisms and clinical outcomes associated with ASM enlargement remain elusive. OBJECTIVE: We sought to compare ASM area in control subjects and patients with mild-to-moderate or severe asthma and to identify specific clinical and pathobiological characteristics associated with ASM enlargement. METHODS: Bronchial biopsy specimens from 12 control subjects, 24 patients with mild-to-moderate asthma, and 105 patients with severe asthma were analyzed for ASM area, basement membrane thickness, vessels, eosinophils, neutrophils, T lymphocytes, mast cells, and protease-activated receptor 2 (PAR-2). In parallel, the levels of several ASM mitogenic factors, including the PAR-2 ligands, mast cell tryptase, trypsin, tissue factor, and kallikrein (KLK) 5 and KLK14, were assessed in bronchoalveolar lavage fluid. Data were correlated with asthma severity and control both at inclusion and after 12 to 18 months of optimal management and therapy. RESULTS: Analyses across ASM quartiles in patients with severe asthma demonstrated that patients with the highest ASM quartile (median value of ASM area, 26.3%) were younger (42.5 vs ≥50 years old in the other groups, P ≤ .04) and had lower asthma control after 1 year of optimal management (P ≤ .006). ASM enlargement occurred independently of features of airway inflammation and remodeling, whereas it was associated with PAR-2 overexpression and higher alveolar tryptase (P ≤ .02) and KLK14 (P ≤ .03) levels. CONCLUSION: Increase in ASM mass, possibly involving aberrant expression and activation of PAR-2-mediated pathways, characterizes younger patients with severe asthma with poor asthma control.
BACKGROUND:Asthma is a complex disease with heterogeneous features of airway inflammation and remodeling. The increase in airway smooth muscle (ASM) mass is an essential component of airway remodeling in patients with severe asthma, yet the pathobiological mechanisms and clinical outcomes associated with ASM enlargement remain elusive. OBJECTIVE: We sought to compare ASM area in control subjects and patients with mild-to-moderate or severe asthma and to identify specific clinical and pathobiological characteristics associated with ASM enlargement. METHODS: Bronchial biopsy specimens from 12 control subjects, 24 patients with mild-to-moderate asthma, and 105 patients with severe asthma were analyzed for ASM area, basement membrane thickness, vessels, eosinophils, neutrophils, T lymphocytes, mast cells, and protease-activated receptor 2 (PAR-2). In parallel, the levels of several ASM mitogenic factors, including the PAR-2 ligands, mast cell tryptase, trypsin, tissue factor, and kallikrein (KLK) 5 and KLK14, were assessed in bronchoalveolar lavage fluid. Data were correlated with asthma severity and control both at inclusion and after 12 to 18 months of optimal management and therapy. RESULTS: Analyses across ASM quartiles in patients with severe asthma demonstrated that patients with the highest ASM quartile (median value of ASM area, 26.3%) were younger (42.5 vs ≥50 years old in the other groups, P ≤ .04) and had lower asthma control after 1 year of optimal management (P ≤ .006). ASM enlargement occurred independently of features of airway inflammation and remodeling, whereas it was associated with PAR-2 overexpression and higher alveolar tryptase (P ≤ .02) and KLK14 (P ≤ .03) levels. CONCLUSION: Increase in ASM mass, possibly involving aberrant expression and activation of PAR-2-mediated pathways, characterizes younger patients with severe asthma with poor asthma control.
Authors: Cameron T Landers; Hui-Ying Tung; J Morgan Knight; Matthew C Madison; Yifan Wu; Zhimin Zeng; Paul C Porter; Antony Rodriguez; Matthew J Flick; Farrah Kheradmand; David B Corry Journal: J Biol Chem Date: 2019-04-16 Impact factor: 5.157
Authors: Marta Michalik; Katarzyna Wójcik-Pszczoła; Milena Paw; Dawid Wnuk; Paulina Koczurkiewicz; Marek Sanak; Elżbieta Pękala; Zbigniew Madeja Journal: Cell Mol Life Sci Date: 2018-08-12 Impact factor: 9.261