title: Airway smooth muscle enlargement is associated with protease-activated receptor 2/ligand overexpression in patients with difficult-to-control severe asthma.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.affiliation: 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.
authors.forename: Michel
authors.initials: M
authors.lastname: Aubier
authors.affiliation: 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.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Thabut
authors.affiliation: 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.
authors.forename: Fatima
authors.initials: F
authors.lastname: Hamidi
authors.affiliation: 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.
authors.forename: Noëlline
authors.initials: N
authors.lastname: Guillou
authors.affiliation: 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.
authors.forename: Julien
authors.initials: J
authors.lastname: Brard
authors.affiliation: 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.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Dombret
authors.affiliation: 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.
authors.forename: Keren
authors.initials: K
authors.lastname: Borensztajn
authors.affiliation: 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.
authors.forename: Brahim
authors.initials: B
authors.lastname: Aitilalne
authors.affiliation: 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.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Poirier
authors.affiliation: 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.
authors.forename: Pascale
authors.initials: P
authors.lastname: Roland-Nicaise
authors.affiliation: 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.
authors.forename: Camille
authors.initials: C
authors.lastname: Taillé
authors.affiliation: 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.
authors.forename: Marina
authors.initials: M
authors.lastname: Pretolani
mesh_terms: D000328:Adult; D000368:Aged; D056151:Airway Remodeling; D001249:Asthma / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001980:Bronchi / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002452:Cell Count; D004804:Eosinophils / Q000276:immunology; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D007610:Kallikreins / Q000378:metabolism; D008024:Ligands; D008297:Male; D008875:Middle Aged; D009130:Muscle, Smooth / Q000473:pathology*; D009504:Neutrophils / Q000276:immunology; D044464:Receptor, PAR-2 / Q000378:metabolism*; D053802:Tryptases / Q000378:metabolism; D014797:Vital Capacity
chemical_list: D008024:Ligands; D044464:Receptor, PAR-2; C400147:KLK5 protein, human; D007610:Kallikreins; D053802:Tryptases
keywords: Airway remodeling; asthma control; kallikreins; mast cells; protease-activated receptor 2; tryptase