Airway smooth muscle enlargement is associated with protease-activated receptor 2/ligand overexpression in patients with difficult-to-control severe asthma

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 severalASMmitogenic 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.