Laminin α4 contributes to airway remodeling and inflammation in asthma

Airway inflammation and remodeling are characteristic features of asthma, with both contributing to airway hyperresponsiveness (AHR) and lung function limitation. Airway smooth muscle (ASM) accumulation and extracellular matrix deposition are characteristic features of airway remodeling, which may contribute to persistent AHR. Laminins containing the alpha 2-chain contribute to characteristics of ASM remodeling in vitro and AHR in animal models of asthma. The role of other laminin chains, including the laminin alpha 4 and alpha 5 chains, which contribute to leukocyte migration in other diseases, is currently unknown. The aim of the current study was to investigate the role of these laminin chains in ASM function and in AHR, remodeling, and inflammation in asthma. Expression of both laminin alpha 4 and alpha 5 was observed in the human and mouse ASM bundle. In vitro, laminin alpha 4 was found to promote a pro-proliferative, pro-contractile, and profibrotic ASM cell phenotype. In line with this, treatment with laminin alpha 4 and alpha 5 function-blocking antibodies reduced allergen-induced increases in ASM mass in a mouse model of allergen-induced asthma. Moreover, eosinophilic inflammation was reduced by the laminin alpha 4 function-blocking antibody as well. Using airway biopsies from healthy subjects and asthmatic patients, we found inverse correlations between ASM alpha 4-chain expression and lung function and AHR, whereas eosinophil numbers correlated positively with expression of laminin alpha 4 in the ASM bundle. This study, for the first time, indicates a prominent role for laminin alpha 4 in ASM function and in inflammation, AHR, and remodeling in asthma, whereas the role of laminin alpha 5 is more subtle.