ABSTRACT
Severe asthma is associated with airway remodeling, characterized by structural changes including increased smooth muscle mass and matrix deposition in the airway, leading to deteriorating lung function. TGF-ß is a pleiotropic cytokine leading to increased synthesis of matrix molecules by human airway smooth muscle (HASM) cells and is implicated in asthmatic airway remodeling. TGF-ß is synthesized as a latent complex, sequestered in the extracellular matrix, and requires activation for functionality. Activation of latent TGF-ß is the rate-limiting step in its bioavailability. This study investigated the effect of the contraction agonists LPA and methacholine on TGF-ß activation by HASM cells and its role in the development of asthmatic airway remodeling. The data presented show that LPA and methacholine induced TGF-ß activation by HASM cells via the integrin αvß5. Our findings highlight the importance of the ß5 cytoplasmic domain because a polymorphism in the ß5 subunit rendered the integrin unable to activate TGF-ß. To our knowledge, this is the first description of a biologically relevant integrin that is unable to activate TGF-ß. These data demonstrate that murine airway smooth muscle cells express αvß5 integrins and activate TGF-ß. Finally, these data show that inhibition, or genetic loss, of αvß5 reduces allergen-induced increases in airway smooth muscle thickness in two models of asthma. These data highlight a mechanism of TGF-ß activation in asthma and support the hypothesis that bronchoconstriction promotes airway remodeling via integrin mediated TGF-ß activation.
