Transgenic overexpression of α7 integrin in smooth muscle attenuates allergen-induced airway inflammation in a murine model of asthma

Asthma is a chronic inflammatory disorder of the lower airways characterized by modulation of airway smooth muscle (ASM) function. Infiltration of smooth muscle by inflammatory mediators is partially regulated by transmembrane integrins and the major smooth muscle laminin receptor alpha 7 beta 1 integrin plays a critical role in the maintenance of ASM phenotype. The goal of the current study was to investigate the role of alpha 7 integrin in asthma using smooth muscle-specific alpha 7 integrin transgenic mice (TgSM-Itg alpha 7) using both acute and chronic OVA sensitization and challenge protocols that mimic mild to severe asthmatic phenotypes. Transgenic over-expression of the alpha 7 integrin in smooth muscle resulted in a significant decrease in airway resistance relative to controls, reduced the total number of inflammatory cells and substantially inhibited the production of crucial Th2 and Th17 cytokines in airways. This was accompanied by decreased secretion of various inflammatory chemokines such as eotaxin/CCL11, KC/CXCL3, MCP-1/CCL2, and MIP-1 beta/CCL4. Additionally, alpha 7 integrin overexpression significantly decreased ERK1/2 phosphorylation in the lungs of TgSM-Itg alpha 7 mice and affected proliferative, contractile, and inflammatory downstream effectors of ERK1/2 that drive smooth muscle phenotype in the lung. Taken together, these results support the hypothesis that enhanced expression of alpha 7 integrin in vivo inhibits allergic inflammation and airway resistance. Moreover, we identify ERK1/2 as a potential target by which alpha 7 integrin signals to regulate airway inflammation. We conclude that identification of therapeutics targeting an increase in smooth muscle alpha 7 integrin expression could serve as a potential novel treatment for asthma.