BACKGROUND AND PURPOSE: Airway wall remodelling in asthma is characterised by a number of structural changes, including an increase in the volume of airway smooth muscle (ASM), and the abundance of the extracellular matrix (ECM) protein, collagen, is increased. We have investigated the mechanism of collagen-induced glucocorticoid resistance of proliferation, and migration of ASM. EXPERIMENTAL APPROACH: ASM cultured from human airways has been seeded on to either type I monomeric collagen or a laminin pentapeptide, YIGSR. The role of alpha2beta1 integrin in the collagen-induced glucocorticoid resistance was investigated using a function blocking monoclonal antibody. KEY RESULTS: Culture of ASM on collagen I, but not laminin, led to a greater proliferative response that was insensitive to regulation by dexamethasone (100 nM). The anti-migratory effects of the glucocorticoid, fluticasone propionate (1 nM) were also impaired by contact of ASM with collagen. The impaired anti-mitogenic action of dexamethasone was associated with a failure to reduce the levels of the rate-limiting cell cycle regulatory protein, cyclin D1. When signalling through the alpha2beta1 integrin was reduced, dexamethasone-mediated reductions in proliferation and cyclin D1 levels were restored. CONCLUSIONS AND IMPLICATIONS: In the collagen-rich microenvironment of the inflamed and fibrotic asthmatic airway, integrin/ECM interactions may contribute to glucocorticoid resistance.
BACKGROUND AND PURPOSE: Airway wall remodelling in asthma is characterised by a number of structural changes, including an increase in the volume of airway smooth muscle (ASM), and the abundance of the extracellular matrix (ECM) protein, collagen, is increased. We have investigated the mechanism of collagen-induced glucocorticoid resistance of proliferation, and migration of ASM. EXPERIMENTAL APPROACH: ASM cultured from human airways has been seeded on to either type I monomeric collagen or a laminin pentapeptide, YIGSR. The role of alpha2beta1 integrin in the collagen-induced glucocorticoid resistance was investigated using a function blocking monoclonal antibody. KEY RESULTS: Culture of ASM on collagen I, but not laminin, led to a greater proliferative response that was insensitive to regulation by dexamethasone (100 nM). The anti-migratory effects of the glucocorticoid, fluticasone propionate (1 nM) were also impaired by contact of ASM with collagen. The impaired anti-mitogenic action of dexamethasone was associated with a failure to reduce the levels of the rate-limiting cell cycle regulatory protein, cyclin D1. When signalling through the alpha2beta1 integrin was reduced, dexamethasone-mediated reductions in proliferation and cyclin D1 levels were restored. CONCLUSIONS AND IMPLICATIONS: In the collagen-rich microenvironment of the inflamed and fibrotic asthmatic airway, integrin/ECM interactions may contribute to glucocorticoid resistance.
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