Abstract
Fibrosis is characterized by fibroblast activation, leading to matrix remodeling culminating in a stiff, type I collagen-rich fibrotic matrix. Alveolar epithelial cell (AEC) apoptosis is also a major feature of fibrogenesis, and AEC apoptosis is sufficient to initiate a robust lung fibrotic response. TGF-β (transforming growth factor-β) is a major driver of fibrosis and can induce both AEC apoptosis and fibroblast activation. We and others have previously shown that changes in extracellular matrix stiffness and composition can regulate the cellular response to TGF-β. In the present study, we find that type I collagen signaling promotes TGF-β-mediated fibroblast activation and inhibits TGF-β-induced AEC death. Fibroblasts cultured on type I collagen or fibrotic decellularized lung matrix had augmented activation in response to TGF-β, whereas AECs on cultured on type I collagen or fibrotic lung matrix were more resistant to TGF-β-induced apoptosis. Both of these responses were mediated by integrin α(2)β(1), a major collagen receptor. AECs treated with an α(2) integrin inhibitor or with deletion of α(2) integrin had loss of collagen-mediated protection from apoptosis. We found that mice with fibroblast-specific deletion of α(2) integrin were protected from fibrosis whereas mice with AEC-specific deletion of α(2) integrin had more lung injury and a greater fibrotic response to bleomycin. Intrapulmonary delivery of an α(2) integrin-activating collagen peptide inhibited AEC apoptosis in vitro and in vivo and attenuated the fibrotic response. These studies underscore the need for a thorough understanding of the divergent response to matrix signaling.