TGFβ is a critical driver of acute lung injury and fibrosis. Injury leads to activation of TGFβ which regulates changes in the cellular and matrix makeup of the lung during the repair and fibrosis phase. TGFβ can also initiate alveolar epithelial cell (AEC) apoptosis. Injury leads to destruction of the laminin-rich basement membrane which is replaced by a provisional matrix composed of RGD motif-containing plasma matrix proteins including vitronectin and fibronectin. To determine the role of specific matrix proteins on TGFβ-induced apoptosis, we studied primary AECs cultured on different matrix conditions and utilized mice with deletion of vitronectin (Vtn-/-) or mice in which the vitronectin RGD motif is mutated to non-integrin binding RGE (VtnRGE/RGE). We found that AECs cultured on fibronectin and vitronectin or in wild-type mouse serum are resistant to TGFβ-induced apoptosis. In contrast, AECs cultured on laminin or in serum from Vtn-/- or VtnRGE/RGE mice undergo robust TGFβ-induced apoptosis. Plasminogen activator inhibitor-1 (PAI-1) sensitizes AECs to greater apoptosis by disrupting AEC engagement to vitronectin. Inhibition of integrin associated signaling proteins augments AECs apoptosis. Mice with transgenic deletion of PAI-1 have less apoptosis after bleomycin, but deletion of vitronectin or disruption of the vitronectin RGD motif reverses this protection suggesting that the pro-apoptotic function of PAI-1 is mediated through vitronectin inhibiton. Collectively, these data suggest that integrin-matrix signaling is an important regulator of TGFβ-mediated AEC apoptosis and that PAI-1 functions as a natural regulator of this interaction.
- Copyright © 2015, American Journal of Physiology - Lung Cellular and Molecular Physiology