| First Author | Wheaton AK | Year | 2016 |
| Journal | Am J Physiol Lung Cell Mol Physiol | Volume | 310 |
| Issue | 11 | Pages | L1206-17 |
| PubMed ID | 27106291 | Mgi Jnum | J:235162 |
| Mgi Id | MGI:5793003 | Doi | 10.1152/ajplung.00424.2015 |
| Citation | Wheaton AK, et al. (2016) The vitronectin RGD motif regulates TGF-beta-induced alveolar epithelial cell apoptosis. Am J Physiol Lung Cell Mol Physiol 310(11):L1206-17 |
| abstractText | Transforming growth factor-beta (TGF-beta) is a critical driver of acute lung injury and fibrosis. Injury leads to activation of TGF-beta, which regulates changes in the cellular and matrix makeup of the lung during the repair and fibrosis phase. TGF-beta 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 arginine-glycine-aspartate (RGD) motif-containing plasma matrix proteins, including vitronectin and fibronectin. To determine the role of specific matrix proteins on TGF-beta-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 nonintegrin-binding arginine-glycine-glutamate (RGE) (Vtn(RGE/RGE)). We found that AECs cultured on fibronectin and vitronectin or in wild-type mouse serum are resistant to TGF-beta-induced apoptosis. In contrast, AECs cultured on laminin or in serum from Vtn(-/-) or Vtn(RGE/RGE) mice undergo robust TGF-beta-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 AEC 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 proapoptotic function of PAI-1 is mediated through vitronectin inhibition. Collectively, these data suggest that integrin-matrix signaling is an important regulator of TGF-beta-mediated AEC apoptosis and that PAI-1 functions as a natural regulator of this interaction. |
