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The vitronectin RGD motif regulates TGF-ß-induced alveolar epithelial cell apoptosis.
Wheaton, Amanda K; Velikoff, Miranda; Agarwal, Manisha; Loo, Tiffany T; Horowitz, Jeffrey C; Sisson, Thomas H; Kim, Kevin K.
Afiliación
  • Wheaton AK; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
  • Velikoff M; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
  • Agarwal M; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
  • Loo TT; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
  • Horowitz JC; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
  • Sisson TH; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
  • Kim KK; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan kevkim@med.umich.edu.
Am J Physiol Lung Cell Mol Physiol ; 310(11): L1206-17, 2016 06 01.
Article en En | MEDLINE | ID: mdl-27106291
Transforming growth factor-ß (TGF-ß) is a critical driver of acute lung injury and fibrosis. Injury leads to activation of TGF-ß, which regulates changes in the cellular and matrix makeup of the lung during the repair and fibrosis phase. TGF-ß 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-ß-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-ß-induced apoptosis. In contrast, AECs cultured on laminin or in serum from Vtn(-/-) or Vtn(RGE/RGE) mice undergo robust TGF-ß-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-ß-mediated AEC apoptosis and that PAI-1 functions as a natural regulator of this interaction.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factor de Crecimiento Transformador beta / Apoptosis / Vitronectina / Células Epiteliales Alveolares Límite: Animals Idioma: En Revista: Am J Physiol Lung Cell Mol Physiol Asunto de la revista: BIOLOGIA MOLECULAR / FISIOLOGIA Año: 2016 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factor de Crecimiento Transformador beta / Apoptosis / Vitronectina / Células Epiteliales Alveolares Límite: Animals Idioma: En Revista: Am J Physiol Lung Cell Mol Physiol Asunto de la revista: BIOLOGIA MOLECULAR / FISIOLOGIA Año: 2016 Tipo del documento: Article Pais de publicación: Estados Unidos