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      Matrix metalloproteinase (MMP)-1 induces lung alveolar epithelial cell migration and proliferation, protects from apoptosis, and represses mitochondrial oxygen consumption.

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          Abstract

          Idiopathic pulmonary fibrosis is a devastating lung disorder of unknown etiology. Although its pathogenesis is unclear, considerable evidence supports an important role of aberrantly activated alveolar epithelial cells (AECs), which produce a large variety of mediators, including several matrix metalloproteases (MMPs), which participate in fibroblast activation and lung remodeling. MMP-1 has been shown to be highly expressed in AECs from idiopathic pulmonary fibrosis lungs although its role is unknown. In this study, we explored the role of MMP-1 in several AECs functions. Mouse lung epithelial cells (MLE12) transfected with human Mmp-1 showed significantly increased cell growth and proliferation at 36 and 48 h of culture (p < 0.01). Also, MMP-1 promoted MLE12 cell migration through collagen I, accelerated wound closing, and protected cells from staurosporine- and bleomycin-induced apoptosis compared with mock cells (p < 0.01). MLE12 cells expressing human MMP-1 showed a significant repression of oxygen consumption ratio compared with the cells with the empty vector. As under hypoxic conditions hypoxia-inducible factor-1α (HIF-1α) mediates a transition from oxidative to glycolytic metabolism, we analyzed activation of HIF-1α. Ηigher activation of this factor was detected in MMP-1-transfected cells under normoxia and hypoxia. Likewise, a significant decrease of both total and mitochondrial reactive oxygen species was observed in MMP-1-transfected cells. Paralleling these findings, attenuation of MMP-1 expression by shRNA in A549 (human) AECs markedly reduced proliferation and migration (p < 0.01) and increased the oxygen consumption ratio. These findings indicate that epithelial expression of MMP-1 inhibits mitochondrial function, increases HIF-1α expression, decreases reactive oxygen species production, and contributes to a proliferative, migratory, and anti-apoptotic AEC phenotype.

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          Author and article information

          Journal
          J Biol Chem
          The Journal of biological chemistry
          American Society for Biochemistry & Molecular Biology (ASBMB)
          1083-351X
          0021-9258
          Sep 06 2013
          : 288
          : 36
          Affiliations
          [1 ] From the Facultad de Ciencias, Universidad Nacional Autónoma de México, México DF 04510, México.
          [2 ] the Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, México DF 14080, México, and.
          [3 ] the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University, Chicago, Illinois 60611.
          [4 ] From the Facultad de Ciencias, Universidad Nacional Autónoma de México, México DF 04510, México,. Electronic address: apardos@unam.mx.
          Article
          S0021-9258(20)53593-X
          10.1074/jbc.M113.459784
          3764801
          23902766
          98406453-886a-4525-bf53-26fa21318857
          History

          Apoptosis,Epithelial Cell,Fibrosis,Hypoxia-inducible Factor (HIF),Idiopathic Pulmonary Fibrosis,Matrix Metalloproteinase (MMP)

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