title: Matrix metalloproteinase (MMP)-1 induces lung alveolar epithelial cell migration and proliferation, protects from apoptosis, and represses mitochondrial oxygen consumption.
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.
authors.affiliation: From the Facultad de Ciencias, Universidad Nacional Autónoma de México, México DF 04510, México.
authors.forename: Iliana
authors.initials: I
authors.lastname: Herrera
authors.affiliation: the Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, México DF 14080, México, and.
authors.forename: José
authors.initials: J
authors.lastname: Cisneros
authors.affiliation: From the Facultad de Ciencias, Universidad Nacional Autónoma de México, México DF 04510, México.
authors.forename: Mariel
authors.initials: M
authors.lastname: Maldonado
authors.affiliation: From the Facultad de Ciencias, Universidad Nacional Autónoma de México, México DF 04510, México.
authors.forename: Remedios
authors.initials: R
authors.lastname: Ramírez
authors.affiliation: the Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, México DF 14080, México, and.
authors.forename: Blanca
authors.initials: B
authors.lastname: Ortiz-Quintero
authors.affiliation: the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University, Chicago, Illinois 60611.
authors.forename: Elena
authors.initials: E
authors.lastname: Anso
authors.affiliation: the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University, Chicago, Illinois 60611.
authors.forename: Navdeep S
authors.initials: NS
authors.lastname: Chandel
authors.affiliation: the Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, México DF 14080, México, and.
authors.forename: Moisés
authors.initials: M
authors.lastname: Selman
authors.affiliation: From the Facultad de Ciencias, Universidad Nacional Autónoma de México, México DF 04510, México,. Electronic address: apardos@unam.mx.
authors.forename: Annie
authors.initials: A
authors.lastname: Pardo
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001761:Bleomycin / Q000494:pharmacology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis* / Q000235:genetics; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology*; D011650:Pulmonary Alveoli / Q000166:cytology / Q000201:enzymology*; D020545:Respiratory Mucosa / Q000166:cytology / Q000201:enzymology*; D019311:Staurosporine / Q000494:pharmacology
chemical_list: D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D001761:Bleomycin; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1; D019311:Staurosporine
keywords: Apoptosis; Epithelial Cell; Fibrosis; Hypoxia-inducible Factor (HIF); Idiopathic Pulmonary Fibrosis; Matrix Metalloproteinase (MMP)
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