ABSTRACT
Idiopathic pulmonary fibrosis (IPF) is a lethal age-related lung disease whose pathogenesis involves an aberrant response of alveolar epithelial cells (AEC). Activated epithelial cells secrete mediators that participate in the activation of fibroblasts and the excessive deposition of extracellular matrix proteins. Previous studies indicate that matrix metalloproteinase 14 (MMP14) is increased in the lung epithelium in patients with IPF, however, the role of this membrane-type matrix metalloproteinase has not been elucidated. In this study, the role of Mmp14 was explored in experimental lung fibrosis induced with bleomycin in a conditional mouse model of lung epithelial MMP14-specific genetic deletion. Our results show that epithelial Mmp14 deficiency in mice increases the severity and extension of fibrotic injury and affects the resolution of the lesions. Gain-and loss-of-function experiments with human epithelial cell line A549 demonstrated that cells with a deficiency of MMP14 exhibited increased senescence-associated markers. Moreover, conditioned medium from these cells increased fibroblast expression of fibrotic molecules. These findings suggest a new anti-fibrotic mechanism of MMP14 associated with anti-senescent activity, and consequently, its absence results in impaired lung repair. Increased MMP14 in IPF may represent an anti-fibrotic mechanism that is overwhelmed by the strong profibrotic microenvironment that characterizes this disease.
Subject(s)
Epithelial Cells/pathology , Idiopathic Pulmonary Fibrosis/genetics , Matrix Metalloproteinase 14/genetics , Pulmonary Alveoli/metabolism , A549 Cells , Actins/genetics , Actins/metabolism , Animals , Bleomycin/administration & dosage , Cellular Senescence/genetics , Collagen Type I/genetics , Collagen Type I/metabolism , Collagen Type I, alpha 1 Chain , Disease Models, Animal , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Fibronectins/genetics , Fibronectins/metabolism , Gene Expression Regulation , Humans , Hypoxanthine Phosphoribosyltransferase/genetics , Hypoxanthine Phosphoribosyltransferase/metabolism , Idiopathic Pulmonary Fibrosis/chemically induced , Idiopathic Pulmonary Fibrosis/metabolism , Idiopathic Pulmonary Fibrosis/pathology , Matrix Metalloproteinase 14/deficiency , Mice , Mice, Inbred C57BL , Mice, Knockout , Primary Cell Culture , Pulmonary Alveoli/drug effects , Pulmonary Alveoli/pathology , Succinate Dehydrogenase/genetics , Succinate Dehydrogenase/metabolism , Transforming Growth Factor beta1/genetics , Transforming Growth Factor beta1/metabolismABSTRACT
Idiopathic pulmonary fibrosis (IPF) is a progressive and usually lethal interstitial lung disease of unknown etiology characterized by aberrant activation of epithelial cells that induce the migration, proliferation and activation of fibroblasts. The resulting distinctive fibroblastic/myofibroblastic foci are responsible for the excessive extracellular matrix (ECM) production and abnormal lung remodeling. We have recently found that matrix metalloproteinase 19 (MMP-19)-deficient (Mmp19-/-) mice develop an exaggerated bleomycin-induced lung fibrosis, but the mechanisms are unclear. In this study, we explored the effect of MMP-19 deficiency on fibroblast gene expression and cell behavior. Microarray analysis of Mmp19-/- lung fibroblasts revealed the dysregulation of several profibrotic pathways, including ECM formation, migration, proliferation, and autophagy. Functional studies confirmed these findings. Compared with wild-type mice, Mmp19-/- lung fibroblasts showed increased α1 (I) collagen gene and collagen protein production at baseline and after transforming growth factor-ß treatment and increased smooth muscle-α actin expression (P < 0.05). Likewise, Mmp19-deficient lung fibroblasts showed a significant increase in proliferation (P < 0.01) and in transmigration and locomotion over Boyden chambers coated with type I collagen or with Matrigel (P < 0.05). These findings suggest that, in lung fibroblasts, MMP-19 has strong regulatory effects on the synthesis of key ECM components, on fibroblast to myofibroblast differentiation, and in migration and proliferation.
Subject(s)
Cell Differentiation , Cell Movement , Cell Proliferation , Matrix Metalloproteinases, Secreted/deficiency , Myofibroblasts/enzymology , Pulmonary Fibrosis/enzymology , Animals , Autoantigens/biosynthesis , Autoantigens/genetics , Cells, Cultured , Extracellular Matrix/enzymology , Extracellular Matrix/genetics , Extracellular Matrix/pathology , Gene Expression Regulation/genetics , Mice , Mice, Knockout , Myofibroblasts/pathology , Non-Fibrillar Collagens/biosynthesis , Non-Fibrillar Collagens/genetics , Pulmonary Fibrosis/genetics , Pulmonary Fibrosis/pathology , Collagen Type XVIIABSTRACT
Se informa el caso de un paciente del sexo masculino con antecedentes de trastornos psiquiátricos y varios intentos suicidas, que se autoadministró en la vena mediana cubital del brazo izquierdo 10 ml de queroseno. De inmediato comenzó a presentar disnea intensa, dolor torácico, acentuada polipnea, por lo que fue trasladado al hospital. A pesar de las medidas terapéuticas aplicadas en la Unidad de Cuidados Intermedios el cuadro respiratorio empeoró, por lo que se decidió su ingreso en la sala de Cuidados Intensivos, donde a través del programa de computación HEMO confeccionado para esa sala se efectuaron estudios hemodinámicos cuyos resultados aportaron a la posible presencia de hipertensión pulmonar arteriolar. De la evolución de este caso se obtuvieron como experiencia y se recomienda ante cuadros similares establecer rápidamente la medida encaminada a prevenir y tratar el edema pulmonar, así como la ventilación artificial con PEED (AU)
Subject(s)
Humans , Male , Respiratory Insufficiency/diagnosis , Toxic SubstancesABSTRACT
Se informa el caso de un paciente del sexo masculino con antecedentes de trastornos psiquiátricos y varios intentos suicidas, que se autoadministró en la vena mediana cubital del brazo izquierdo 10 ml de queroseno. De inmediato comenzó a presentar disnea intensa, dolor torácico, acentuada polipnea, por lo que fue trasladado al hospital. A pesar de las medidas terapéuticas aplicadas en la Unidad de Cuidados Intermedios el cuadro respiratorio empeoró, por lo que se decidió su ingreso en la sala de Cuidados Intensivos, donde a través del programa de computación HEMO confeccionado para esa sala se efectuaron estudios hemodinámicos cuyos resultados aportaron a la posible presencia de hipertensión pulmonar arteriolar. De la evolución de este caso se obtuvieron como experiencia y se recomienda ante cuadros similares establecer rápidamente la medida encaminada a prevenir y tratar el edema pulmonar, así como la ventilación artificial con PEED
