Loss of MT1-MMP in Alveolar Epithelial Cells Exacerbates Pulmonary Fibrosis

International Journal of Molecular Sciences

AnaL. Mora¹  Annie Pardo²  Luis Placido²  Yair Romero²  Remedios Ramírez²  Jazmín Calyeca²  Fernanda Toscano-Marquez²  Mariel Maldonado³  Moisés Selman³ 

[1] Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA;Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico;Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío Villegas”, Mexico City 14080, Mexico;

关键词: Matrix metalloproteinases;    MMP;    lung fibrosis;    IPF;   

DOI  :  10.3390/ijms22062923

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown