Cargando…

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

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 m...

Descripción completa

Detalles Bibliográficos
Autores principales: Placido, Luis, Romero, Yair, Maldonado, Mariel, Toscano-Marquez, Fernanda, Ramírez, Remedios, Calyeca, Jazmín, Mora, Ana L., Selman, Moisés, Pardo, Annie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998872/
https://www.ncbi.nlm.nih.gov/pubmed/33805743
http://dx.doi.org/10.3390/ijms22062923
_version_ 1783670652385886208
author Placido, Luis
Romero, Yair
Maldonado, Mariel
Toscano-Marquez, Fernanda
Ramírez, Remedios
Calyeca, Jazmín
Mora, Ana L.
Selman, Moisés
Pardo, Annie
author_facet Placido, Luis
Romero, Yair
Maldonado, Mariel
Toscano-Marquez, Fernanda
Ramírez, Remedios
Calyeca, Jazmín
Mora, Ana L.
Selman, Moisés
Pardo, Annie
author_sort Placido, Luis
collection PubMed
description 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.
format Online
Article
Text
id pubmed-7998872
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-79988722021-03-28 Loss of MT1-MMP in Alveolar Epithelial Cells Exacerbates Pulmonary Fibrosis Placido, Luis Romero, Yair Maldonado, Mariel Toscano-Marquez, Fernanda Ramírez, Remedios Calyeca, Jazmín Mora, Ana L. Selman, Moisés Pardo, Annie Int J Mol Sci Article 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. MDPI 2021-03-13 /pmc/articles/PMC7998872/ /pubmed/33805743 http://dx.doi.org/10.3390/ijms22062923 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Placido, Luis
Romero, Yair
Maldonado, Mariel
Toscano-Marquez, Fernanda
Ramírez, Remedios
Calyeca, Jazmín
Mora, Ana L.
Selman, Moisés
Pardo, Annie
Loss of MT1-MMP in Alveolar Epithelial Cells Exacerbates Pulmonary Fibrosis
title Loss of MT1-MMP in Alveolar Epithelial Cells Exacerbates Pulmonary Fibrosis
title_full Loss of MT1-MMP in Alveolar Epithelial Cells Exacerbates Pulmonary Fibrosis
title_fullStr Loss of MT1-MMP in Alveolar Epithelial Cells Exacerbates Pulmonary Fibrosis
title_full_unstemmed Loss of MT1-MMP in Alveolar Epithelial Cells Exacerbates Pulmonary Fibrosis
title_short Loss of MT1-MMP in Alveolar Epithelial Cells Exacerbates Pulmonary Fibrosis
title_sort loss of mt1-mmp in alveolar epithelial cells exacerbates pulmonary fibrosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998872/
https://www.ncbi.nlm.nih.gov/pubmed/33805743
http://dx.doi.org/10.3390/ijms22062923
work_keys_str_mv AT placidoluis lossofmt1mmpinalveolarepithelialcellsexacerbatespulmonaryfibrosis
AT romeroyair lossofmt1mmpinalveolarepithelialcellsexacerbatespulmonaryfibrosis
AT maldonadomariel lossofmt1mmpinalveolarepithelialcellsexacerbatespulmonaryfibrosis
AT toscanomarquezfernanda lossofmt1mmpinalveolarepithelialcellsexacerbatespulmonaryfibrosis
AT ramirezremedios lossofmt1mmpinalveolarepithelialcellsexacerbatespulmonaryfibrosis
AT calyecajazmin lossofmt1mmpinalveolarepithelialcellsexacerbatespulmonaryfibrosis
AT moraanal lossofmt1mmpinalveolarepithelialcellsexacerbatespulmonaryfibrosis
AT selmanmoises lossofmt1mmpinalveolarepithelialcellsexacerbatespulmonaryfibrosis
AT pardoannie lossofmt1mmpinalveolarepithelialcellsexacerbatespulmonaryfibrosis