Role of matrix metalloproteinases in the pathogenesis of idiopathic pulmonary fibrosis.

Annie Pardo,Sandra Cabrera,Moisés Selman,Mariel Maldonado

doi:10.1186/s12931-016-0343-6

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and devastating lung disorder of unknown origin, with very poor prognosis and no effective treatment. The disease is characterized by abnormal activation of alveolar epithelial cells, which secrete numerous mediators involved in the expansion of the fibroblast population, its differentiation to myofibroblasts, and in the exaggerated accumulation of extracellular matrix provoking the loss of lung architecture. Among the excessively produced mediators are several matrix metalloproteases (MMPs) which may contribute to modify the lung microenvironment by various mechanisms. Thus, these enzymes can not only degrade all the components of the extracellular matrix, but they are also able to release, cleave and activate a wide range of growth factors, cytokines, chemokines and cell surface receptors affecting numerous cell functions including adhesion, proliferation, differentiation, recruiting and transmigration, and apoptosis. Therefore, dysregulated expression of MMPs may have profound impact on the biopathological mechanisms implicated in the development of IPF. This review focuses on the current and emerging evidence regarding the role of MMPs on the fibrotic processes in IPF as well as in mouse models of lung fibrosis.

Highlights

Idiopathic pulmonary fibrosis Idiopathic pulmonary fibrosis (IPF), the most aggressive fibrotic lung disorder, is a chronic, progressive, irreversible, and usually lethal lung disease of unknown etiology [1, 2].IPF is an aging-associated disease usually found in people over 50 and its incidence and prevalence increases markedly in the elderly
We have found that in IPF lungs that MMP14 was the most highly expressed of the membrane type matrix metalloproteases (MMPs) and was expressed by alveolar epithelial cells, its role in this disease is presently unknown [63]
In the last two decades, MMPs have emerged as critical players in the pathogenesis of lung fibrosis

Summary

Background

Idiopathic pulmonary fibrosis Idiopathic pulmonary fibrosis (IPF), the most aggressive fibrotic lung disorder, is a chronic, progressive, irreversible, and usually lethal lung disease of unknown etiology [1, 2]. The underlying mechanisms linking aging with IPF are not fully understood, it has been hypothesized that IPF patients may have an accelerated process of lung aging, characterized by increased genomic instability, abnormal shortening of telomeres, epithelial cell senescence, mitochondrial dysfunction, and loss of proteostasis, among others [3, 4]. How these mechanisms of aging interrelate is currently largely unknown. ↑ Lung Mmp12-null mice no changes with WT in bleo fibrosis ↑ Lung Mmp13-null mice increased bleo fibrosis protected from radiation fibrosis ↑ Lung Deficient mice die between 20 and 90 days after birth No data

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Findings

Conclusions