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.
Highlights
Idiopathic pulmonary fibrosis (IPF) is an age-related chronic, progressive, and usually lethal interstitial lung disease of unknown etiology
A growing body of evidence indicates that the disease represents an epithelial-driven disorder whereby an aberrantly activated lung epithelium produces mediators for fibroblast migration, proliferation, and differentiation into active myofibroblasts that secrete exaggerated molecules of extracellular matrix (ECM) provoking a progressive and irreversible loss of lung structure and function [1,2,3]
matrix metalloproteinase 14 (MMP14), called membrane type-1 matrix metalloproteinase (MT1-matrix metalloproteases (MMPs)), is a membrane-associated MMP that was originally discovered as a proMMP-2 activator, expressed on the surface of invasive cancer cells [12]
Summary
Idiopathic pulmonary fibrosis (IPF) is an age-related chronic, progressive, and usually lethal interstitial lung disease of unknown etiology. Previous studies in our lab showed that MT1-MMP (Mmp14) is increased in bleomycin-induced lung fibrosis and in IPF the enzyme is localized mainly in the alveolar epithelium [14,15]. The role of MMPs in cell function has been strengthened by the analysis of experimental models with transgenic mice lacking the different enzymes; loss of mouse MT1-MMP (Mmp null mice) results in premature death 3 weeks after birth [16]. In this context, in this study we developed a conditional
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