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

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.

Regeneration or Repair? The Role of Alveolar Epithelial Cells in the Pathogenesis of Idiopathic Pulmonary Fibrosis (IPF)

“…On the contrary, there are MMPs (MMP19 and MMP13) that showed an antifibrotic effect and are downregulated in IPF patients. The role of MMP14 is currently the subject of debate, as several studies have confirmed that it is upregulated in IPF patients [76], whereas a recent publication using a conditional mouse model of lung epithelium-specific MMP14 genetic deletion showed that a lack of MMP14 in lung epithelial cells impaired the spontaneous regeneration of the lung and increased the progression of fibrotic lesions when mice were treated with bleomycin. The absence of MMP14 resulted in increased expression of senescence-associated markers [76,77].…”

MUC16 Is Overexpressed in Idiopathic Pulmonary Fibrosis and Induces Fibrotic Responses Mediated by Transforming Growth Factor-β1 Canonical Pathway

“…A549 and MRC5 cell lines have been broadly used in IPF studies [ 15 , 69 , 70 , 71 ]. However, the fact that we used A549 and MRC5 cell lines instead of primary cells from IPF patients to explore the collaboration of MUC16 on the fibrotic effects of TGF-β1 could be interpreted as a limitation of this study.…”

Matrix Metalloproteinases and Their Inhibitors in Pulmonary Fibrosis: EMMPRIN/CD147 Comes into Play

“…It was discovered as a proMMP2 activator, expressed on the surface of invasive cancer cells [108]. MMP-14 is overexpressed in AECs of IPF lungs, mainly in hyperplastic cuboidal type 2 pneumocytes and bleomycin-induced lung fibrosis [56,194,195]. It processes types I-III collagen [196].…”

“…Moreover, bleomycin-induced experimental lung fibrosis is exacerbated by epithelial MMP-14 deficiency since it reveals abnormal proteolytic processing of ECM, a process associated with an epithelial senescence phenotype [55] related to the aggravation of fibrosis [202]. These epithelial senescence cells overexpress TGF-β1 and increase profibrotic markers in fibroblasts such as acta2 and fn1 (Fibronectin) by RT-PCR [56].…”