Role of matrix metalloprotease-2 and MMP-9 in experimental lung fibrosis in mice

Abstract

Background Idiopathic pulmonary fibrosis (IPF) is a diffuse parenchymal lung disease characterized by exuberant deposition of extracellular matrix (ECM) proteins in the lung interstitium, which contributes to substantial morbidity and mortality in IPF patients. Matrix metalloproteinases (MMPs) are a large family of zinc-dependent endopeptidases, many of which have been implicated in the regulation of ECM degradation in lung fibrosis. However, the roles of MMP-2 and -9 (also termed gelatinases A and B) have not yet been explored in lung fibrosis in detail. Methods AdTGF-β1 was applied via orotracheal routes to the lungs of WT, MMP-2 KO, MMP-9 KO and MMP-2/-9 dKO mice on day 0 to induce lung fibrosis. Using hydroxyproline assay, FlexiVent based lung function measurement, histopathology, western blot and ELISA techniques, we analyzed MMP-2 and MMP-9 levels in BAL fluid and lung, collagen contents in lung and lung function in mice on day 14 and 21 post-treatment. Result IPF lung homogenates exhibited significantly increased levels of MMP-2 and MMP-9, relative to disease controls. Enzymatically active MMP-2 and MMP-9 was increased in lungs of mice exposed to adenoviral TGF-β1, suggesting a role for these metalloproteinases in lung fibrogenesis. However, we found that neither MMP-2 or MMP-9 nor combined MMP-2/-9 deletion had any effect on experimental lung fibrosis in mice. Conclusion Together, our data strongly suggest that both gelatinases MMP-2 and MMP-9 play only a subordinate role in experimental lung fibrosis in mice.

Amelioration of Pulmonary Fibrosis by Matrix Metalloproteinase-2 Overexpression

“…Acceleration of experimental diabetic nephropathy in MMP-2 knockout mice and prevention of cardiac ventricular fibrosis after myocardial infarction by MMP-2 secretion from mesenchymal cells also indicate the protective activity of MMP-2 in organ fibrosis [ 69 , 70 ]. The different models of lung fibrosis used in the experiment may explain the discrepant results previously reported by Bormann et al [ 42 ].…”

“…Increased expression of hMMP-2 has been reported in pulmonary fibrosis, but whether it plays a pro-, antifibrotic, or no role remains unclear [ 58 , 59 ]. Bormann et al found no difference in the severity of pulmonary fibrosis between WT and MMP-2 knockout mice that orotracheally received an adenoviral vector carrying the cDNA of active porcine TGFβ1 [ 42 ]. However, other studies have shown that MMP-2 may degrade epithelial cell basement membrane, leading to inflammatory exudation, angiogenesis, and fibro-proliferative responses, and that MMP-2 may promote epithelial–mesenchymal transition by inducing aberrant activation of the Wnt/β-catenin signaling pathway [ 60 , 61 , 62 , 63 , 64 , 65 , 66 ].…”

“…MMP-1, -7, -13, and -14 have been reported to promote or suppress fibrosis [ 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ]. Profibrotic activity, antifibrotic activity or no effect on collagen deposition has been reported for MMP-9 and MMP-12 [ 21 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ]. The roles of MMP-15, -16, -17, -20, -21, -22, -23, -24, -25, -26, and -27 in lung fibrosis remain unexplored [ 19 ].…”

“…However, there are contradicting reports on the role of MMP-2 in the fibrotic process. Previous studies have attributed either a profibrotic activity or no effect on fibrosis to MMP-2 [ 42 , 50 ]. The present study aimed to evaluate the effect of human MMP-2 overexpression on the development of pulmonary fibrosis in a bleomycin mouse model.…”

Mesenchyme Stem Cell-Derived Conditioned Medium as a Potential Therapeutic Tool in Idiopathic Pulmonary Fibrosis

“…Idiopathic pulmonary fibrosis (IPF) is a rare pulmonary disease of unknown cause, characterized by inflammation, and the progressive deposition of extracellular matrix that is associated with the formation of scar tissue leading to significant remodeling of the lungs [ 8 , 9 , 10 ]. IPF is a diffuse parenchymal lung disease (DPLD) [ 11 ] and it distinguishes itself from other DLPDs with a unique histological pattern known as usual interstitial pneumonia (UIP) [ 12 ]. UIP presents with significant lung volume loss, peripheral septal thickening, bronchiectasis, and a honeycomb pattern of fibrosis [ 13 ].…”