Matrix metalloproteinase-19 is a key regulator of lung fibrosis in mice and humans.
ABSTRACT Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by epithelial phenotypic changes and fibroblast activation. Based on the temporal heterogeneity of IPF, we hypothesized that hyperplastic alveolar epithelial cells regulate the fibrotic response. Objectives: To identify novel mediators of fibrosis comparing the transcriptional signature of hyperplastic epithelial cells and conserved epithelial cells in the same lung. Methods: Laser capture microscope and microarrays analysis were used to identify differentially expressed genes in IPF lungs. Bleomycin-induced lung fibrosis was evaluated in Mmp19-deficient and wild-type (WT) mice. The role of matrix metalloproteinase (MMP)-19 was additionally studied by transfecting the human MMP19 in alveolar epithelial cells. Measurements and Main Results: Laser capture microscope followed by microarray analysis revealed a novel mediator, MMP-19, in hyperplastic epithelial cells adjacent to fibrotic regions. Mmp19(-/-) mice showed a significantly increased lung fibrotic response to bleomycin compared with WT mice. A549 epithelial cells transfected with human MMP19 stimulated wound healing and cell migration, whereas silencing MMP19 had the opposite effect. Gene expression microarray of transfected A549 cells showed that PTGS2 (prostaglandin-endoperoxide synthase 2) was one of the highly induced genes. PTGS2 was overexpressed in IPF lungs and colocalized with MMP-19 in hyperplastic epithelial cells. In WT mice, PTGS2 was significantly increased in bronchoalveolar lavage and lung tissues after bleomycin-induced fibrosis, but not in Mmp19(-/-) mice. Inhibition of Mmp-19 by siRNA resulted in inhibition of Ptgs2 at mRNA and protein levels. Conclusions: Up-regulation of MMP19 induced by lung injury may play a protective role in the development of fibrosis through the induction of PTGS2.
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ABSTRACT: The aim of this study was to evaluate the effect and underlying mechanism of Yangyinqingfei decoction on radiation-induced lung injury in rats. Wistar rats (n=75) were randomly divided into five experimental groups (A-E). Rats in two of the groups were administered saline solution, whereas rats in the remaining three groups were administered different doses of Yangyinqingfei decoction. After one week, the rats were irradiated with a single dose of 25 Gy to their right hemi-thoraxes by a (60)Co γ-ray, with the exception of the control group, which underwent sham irradiation. The effect of Yangyinqingfei decoction was assessed one, two and four weeks post-irradiation according to the pathological changes and the right lung index (wet weight of right lung/body weight ×100%). Expression levels of matrix metalloproteinase-12 (MMP-12) and tissue inhibitors of metalloproteinases-1 (TIMP-1) in lung tissue were determined using the reverse transcription-polymerase chain reaction and western blot analysis. Pretreatment with Yangyinqingfei resulted in a significant dose-dependent resistance to radiation-induced body weight loss. The expression of MMP-12 and TIMP-1 increased following irradiation. However, the levels of MMP-12 and TIMP-1 in groups receiving Yangyinqingfei were lower four weeks after irradiation compared with those in rats administered saline. Cumulatively, these results suggest that Yangyinqingfei has a protective effect on radiation-induced lung injury in rats, possibly by downregulating MMP-12 and TIMP-1 expression.Experimental and therapeutic medicine 07/2014; 8(1):9-14. · 0.34 Impact Factor
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ABSTRACT: Rationale: Lung cancer is the leading cause of cancer death in both men and women in the United States and worldwide. Matrix metalloproteinases (MMPs) have been implicated in the development and progression of lung cancer, but their role in the molecular pathogenesis of lung cancer remains unclear. We have found that MMP19, a relatively novel member of the MMP family, is overexpressed in lung tumors when compared to controls. Objective: In this study, we tested the hypothesis that MMP19 plays a significant role in the development and progression of non-small cell lung cancer (NSCLC). Methods: We have analyzed lung cancer gene expression data, immunostained lung tumors for MMP19, and performed in vitro assays to test the effects of MMP19 in NSCLC cells. Main Results: We found that MMP19 gene and protein expression is increased in lung cancer tumors compared to adjacent and histologically normal lung tissues. In three independent datasets, increased MMP19 gene expression conferred a poorer prognosis in NSCLC. In vitro, we found that overexpression of MMP19 promotes epithelial-mesenchymal transition (EMT), migration, and invasiveness in multiple NSCLC cell lines, Overexpression of MMP19 with a mutation at the catalytic site did not impair EMT or expression of pro-metastasis genes. We also found that miR-30 isoforms, a microRNA family predicted to target MMP19, is markedly down-regulated in human lung cancer and regulates MMP19 expression. Conclusions: Taken together, these findings suggest that MMP19 is associated with the development and progression of NSCLC and may be a potential biomarker of disease severity and outcome.American Journal of Respiratory and Critical Care Medicine 09/2014; · 11.04 Impact Factor
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ABSTRACT: Fibrosis - a debilitating condition that can occur in most organs - is characterized by excess deposition of a collagen-rich extracellular matrix (ECM). At first sight, the activities of proteinases that can degrade matrix, such as matrix metalloproteinases (MMPs), might be expected to be under-expressed in fibrosis or, if present, could function to resolve the excess matrix. However, as we review here, some MMPs are indeed anti-fibrotic, whereas others can have pro-fibrotic functions. MMPs modulate a range of biological processes, especially processes related to immunity and tissue repair and/or remodeling. Although we do not yet know precisely how MMPs function during fibrosis - that is, the protein substrate or substrates that an individual MMP acts on to effect a specific process - experiments in mouse models demonstrate that MMP-dependent functions during fibrosis are not limited to effects on ECM turnover. Rather, data from diverse models indicate that these proteinases influence cellular activities as varied as proliferation and survival, gene expression, and multiple aspects of inflammation that, in turn, impact outcomes related to fibrosis.Disease Models and Mechanisms 02/2014; 7(2):193-203. · 4.96 Impact Factor