Matrix Metalloproteinase 3 Is a Mediator of Pulmonary Fibrosis

Department of Medicine, University of Western Ontario, London, Ontario, Canada.
American Journal Of Pathology (Impact Factor: 4.59). 08/2011; 179(4):1733-45. DOI: 10.1016/j.ajpath.2011.06.041
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Idiopathic pulmonary fibrosis (IPF) may be triggered by epithelial injury that results in aberrant production of growth factors, cytokines, and proteinases, leading to proliferation of myofibroblasts, excess deposition of collagen, and destruction of the lung architecture. The precise mechanisms and key signaling mediators responsible for this aberrant repair process remain unclear. We assessed the importance of matrix metalloproteinase-3 (MMP-3) in the pathogenesis of IPF through i) determination of MMP-3 expression in patients with IPF, ii) in vivo experiments examining the relevance of MMP-3 in experimental models of fibrosis, and iii) in vitro experiments to elucidate possible mechanisms of action. Gene expression analysis, quantitative RT-PCR, and Western blot analysis of explanted human lungs revealed enhanced expression of MMP-3 in IPF, compared with control. Transient adenoviral vector-mediated expression of recombinant MMP-3 in rat lung resulted in accumulation of myofibroblasts and pulmonary fibrosis. Conversely, MMP-3-null mice were protected against bleomycin-induced pulmonary fibrosis. In vitro treatment of cultured lung epithelial cells with purified MMP-3 resulted in activation of the β-catenin signaling pathway, via cleavage of E-cadherin, and induction of epithelial-mesenchymal transition. These processes were inhibited in bleomycin-treated MMP-3-null mice, as assessed by cytosolic translocation of β-catenin and cyclin D1 expression. These observations support a novel role for MMP-3 in the pathogenesis of IPF, through activation of β-catenin signaling and induction of epithelial-mesenchymal transition.

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Available from: Guoying Yu, Nov 26, 2014
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    • "Idiopathic pulmonary fibrosis (IPF) is a specific kind of chronic, progressive fibrosing interstitial pneumonia of unknown origin and there is no sufficient evidence to support the use of any specific pharmacologic therapy (1, 2). To date, animal trials on therapeutic drugs for the treatment of IPF suggest a possible benefit, but most of these studies relied on the pathologic examination to establish the results (3, 4, 5, 6). Recently, micro-CT has become a useful imaging tool for the investigation of lung diseases in rats and mice, and it has been reported that findings of lung fibrosis on imaging correlated to pathologic findings (7, 8, 9, 10, 11). "
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    ABSTRACT: Objective The aim of this study was to assess the therapeutic effects of rosiglitazone with serial micro-CT findings before and after rosiglitazone administration in a lung fibrosis mouse model induced with bleomycin. Materials and Methods We instilled the bleomycin solution directly into the trachea in twenty mice (female, C57BL/6 mice). After the instillation with bleomycin, mice were closely observed for 3 weeks and then all mice were scanned using micro-CT without sacrifice. At 3 weeks, the mice were treated with rosiglitazone on days 21 to 27 if they had abnormal CT findings (n = 9, 45%). For the mice treated with rosiglitazone, we performed micro-CT with mouse sacrifice 2 weeks after the rosiglitazone treatment completion. We assessed the abnormal CT findings (ground glass attenuation, consolidation, bronchiectasis, reticular opacity, and honeycombing) using a five-point scale at 3 and 6 weeks using Wilcoxon-signed ranked test. The micro-CT findings were correlated with the histopathologic results. Results One out of nine (11.1%) mice improved completely. In terms of consolidation, all mice (100%) showed marked decrease from 3.1 ± 1.4 at 3 weeks to 0.9 ± 0.9 at 6 weeks (p = 0.006). At 6 weeks, mild bronchiectasis (n = 6, 66.7%), mild reticular opacity (n = 7, 77.8%) and mild honeycomb patterns (n = 3, 33.3%) appeared. Conclusion A serial micro-CT enables the evaluation of drug effects in a lung fibrosis mouse model.
    Korean journal of radiology: official journal of the Korean Radiological Society 07/2014; 15(4):448-55. DOI:10.3348/kjr.2014.15.4.448 · 1.57 Impact Factor
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    • "Other work has reported a role for MMP3, which is elevated in the IPF lung [28]. Overexpression of MMP3 leads to pulmonary fibrosis in the rat lung, while mice lacking MMP3 are protected [28]. In vitro work suggests a role for MMP3 in the activation of β-catenin signaling and the induction of epithelial-to-mesenchymal transition, a process thought to contribute to the pathogenesis of IPF [29]. "
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    ABSTRACT: Repairing damaged tissues is an essential homeostatic mechanism that enables clearance of dead or damaged cells after injury, and the maintenance of tissue integrity. However, exaggeration of this process in the lung can lead to the development of fibrotic scar tissue. This is characterized by excessive accumulation of extracellular matrix (ECM) components such as fibronectin, proteoglycans, hyaluronic acid, and interstitial collagens. After tissue injury, or a breakdown of tissue integrity, a cascade of events unfolds to maintain normal tissue homeostasis. Inflammatory mediators are released from injured epithelium, leading to both platelet activation and inflammatory cell migration. Inflammatory cells are capable of releasing multiple pro-inflammatory and fibrogenic mediators such as transforming growth factor (TGF)beta and interleukin (IL)-13, which can trigger myofibroblast proliferation and recruitment. The myofibroblast population is also expanded as a result of epithelial cells undergoing epithelial-to-mesenchymal transition and of the activation of resident fibroblasts, leading to ECM deposition and tissue remodeling. In the healthy lung, wound healing then proceeds to restore the normal architecture of the lung; however, fibrosis can develop when the wound is severe, the tissue injury persists, or the repair process becomes dysregulated. Understanding the processes regulating aberrant wound healing and the matrix in the chronic fibrotic lung disease idiopathic pulmonary fibrosis (IPF), is key to identifying new treatments for this chronic debilitating disease. This review focuses primarily on the emerging role of enzymes in the lungs of patients with IPF. Elevated expression of a number of enzymes that can directly modulate the ECM has been reported, and recent data indicates that modulating the activity of these enzymes can have a downstream effect on fibrotic tissue remodeling.
    Fibrogenesis & Tissue Repair 11/2013; 6(1):20. DOI:10.1186/1755-1536-6-20
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    • "Recently, it was reported enhanced expression of MMP-3 in IPF, compared with control lungs and MMP-3-null mice were protected from bleomycin-induced pulmonary fibrosis [35]. Interestingly, in vitro treatment of lung epithelial cells with MMP-3 resulted in activation of the β-catenin signaling pathway, via cleavage of E-cadherin, with the subsequent induction of epithelial-mesenchymal transition. "
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    ABSTRACT: Lung fibrosis is the final common pathway of a large variety of chronic lung disorders, named interstitial lung diseases. The most aggressive form is the idiopathic pulmonary fibrosis [IPF] characterized by alveolar epithelial cell injury/activation, expansion of the fibroblast/myofibroblast population, and the exaggerated accumulation of extracellular matrix [ECM] components which ultimately result in the destruction of the lung parenchyma. Several matrix metalloproteases [MMPs] are upregulated in the IPF lungs and have been shown to actively participate in the pathogenesis of the disease through extracellular matrix remodeling and basement membrane disruption. However, MMPs can also breakdown molecules that mediate cell-cell and cell-ECM interactions, and can activate growth factors and growth factor receptors indicating that they likely contribute to other local biopathological processes such as apoptosis, migration, proliferation and angiogenesis.
    Fibrogenesis & Tissue Repair 06/2012; 5 Suppl 1(Suppl 1):S9. DOI:10.1186/1755-1536-5-S1-S9
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