Lanone, S. et al. Overlapping and enzyme-specific contributions of matrix metalloproteinases-9 and-12 in IL-13-induced inflammation and remodeling. J. Clin. Invest. 110, 463-474

Section of Pulmonary and Critical Care Medicine, Department of Internal Medicine, and. Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 09/2002; 110(4):463-74. DOI: 10.1172/JCI14136
Source: PubMed


IL-13 potently stimulates eosinophilic and lymphocytic inflammation and alveolar remodeling in the lung, effects that depend on the induction of various matrix metalloproteinases (MMPs). Here, we compared the remodeling and inflammatory effects of an IL-13 transgene in lungs of wild-type, MMP-9-deficient, or MMP-12-deficient mice. IL-13-induced alveolar enlargement, lung enlargement, compliance alterations, and respiratory failure and death were markedly decreased in the absence of MMP-9 or MMP-12. Moreover, IL-13 potently induced MMPs-2, -12, -13, and -14 in the absence of MMP-9, while induction of MMPs-2, -9, -13, and -14 by IL-13 was diminished in the absence of MMP-12. A deficiency in MMP-9 did not alter eosinophil, macrophage, or lymphocyte recovery, but increased the recovery of total leukocytes and neutrophils in bronchoalveolar lavage (BAL) fluids from IL-13 transgenic mice. In contrast, a deficiency in MMP-12 decreased the recovery of leukocytes, eosinophils, and macrophages, but not lymphocytes or neutrophils. These studies demonstrate that IL-13 acts via MMPs-9 and -12 to induce alveolar remodeling, respiratory failure, and death and that IL-13 induction of MMPs-2, -9, -13, and -14 is mediated at least partially by an MMP-12-dependent pathway. The also demonstrate that MMPs-9 and -12 play different roles in the generation of IL-13-induced inflammation, with MMP-9 inhibiting neutrophil accumulation and MMP-12 contributing to the accumulation of eosinophils and macrophages.

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    • "MMP-9 may play important physiologic roles in lung extracellular matrix remodeling and repair, and in regulating the lung inflammatory response to injury [18]. However, MMP-9 has also been implicated in the pathogenesis of various lung diseases including chronic obstructive pulmonary diseases [11] [19] [20]. "
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    ABSTRACT: Background Chronic obstructive pulmonary disease (COPD) is a major cause of respiratory morbidity and mortality worldwide. One of the main hypotheses concerning the pathogenesis of emphysema, a key cause of morbidity and mortality in COPD, is the protease antiprotease imbalance. Irreversible airflow obstruction in Chronic Obstructive Pulmonary Disease (COPD) is thought to result from airway remodeling associated with aberrant inflammation. This study examined changes in sputum as regards MMP-9, TIMP-1 and levels of inflammatory cells in COPD patients compared with sputum of healthy smokers and non smokers. Methods Forty patients were included in this study. FEV1 before and after salbutamol inhalation, MMP-9, TIMP-1 and inflammatory cell count in the sputum of COPD patients, healthy smokers and non- smokers were investigated. Results MMP-9 was significantly increased in both COPD patients (194.4 ± 100.6), and healthy smokers (104.5 ± 42.1) compared with healthy non smokers (34.5 ± 36.1). TIMP-1 was increased more in healthy non-smokers (192.7 ± 37.7) than COPD patients (115 ± 55.5) and healthy smokers (145.3 ± 35.1). MMP-9/TIMP-1 was high in COPD patients (1.7 ± 0.9) and healthy smokers (0.7 ± 0.3) compared with healthy non smokers (0.2 ± 0.2). Mean sputum total leucocytic count (TLC) was highly statistically significantly different between the three groups. COPD group showed the highest means value while non smokers group showed the lowest one. Conclusions COPD is characterized by an imbalance between MMP-9 and TIMP-1 which may play an important role in the pathogenesis of tissue remodeling and airway obstruction.
    07/2014; 63(4). DOI:10.1016/j.ejcdt.2014.06.014
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    • "Observations from animals infected with S. mansoni suggest that MMP-12 promotes fibrosis indirectly by suppressing expression of other anti-fibrotic MMPs (Madala et al., 2010). Contrary to previous studies suggesting a pro-fibrotic role, two contrasting studies, one using a fibrosis model with transgenic mice expressing IL-13 (Lanone et al., 2002) and the other a model involving radiation injury followed by bone-marrow transfer (socalled 'RAD+BMT') (England et al., 2011), observed either no effect or an anti-fibrotic effect of MMP-12, respectively. Although a direct mechanistic link to fibrosis is unclear, both studies reported altered expression of other MMPs in Mmp12 –/– mice, similar to that found in the S. mansoni model (Madala et al., 2010). "
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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. DOI:10.1242/dmm.012062 · 4.97 Impact Factor
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    • "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]. IL-13 can directly induce a number of pro-fibrotic MMPs, including MMP9 and MMP12 [30], and MMP7 [31], all of which are elevated in the lungs of patients with IPF. In addition to MMP3, pro-MMP7 is also elevated in the bronchoalveolar lavage fluid of patients with IPF, and is thought to be produced by the hyperplastic alveolar and metaplastic bronchiolar epithelial cells, and activated locally in the lung [32]. "
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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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