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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    • ". (7) Tricuspid regurgitant velocity (TRV) recorded by continuous wave Doppler. Pulmonary hypertension was considered when TRV was P 2.8 m s À1 [22], and subsequently graded as mild (2.8–3.4 m s À1 ) or moderate–severe (>3.4 m s À1 ) (Fig. 1). "
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    ABSTRACT: Chronic obstructive pulmonary disease (COPD) is a common preventable and treatable disease characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases. It has some significant extra pulmonary effects that may contribute to its severity in individual patient. Among COPD patients, cardiovascular diseases (CVD) are responsible for approximately 50% of all hospitalizations and 20% of all deaths. Left ventricular diastolic dysfunction (LVDD) is a frequent condition in COPD patients. Inflammation is considered to be one of the systemic manifestations of COPD and provides an alternative hypothesis to explain the relationship between airflow limitation and cardiovascular risk. The present study aimed to assess the prevalence of LV diastolic dysfunction in COPD patients and its relation to the disease severity and presence of inflammatory markers.
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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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