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

Yale University, New Haven, Connecticut, United States
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.
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