Overlapping and enzyme-specific contributions of matrix metalloproteinases-9 and-12 in IL-13-induced inflammation and remodeling
Overlapping and enzyme-specific contributions of matrix metalloproteinases-9 and-12 in IL-13-induced inflammation and remodeling
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DOI：
10.1172/jci200214136
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发表时间：
2002-08-01
影响因子：
15.9
通讯作者：
Elias, JA
中科院分区：
文献类型：
--
作者：
Lanone, S;Zheng, T;Elias, JA
IL-13 有效刺激肺部嗜酸性粒细胞和淋巴细胞炎症以及肺泡重塑，其作用取决于各种基质金属蛋白酶 (MMP) 的诱导。在这里，我们比较了野生型、MMP-9 缺陷型或 MMP-12 缺陷型小鼠肺中 IL-13 转基因的重塑和炎症作用。在缺乏 MMP-9 或 MMP-12 的情况下，IL-13 诱导的肺泡扩大、肺扩大、顺应性改变以及呼吸衰竭和死亡均显着减少。此外，在没有MMP-9的情况下，IL-13有效诱导MMPs-2、-12、-13和-14，而在没有MMP-12的情况下，IL-13对MMPs-2、-9、-13和-14的诱导作用减弱。 MMP-9 缺陷不会改变嗜酸性粒细胞、巨噬细胞或淋巴细胞的恢复，但会增加 IL-13 转基因小鼠的支气管肺泡灌洗 (BAL) 液中总白细胞和中性粒细胞的恢复。相比之下，MMP-12 的缺乏会降低白细胞、嗜酸性粒细胞和巨噬细胞的恢复，但不会降低淋巴细胞或中性粒细胞的恢复。这些研究表明，IL-13 通过 MMPs-9 和 -12 起作用，诱导肺泡重塑、呼吸衰竭和死亡，并且 IL-13 对 MMPs-2、-9,43 和 -14 的诱导至少部分是由 MMP-12 依赖性途径介导的。还表明MMP-9和-12在IL-13诱导的炎症的产生中发挥不同的作用，MMP-9抑制中性粒细胞积累，而MMP-12有助于嗜酸性粒细胞和巨噬细胞的积累。
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, -9,43, 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.