Martin Erica L, Moyer Brent Z, Pape M Cynthia, Starcher Barry, Leco Kevin J, Veldhuizen Ruud A W
Department of Physiology, Lawson Health Research Institute, H417, 268 Grosvenor St., The University of Western Ontario, London, ON, Canada, N6A 4V2.
Am J Physiol Lung Cell Mol Physiol. 2003 Dec;285(6):L1222-32. doi: 10.1152/ajplung.00141.2003. Epub 2003 Aug 8.
Matrix metalloproteinases (MMPs) are degradative enzymes, which act to remodel tissue. Their activity is regulated by the tissue inhibitors of metalloproteinases (TIMPs). An imbalance in the degradation/inhibition activities has been associated with many diseases, including sepsis. We have previously shown that TIMP-3 knockout animals develop spontaneous, progressive air space enlargement. The objectives of this study were to determine the effects of a septic lung stress induced by cecal ligation and perforation (CLP) on lung function, structure, pulmonary surfactant, and inflammation in TIMP-3 null mice. Knockout and wild-type animals were randomized to either sham or CLP surgery, allowed to recover for 6 h, and then euthanized. TIMP-3 null animals exposed to sham surgery had a significant increase in lung compliance when compared with sham wild-type mice. Additionally, the TIMP-3 knockout mice showed a significant increase in compliance following CLP. Rapid compliance changes were accompanied by significantly decreased collagen and fibronectin levels and increased gelatinase (MMP-2 and -9) abundance and activation. Additionally, in situ zymography showed increased airway-associated gelatinase activity in the knockout animals enhanced following CLP. In conclusion, exposing TIMP-3 null animals to sepsis rapidly enhances the phenotypic abnormalities of these mice, due to increased MMP activity induced by CLP.
基质金属蛋白酶（MMPs）是降解酶，其作用是重塑组织。它们的活性受金属蛋白酶组织抑制剂（TIMPs）调节。降解/抑制活性的失衡与包括脓毒症在内的许多疾病相关。我们之前已经表明，TIMP-3基因敲除动物会出现自发性、进行性气腔扩大。本研究的目的是确定盲肠结扎和穿孔（CLP）诱导的脓毒症肺应激对TIMP-3基因敲除小鼠的肺功能、结构、肺表面活性物质和炎症的影响。将基因敲除和野生型动物随机分为假手术组或CLP手术组，使其恢复6小时，然后实施安乐死。与假手术野生型小鼠相比，接受假手术的TIMP-3基因敲除动物的肺顺应性显著增加。此外，TIMP-3基因敲除小鼠在CLP后顺应性显著增加。快速的顺应性变化伴随着胶原蛋白和纤连蛋白水平显著降低，以及明胶酶（MMP-2和-9）丰度和活性增加。此外，原位酶谱分析显示，基因敲除动物气道相关明胶酶活性在CLP后增强。总之，由于CLP诱导MMP活性增加，使TIMP-3基因敲除动物暴露于脓毒症中会迅速加剧这些小鼠的表型异常。
