Sands Mark F, Ohtake Patricia J, Mahajan Supriya D, Takyar Shervin S, Aalinkeel Ravikumar, Fang Yisheng V, Blume Jessica W, Mullan Barbara A, Sykes Don E, Lachina Sandra, Knight Paul R, Schwartz Stanley A
VA Western New York Healthcare System, Buffalo, NY 14215, USA.
Clin Immunol. 2009 Feb;130(2):186-98. doi: 10.1016/j.clim.2008.08.029. Epub 2008 Oct 26.
Matrix metalloproteinases (MMPs) modulate development, inflammation, and repair in lungs. Tissue inhibitors of MMPs (TIMPs) interact with MMPs, controlling the intensity and nature of the response to injury. Absence of MMP-9, -2, and -8 activities is associated with altered lung inflammation during allergic sensitization. To test the hypothesis that the absence of TIMP-1 enhances allergic lung inflammation, airway hyperreactivity (AHR), and lung remodeling in asthma, we studied TIMP-1 null (TIMP-1 KO) mice and their WT controls using an ovalbumin (OVA) asthma model. TIMP-1 KO mice, compared to WT controls, developed an asthma phenotype characterized by AHR, pronounced cellular lung infiltrates, greater reduction in lung compliance, enhanced Th2 cytokine mRNA and protein expression, and altered collagen lung content associated with enhanced MMP-9 activity. Our findings support the hypothesis that TIMP-1 plays a protective role by preventing AHR and modulating inflammation, remodeling, and cytokine expression in an animal model of asthma.
基质金属蛋白酶（MMPs）调节肺部的发育、炎症和修复。MMPs的组织抑制剂（TIMPs）与MMPs相互作用，控制对损伤反应的强度和性质。MMP-9、-2和-8活性的缺失与过敏性致敏期间肺部炎症的改变有关。为了验证TIMP-1的缺失会增强哮喘中过敏性肺部炎症、气道高反应性（AHR）和肺重塑这一假说，我们使用卵清蛋白（OVA）哮喘模型研究了TIMP-1基因敲除（TIMP-1 KO）小鼠及其野生型对照。与野生型对照相比，TIMP-1 KO小鼠出现了以AHR、明显的肺部细胞浸润、肺顺应性更大程度降低、Th2细胞因子mRNA和蛋白表达增强以及与MMP-9活性增强相关的肺胶原含量改变为特征的哮喘表型。我们的研究结果支持了TIMP-1在哮喘动物模型中通过预防AHR以及调节炎症、重塑和细胞因子表达发挥保护作用这一假说。
