Department of Biología Funcional, Universidad de Oviedo, Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain.
Am J Respir Cell Mol Biol. 2010 Nov;43(5):555-63. doi: 10.1165/rcmb.2009-0034OC. Epub 2009 Dec 7.
Mechanical ventilation is a life-saving therapy that can also damage the lungs. Ventilator-induced lung injury (VILI) promotes inflammation and up-regulates matrix metalloproteinases (MMPs). Among these enzymes, MMP-8 is involved in the onset of inflammation by processing different immune mediators. To clarify the role of MMP-8 in a model of VILI and their relevance as a therapeutic target, we ventilated wild-type and MMP-8-deficient mice with low or high pressures for 2 hours. There were no significant differences after low-pressure ventilation between wild-type and knockout animals. However, lack of MMP-8 results in better gas exchange, decreased lung edema and permeability, and diminished histological injury after high-pressure ventilation. Mmp8(-/-) mice had a different immune response to injurious ventilation, with decreased neutrophilic infiltration, lower levels of IFN-γ and chemokines (LPS-induced CXC chemokine, macrophage inflammatory protein-2), and significant increases in anti-inflammatory cytokines (IL-4, IL-10) in lung tissue and bronchoalveolar lavage fluid. There were no differences in MMP-2, MMP-9, or tissue inhibitor of metalloproteinase-1 between wild-type and knockout mice. These results were confirmed by showing a similar protective effect in wild-type mice treated with a selective MMP-8 inhibitor. We conclude that MMP-8 promotes acute inflammation after ventilation with high pressures, and its short-term inhibition could be a therapeutic goal to limit VILI.
机械通气是一种救生疗法,但也会对肺部造成损伤。呼吸机相关肺损伤(VILI)会促进炎症反应并上调基质金属蛋白酶(MMPs)。在这些酶中,MMP-8 通过处理不同的免疫介质参与炎症的发生。为了阐明 MMP-8 在 VILI 模型中的作用及其作为治疗靶点的相关性,我们用低或高压力对野生型和 MMP-8 缺陷型小鼠进行了 2 小时通气。低压力通气后,野生型和敲除动物之间没有明显差异。然而,缺乏 MMP-8 导致高压力通气后气体交换更好,肺水肿和通透性降低,组织损伤减轻。Mmp8(-/-) 小鼠对损伤性通气的免疫反应不同,中性粒细胞浸润减少,IFN-γ 和趋化因子(LPS 诱导的 CXC 趋化因子、巨噬细胞炎症蛋白-2)水平降低,抗炎细胞因子(IL-4、IL-10)在肺组织和支气管肺泡灌洗液中显著增加。野生型和敲除型小鼠之间 MMP-2、MMP-9 或金属蛋白酶组织抑制剂-1 无差异。在接受选择性 MMP-8 抑制剂治疗的野生型小鼠中,观察到类似的保护作用,证实了这些结果。我们得出结论,MMP-8 促进高压通气后的急性炎症,其短期抑制可能是限制 VILI 的治疗目标。