Interleukin-18 Exacerbates Pulmonary Injury after Hepatic Ischemia/Reperfusion in Mice
Interleukin-18 Exacerbates Pulmonary Injury after Hepatic Ischemia/Reperfusion in Mice
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DOI：
10.1016/j.jss.2008.08.009
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发表时间：
2010-01-01
影响因子：
2.2
通讯作者：
Miyazaki, Masaru
中科院分区：
文献类型：
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作者：
Takeuchi, Dan;Yoshidome, Hiroyuki;Miyazaki, Masaru
背景肝脏缺血/再灌注已被证明会导致局部和远端器官（例如肺）损伤，这是由中性粒细胞在局部和远端器官中的积聚引起的，从而导致中性粒细胞依赖性器官损伤。白细胞介素（IL）-18通过抑制抗炎性细胞因子的表达来促进嗜中性粒细胞依赖性局部肝损伤，但关于这种细胞因子参与远端器官损伤的情况知之甚少。本研究的目的是确定IL-18是否有助于肝缺血/再灌注引起的肺损伤。使C57 BL/6小鼠和IL-18敲除小鼠（C57 BL/6背景）经受90分钟的部分肝缺血和随后的再灌注。通过肺髓过氧化物酶含量评估肺中的神经元积聚。通过组织酶联免疫吸附试验（ELISA）测定角质形成细胞衍生的趋化因子（KC，CXCL 1）、巨噬细胞趋化蛋白-1（MCP-1，CCL 2）、肿瘤坏死因子-α、干扰素-γ、IL-4和IL-10的肺表达。肺水肿通过肺湿重与干重的比值来量化。肝脏缺血/再灌注引起肺中性粒细胞募集和肺水肿显著增加。肺组织中KC和MCP-1表达上调。在IL-18基因敲除小鼠中，肝脏缺血/再灌注诱导的肺中性粒细胞募集增加、肺水肿定义的肺损伤和肺趋化因子表达减弱。此外，在IL-18基因敲除小鼠中，抗炎细胞因子IL-4的肺部表达和全身IL-10的表达显著上调。这些数据表明，IL-18通过上调促炎介质和可能抑制抗炎细胞因子的表达在肝缺血/再灌注后肺损伤的发展中起重要作用。(C)2010年爱思唯尔公司All rights reserved.
Background. Hepatic ischemia/reperfusion has been shown to cause both local hepatic and distant organ (such as lung) injury caused by accumulation of neutrophils in the local and distant organs, leading to neutrophil-dependent organ injury. Interleukin (IL) -18 is required for facilitating neutrophil-dependent local hepatic injury by suppressing anti-inflammatory cytokine expression, but less is known about the involvement of this cytokine in distant organ injury. The objective of this study was to determine whether IL-18 contributes to pulmonary injury induced by hepatic ischemia/reperfusion.Methods. C57BL/6 mice and IL-18 knockout mice (C57BL/6 background) were subjected to 90 min of partial hepatic ischemia and subsequent reperfusion. Neutrophil accumulation in the lung was assessed by pulmonary myeloperoxidase contents. Pulmonary expressions of keratinocyte derived chemokine (KC, CXCL1), macrophage chemoattractant protein-1 (MCP-1, CCL2), tumor necrosis factor-alpha, interferon-gamma, IL-4, and IL-10 were measured by tissue enzyme-linked immunosorbent assay (ELISA). Lung edema was quantified by the pulmonary wet to dry weight ratios.Results. Hepatic ischemia/reperfusion caused significant increases in pulmonary neutrophil recruitment and lung edema. Also, pulmonary expression of KC and MCP-1 were up-regulated. In the IL-18 knockout mice, hepatic ischemia/reperfusion-induced increases in pulmonary neutrophil recruitment, lung injury defined by lung edema, and pulmonary chemokine expression were attenuated. Furthermore, pulmonary expression of an anti-inflammatory cytokine IL-4 and systemic IL-10 expression were significantly up-regulated in the IL-18 knockout mice.Conclusions. The data suggested that IL-18 plays an important role in the development of pulmonary injury after hepatic ischemia/reperfusion by up-regulating proinflammatory mediators and possibly suppressing anti-inflammatory cytokine expression. (C) 2010 Elsevier Inc. All rights reserved.