Furuichi Kengo, Wada Takashi, Iwata Yasunori, Kokubo Satoshi, Hara Akinori, Yamahana Junya, Sugaya Takeshi, Iwakura Yoichiro, Matsushima Kouji, Asano Masahide, Yokoyama Hitoshi, Kaneko Shuichi
Department of Gastroenterology and Nephrology and Division of Blood Purification, Kanazawa University, Japan.
Crit Care Med. 2006 Sep;34(9):2447-55. doi: 10.1097/01.CCM.0000233878.36340.10.
Ischemia-reperfusion injury is known to cause organ failure, but the mechanisms of pathogenesis remain unclear. Inflammation is a factor in tissue destruction in ischemia reperfusion injury, and interleukin (IL)-1 is a key promoter of inflammation.
Prospective, randomized, and controlled study.
University laboratory.
Male mice 6-8 wks of age, in which genes for IL-1alpha and IL-1beta (IL-1alpha/beta deficient) and IL-1 receptor antagonist (IL-1RA deficient) are deleted by homologous recombination, and wild-type controls on a Balb/c background.
In this study, the role of IL-1 on inflammatory cascades, including chemokine expression, inflammatory cell infiltration, and tissue destruction, was investigated in 45 mins of unilateral renal ischemic injury using IL-1alpha/beta-deficient mice and IL-1RA-deficient mice. In addition, the effects of IL-1 on chemokine expression in cultured tubular epithelial cells were investigated.
In vivo study revealed that the number of interstitial infiltrated neutrophils and macrophages, which accompanied the increase of the serum levels of keratinocyte-derived chemokine (KC) and macrophage inflammatory protein (MIP)-1alpha, respectively, significantly increased in IL-1RA-deficient mice. The number of interstitial infiltrated neutrophils correlated well with serum levels of KC at 24 hrs after reperfusion, whereas the number of interstitial infiltrated macrophages correlated well with the serum levels of MIP-1alpha and monocyte chemoattractant protein (MCP)-1 at 24 and 48 hrs after reperfusion, respectively. Likewise, in vitro study revealed that stimulation of tubular epithelial cells by IL-1beta and/or H2O2 sequentially induced KC, MIP-1alpha, and MCP-1 in both protein and messenger RNA levels, which is consistent with in vivo results.
IL-1-dependent inflammatory cascades, followed by inflammatory cell infiltration and subsequent tissue destruction, may affect pathogenesis of renal ischemia-reperfusion injury.
缺血再灌注损伤可导致器官衰竭，但其发病机制尚不清楚。炎症是缺血再灌注损伤中组织破坏的一个因素，而白细胞介素（IL）-1是炎症的关键促进因子。
前瞻性、随机对照研究。
大学实验室。
6-8周龄雄性小鼠，其IL-1α和IL-1β基因（IL-1α/β缺陷型）以及IL-1受体拮抗剂基因（IL-1RA缺陷型）通过同源重组被敲除，以及Balb/c背景的野生型对照小鼠。
在本研究中，使用IL-1α/β缺陷型小鼠和IL-1RA缺陷型小鼠，对单侧肾脏缺血损伤45分钟后IL-1在包括趋化因子表达、炎症细胞浸润和组织破坏在内的炎症级联反应中的作用进行了研究。此外，还研究了IL-1对培养的肾小管上皮细胞趋化因子表达的影响。
体内研究显示，IL-1RA缺陷型小鼠间质中浸润的中性粒细胞和巨噬细胞数量显著增加，同时角质形成细胞衍生趋化因子（KC）和巨噬细胞炎性蛋白（MIP）-1α的血清水平分别升高。再灌注24小时后，间质中浸润的中性粒细胞数量与血清KC水平密切相关，而再灌注24小时和48小时后，间质中浸润的巨噬细胞数量分别与血清MIP-1α和单核细胞趋化蛋白（MCP）-1水平密切相关。同样，体外研究显示，IL-1β和/或H2O2刺激肾小管上皮细胞可依次诱导KC、MIP-1α和MCP-1的蛋白和信使RNA水平升高，这与体内结果一致。
IL-1依赖性炎症级联反应，随后炎症细胞浸润及随后的组织破坏，可能影响肾脏缺血再灌注损伤的发病机制。
