ABSTRACT Intercellular adhesion molecule 1 (ICAM-1) plays an important role in the transmigration of polymorphonuclear neutrophils (PMN) in sepsis. Moreover, the transmigration rate of leukocytes from the blood via endothelial adhesion molecules into tissues correlates with the severity of multi organ failure. We examined the effect of the deletion of the ICAM-1 gene in polymicrobial sepsis using a cecal ligation and puncture (CLP) sepsis model in mice. Twenty male ICAM-1 knockout (KO) mice and 20 wild-type (WT) male C57BL/6 mice were studied. CLP was performed. At several time points during a 96-hour postoperative observation period, we measured mortality, body weight, and temperature. The delayed type of hypersensitivity (DTH) reaction was determined by pinna swelling after sensitization with 50 &mgr;L of dinitrofluorobenzene (DNFB) 1%. Lymphocyte subpopulations (CD4+, CD8+, and CD56+) and cytokines [tumor necrosis factor-&agr; (TNF-&agr;), interleukin-1&bgr; (IL-1&bgr;), interleukin-6 (IL-6), and interleukin-10 (IL-10)] were measured using flow cytometry and ELISA testing, respectively. Also, a histologic examination of the liver and lung was performed. CLP-induced mortality was lower in the ICAM-1 −/− group compared to normal mice (5% vs 45.0%). So were the ratios of lymphocyte subpopulations in the KO versus the WT group [CD4+: 16.4 ± 1.6% vs 25.7 ± 4.7%; CD8+: 18.3 ± 1.4% vs 34.9 ± 2.9%; natural killer (NK) cells: 5.6 ± 0.3% vs 49.5 ± 0.7%; P < 0.01]. And also the cytokine blood levels of the KO mice were significantly lower versus the WT mice (TNF-&agr;: 67.2 ± 42.2 vs 823.9 ± 170.5 pg/mL; IL-1&bgr;: 5.9 ± 0.9 vs 296.2 ± 66.2 pg/mL; IL-6: 223.1 ± 48.8 vs 3062.5 ± 1222.8 pg/mL; IL-10: 34.6 ± 5.8 vs 1565.6 ± 448.8 pg/mL; P < 0.01). With respect to the histology, significantly less leukocyte invasion and organ damage (eg, hydropic degeneration) were present in the ICAM-1 −/− group compared to controls in liver and lung tissues. The DTH reaction was significantly decreased in ICAM-1 −/− mice versus WT mice (0.34 vs 0.41 mm; P < 0.05). Our results demonstrate a significant reduction of mortality after septic challenge in ICAM-1 −/− mice compared to normal mice. This is associated with a decrease in lymphocyte subpopulations, cytokine levels, and DTH type 4 reaction, possibly reflecting an overall attenuation of the immune system.

中文翻译：

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通过 ICAM-1 的白细胞-内皮相互作用对多微生物败血症有害

摘要 细胞间粘附分子 1 (ICAM-1) 在脓毒症中多形核中性粒细胞 (PMN) 的迁移中起重要作用。此外，白细胞通过内皮粘附分子从血液中迁移到组织中的速度与多器官衰竭的严重程度相关。我们在小鼠中使用盲肠结扎和穿刺 (CLP) 脓毒症模型检查了 ICAM-1 基因缺失在多微生物脓毒症中的影响。研究了 20 只雄性 ICAM-1 敲除 (KO) 小鼠和 20 只野生型 (WT) 雄性 C57BL/6 小鼠。进行了 CLP。在术后 96 小时观察期内的几个时间点，我们测量了死亡率、体重和体温。迟发型超敏反应 (DTH) 反应由 50 μL 1% 二硝基氟苯 (DNFB) 致敏后耳廓肿胀确定。淋巴细胞亚群（CD4+、CD8+ 和 CD56+）和细胞因子 [肿瘤坏死因子-&agr; (TNF-&agr;), 白细胞介素-1&bgr; (IL-1&bgr;)、白介素-6 (IL-6) 和白介素-10 (IL-10)] 分别使用流式细胞术和 ELISA 测试进行测量。此外，还进行了肝脏和肺的组织学检查。与正常小鼠相比，ICAM-1 -/- 组中的 CLP 诱导的死亡率较低（5% 对 45.0%）。KO 组与 WT 组中淋巴细胞亚群的比率也是如此 [CD4+：16.4 ± 1.6% 对 25.7 ± 4.7%；CD8+：18.3 ± 1.4% 与 34.9 ± 2.9%；自然杀伤 (NK) 细胞：5.6 ± 0.3% 对 49.5 ± 0.7%；P < 0.01]。而且 KO 小鼠的细胞因子血液水平显着低于 WT 小鼠（TNF-&agr;：67.2 ± 42.2 vs 823.9 ± 170.5 pg/mL；IL-1&bgr;：5.9 ± 0.9 vs 296.2 ± 66.2 pg/mL； IL-6：223。1 ± 48.8 与 3062.5 ± 1222.8 pg/mL；IL-10：34.6 ± 5.8 与 1565.6 ± 448.8 pg/mL；P < 0.01)。关于组织学，与肝和肺组织中的对照相比，ICAM-1 -/- 组中存在显着更少的白细胞侵袭和器官损伤（例如，水肿变性）。与WT小鼠相比，ICAM-1 -/- 小鼠中的DTH反应显着降低（0.34 vs 0.41 mm；P < 0.05）。我们的结果表明，与正常小鼠相比，ICAM-1 -/- 小鼠脓毒症攻击后死亡率显着降低。这与淋巴细胞亚群、细胞因子水平和 DTH 4 型反应的减少有关，可能反映了免疫系统的整体减弱。与肝和肺组织中的对照相比，ICAM-1 -/- 组中存在显着更少的白细胞侵袭和器官损伤（例如，水肿变性）。与WT小鼠相比，ICAM-1 -/- 小鼠中的DTH反应显着降低（0.34 vs 0.41 mm；P < 0.05）。我们的结果表明，与正常小鼠相比，ICAM-1 -/- 小鼠脓毒症攻击后死亡率显着降低。这与淋巴细胞亚群、细胞因子水平和 DTH 4 型反应的减少有关，可能反映了免疫系统的整体减弱。与肝和肺组织中的对照相比，ICAM-1 -/- 组中存在显着更少的白细胞侵袭和器官损伤（例如，水肿变性）。与WT小鼠相比，ICAM-1 -/- 小鼠中的DTH反应显着降低（0.34 vs 0.41 mm；P < 0.05）。我们的结果表明，与正常小鼠相比，ICAM-1 -/- 小鼠脓毒症攻击后死亡率显着降低。这与淋巴细胞亚群、细胞因子水平和 DTH 4 型反应的减少有关，可能反映了免疫系统的整体减弱。我们的结果表明，与正常小鼠相比，ICAM-1 -/- 小鼠脓毒症攻击后死亡率显着降低。这与淋巴细胞亚群、细胞因子水平和 DTH 4 型反应的减少有关，可能反映了免疫系统的整体减弱。我们的结果表明，与正常小鼠相比，ICAM-1 -/- 小鼠脓毒症攻击后死亡率显着降低。这与淋巴细胞亚群、细胞因子水平和 DTH 4 型反应的减少有关，可能反映了免疫系统的整体减弱。