Toll-like receptor 4 signaling leads to neutrophil migration impairment in polymicrobial sepsis
Toll-like receptor 4 signaling leads to neutrophil migration impairment in polymicrobial sepsis
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DOI：
10.1097/01.ccm.0000198527.71819.e1
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发表时间：
2006-02-01
影响因子：
8.8
通讯作者：
Cunha, FQ
中科院分区：
文献类型：
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作者：
Alves, JC;de Freitas, A;Cunha, FQ
目的：我们记录了严重脓毒症中中性粒细胞向感染灶的迁移受损。这种现象似乎是由一氧化氮介导的，一氧化氮的释放是由免疫细胞在受到细菌和/或其产物刺激后释放的循环炎性细胞因子刺激的。toll样受体4 （TLR4）是脂多糖的主要识别受体，脂多糖是革兰氏阴性细菌细胞壁的一种成分。在本研究中，我们研究了TLR4是否参与了多微生物或革兰氏阴性脓毒症小鼠中性粒细胞迁移失败。设计：对照动物研究。大学研究实验室。研究对象：雄性C3H/HeJ （tlr4缺陷）和C3H/ heas （tlr4正常）小鼠。小鼠分别接受盲肠结扎穿刺或腹腔多微生物接种诱导的亚致死性和致死性多微生物脓毒症，以及腹腔接种鼠伤寒沙门菌（Salmonella typhimurium， GNI）诱导的亚致死性革兰氏阴性脓毒症。监测生存5天。在单独的实验中，小鼠在脓毒症诱导后6小时被杀死，并评估腹腔中性粒细胞迁移、菌血症、肺中性粒细胞隔离以及细胞因子、趋化因子和硝酸盐的水平。测量和结果：tlr4缺陷（C3H/HeJ）小鼠在亚致死性GNI后无法促进中性粒细胞向感染部位募集，导致高死亡率。然而，在盲肠结扎、穿刺和多微生物接种诱导的亚致死性多微生物脓毒症模型中，中性粒细胞迁移并不是TLR4信号所必需的，但令人惊讶的是，在致死性多微生物脓毒症中，建立中性粒细胞迁移障碍至关重要，因为TLR4缺陷小鼠在进行致死性盲肠结扎、穿刺或多微生物接种后没有出现中性粒细胞迁移到感染病灶的失败。结果，这些动物表现出低菌血症和高存活率，并且没有表现出全身性炎症，这是由高水平的循环细胞因子和肺中性粒细胞隔离和趋化因子产生决定的。这些结果强调了TLR4信号在多微生物严重脓毒症中的有害作用。
Objective: We have documented an impaired neutrophil migration toward the infectious focus in severe sepsis. This phenomenon appears to be mediated by nitric oxide, the release of which is stimulated by circulating inflammatory cytokines released by immune cells after stimulation by bacteria and/or their products. Toll-like receptor 4 (TLR4) is the major recognition receptor for lipopolysaccharide, a component of Gram-negative bacterial cell walls. In the present study, we investigated whether TLR4 is involved in the failure of neutrophil migration in mice subjected to polymicrobial or Gram-negative sepsis.Design: Controlled animal study.Setting. University research laboratory.Subjects: Male C3H/HeJ (TLR4-deficient) and C3H/HePas (TLR4-normal) mice.Interventions. Mice were subjected to sublethal or lethal polymicrobial sepsis, both induced by cecal ligation and puncture or intraperitoneal polymicrobial inoculation, and subjected to sublethal Gram-negative sepsis induced by intraperitoneal Salmonella typhimurium inoculation (GNI). survival was monitored for 5 days. In separate experiments, mice were killed 6 hrs after sepsis induction, and intraperitoneal neutrophil migration, bacteremia, lung neutrophil sequestration, and levels of cytokines, chemokines, and nitrate were evaluated.Measurements and Results: TLR4-deficient (C3H/HeJ) mice presented incapacity to promote neutrophil recruitment to the infectious site after sublethal GNI, resulting in high mortality. However, TLR4 signaling is not essential to display neutrophil migration in sublethal polymicrobial sepsis induced by both cecal ligation and puncture and polymicrobial inoculation models, but surprisingly, it is crucial to establish the impairment of neutrophil migration in lethal polymicrobial sepsis, since TLR4-deficient mice that underwent lethal cecal ligation and puncture or polymicrobial inoculation did not present failure of neutrophil migration to infectious focus. As a consequence, these animals presented low bacteremia and a high survival rate and did not display systemic inflammation, determined by high levels of circulating cytokines and lung neutrophil sequestration and chemokine production.Conclusion. These results highlight the harmful role of TLR4 signaling in polymicrobial severe sepsis.