HYDROCORTISONE REDUCES THE BENEFICIAL EFFECTS OF TOLL-LIKE RECEPTOR 2 DEFICIENCY ON SURVIVAL IN A MOUSE MODEL OF POLYMICROBIAL SEPSIS
HYDROCORTISONE REDUCES THE BENEFICIAL EFFECTS OF TOLL-LIKE RECEPTOR 2 DEFICIENCY ON SURVIVAL IN A MOUSE MODEL OF POLYMICROBIAL SEPSIS
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DOI：
10.1097/shk.0000000000000029
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发表时间：
2013-11-01
期刊：
影响因子：
3.1
通讯作者：
Roesner, Jan P.
中科院分区：
文献类型：
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作者：
Bergt, Stefan;Wagner, Nana-Maria;Roesner, Jan P.
Introduction: Toll-like receptors (TLRs) play a crucial role in early host defense against microorganisms. Toll-like receptor 2 (TLR2) polymorphisms have a prevalence of 10%; TLR2 的功能缺陷与对革兰氏阳性菌的敏感性较高有关，而 TLR2 缺陷与肾上腺应激反应受损有关。在本研究中，我们比较了野生型（WT）和TLR2缺陷型（TLR2（-/-））小鼠的内源性皮质酮产生，并分析了盲肠结扎穿刺（CLP）引起的败血症期间氢化可的松治疗后的存活率。方法：雄性 C57BL/6J (WT)； B6.129-Tlr2tm1Kir/J (TLR2(-/-)) 小鼠接受 CLP 或假手术，并随机分配接受氢化可的松 (5 mg/kg) 或载体术后治疗（n = 10 只小鼠/组）。 Survival was documented for an observation period of 48 h.氢化可的松治疗和脂磷壁酸 (LTA) 暴露后内源性皮质酮的产生、白细胞介素 6 (IL-6) 和 IL-1 β 血浆水平以及假手术或 CLP 后使用另一只 n = 5 只小鼠/组测定血细胞计数。 Statistical analysis was performed using analysis of variance/Bonferroni.结果：TLR2(-/-)小鼠在氢化可的松或LTA治疗后分别表现出内源性皮质酮产生缺乏抑制和减弱的增加。 CLP 后，与 WT 对照相比，TLR2(-/-) 小鼠表现出不受损害的肾上腺应激反应、更高的 IL-6 水平和更高的存活率（75% vs. 35%；P < 0.05）。 TLR2(-/-) 小鼠的氢化可的松治疗完全消除了这一优势（与媒介物治疗的 TLR2(-/-) 小鼠相比，存活率降低至 45%，P < 0.05），并且与 IL-1 血浆浓度降低相关。结论：Toll 样受体 2 缺陷与多种微生物败血症期间肾上腺应激反应不受损害和生存率增加有关。氢化可的松治疗会增加脓毒症 TLR2(-/-) 小鼠的死亡率，表明氢化可的松治疗可能对具有功能性 TLR2 多态性的个体有害。
Introduction: Toll-like receptors (TLRs) play a crucial role in early host defense against microorganisms. Toll-like receptor 2 (TLR2) polymorphisms have a prevalence of 10%; functional defects of TLR2 are associated with higher susceptibility toward gram-positive bacteria, and TLR2 deficiency has been associated with an impaired adrenal stress response. In the present study, we compared endogenous corticosterone production of wild-type (WT) and TLR2-deficient (TLR2(-/-)) mice and analyzed survival after hydrocortisone therapy during sepsis induced by cecal ligation and puncture (CLP). Methods: Male C57BL/6J (WT); and B6.129-Tlr2tm1Kir/J (TLR2(-/-)) mice were subjected to CLP or sham operation and randomly assigned to postoperative treatment with either hydrocortisone (5 mg/kg) or vehicle (n = 10 mice/group). Survival was documented for an observation period of 48 h. Endogenous corticosterone production following hydrocortisone treatment and lipoteichoic acid (LTA) exposure, interleukin 6 (IL-6) and IL-1 beta plasma levels, and blood counts were determined following sham operation or CLP using another n = 5 mice/group. Statistical analysis was performed using analysis of variance/Bonferroni. Results: TLR2(-/-) mice exhibited a lack of suppression and an attenuated increase in endogenous corticosterone production following hydrocortisone or LTA treatment, respectively. After CLP, TLR2(-/-) mice exhibited an uncompromised adrenal stress response, higher IL-6 levels, and increased survival compared with WT controls (75 vs. 35%; P < 0.05). Hydrocortisone therapy of TLR2(-/-) mice completely abolished this advantage (decrease in survival to 45%, P < 0.05 vs. vehicle-treated TLR2(-/-) mice) and was associated with decreased IL-1 beta plasma concentrations. Conclusions: Toll-like receptor 2 deficiency is associated with an uncompromised adrenal stress response and increased survival rates during polymicrobial sepsis. Hydrocortisone treatment increases mortality of septic TLR2(-/-) mice, suggesting that hydrocortisone therapy might be harmful for individuals with functional TLR2 polymorphisms.