Critical role of endogenous histamine in promoting end-organ tissue injury in sepsis.
Critical role of endogenous histamine in promoting end-organ tissue injury in sepsis.
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DOI：
10.1186/s40635-016-0109-y
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发表时间：
2016-12
影响因子：
3.5
通讯作者：
Hattori Y
中科院分区：
文献类型：
--
作者：
Hattori M;Yamazaki M;Ohashi W;Tanaka S;Hattori K;Todoroki K;Fujimori T;Ohtsu H;Matsuda N;Hattori Y
组胺在与炎症和免疫反应相关的各种病理性疾病中作为主要介质发挥重要作用。然而，组胺在脓毒症的病理状态和症状中的参与仍然完全未知。在这项研究中，我们确定组胺被确定为促进脓毒症中器官损伤发展的贡献介质。对组氨酸脱羧酶（HDC）基因敲除（HDC−/−）小鼠、组胺H1-/H2受体基因双敲除（H1 R −/−/H2 R −/−）小鼠及其同窝野生型（WT）C57 BL/6 J小鼠进行盲肠结扎穿孔（CLP）或假手术。在CLP前60 min，分别向WT小鼠腹腔注射d-氯苯那敏和法莫替丁，以阻断H1和H2受体。在CLP致脓毒症的小鼠中，组织组胺水平升高与HDC表达增加相关。脓毒症诱导的异常细胞因子产生和多器官损伤（肺、肝和肾）在HDC−/−小鼠中显著低于WT对照组，并且HDC缺陷改善了脓毒症的存活率。这种益处与核因子（NF）-κB信号通路的活化水平显著降低相对应。H1 R −/−/H2 R −/−小鼠在减少脓毒症相关病理变化方面的表现显然与HDC敲除小鼠相似。H1和H2受体拮抗剂的药理学干预表明，H1和H2受体参与脓毒性肺和肝损伤，而只有H2受体导致脓毒性肾损伤。在脓毒症的情况下，组胺通过激活H1和H2受体，作为加重介质，促进脓毒症驱动的主要终末器官衰竭的发展。本文的在线版本（doi：10.1186/s40635-016-0109-y）包含补充材料，可供授权用户使用。
Histamine assumes an important role as a major mediator in various pathologic disorders associated with inflammation and immune reactions. However, the involvement of histamine in the pathological conditions and symptoms of sepsis remains entirely unknown. In this study, we establish that histamine is identified as a contributory mediator to promoting the development of organ injury in sepsis. Histidine decarboxylase (HDC) gene knockout (HDC−/−) mice, histamine H1-/H2-receptor gene-double knockout (H1R−/−/H2R−/−) mice, and their littermate wild-type (WT) C57BL/6J mice underwent cecal ligation and puncture (CLP) or sham operation. Some WT mice were injected intraperitoneally with d-chlorpheniramine and famotidine 60 min before CLP to block H1- and H2-receptors, respectively. In mice rendered septic by CLP, tissue histamine levels were elevated in association with increased HDC expression. Sepsis-induced abnormal cytokine production and multiple organ injury (lung, liver, and kidney) were significantly less pronounced in HDC−/− mice as compared with WT controls, and HDC deficiency had improved survival in sepsis. This benefit corresponded with a significant reduction in activation levels of the nuclear factor (NF)-κB signaling pathway. H1R−/−/H2R−/− mice apparently behaved similar to HDC knockout mice in reducing sepsis-related pathological changes. Pharmacological interventions with H1- and H2-receptor antagonists indicated that both H1- and H2-receptors were involved in septic lung and liver injury, whereas only H2-receptors contributed to septic kidney injury. In the setting of sepsis, histamine, through activation of H1- and H2-receptors, serves as an aggravating mediator to contribute to the development of sepsis-driven major end-organ failure. The online version of this article (doi:10.1186/s40635-016-0109-y) contains supplementary material, which is available to authorized users.