Background: Histamine assumes an important role as a major mediator in various\npathologic disorders associated with inflammation and immune reactions. However,\nthe involvement of histamine in the pathological conditions and symptoms of sepsis\nremains entirely unknown. In this study, we establish that histamine is identified as a\ncontributory mediator to promoting the development of organ injury in sepsis.\nMethods: Histidine decarboxylase (HDC) gene knockout (HDCâË?â??/âË?â??) mice, histamine H1-/\nH2-receptor gene-double knockout (H1RâË?â??/âË?â??/H2RâË?â??/âË?â??) mice, and their littermate wild-type\n(WT) C57BL/6J mice underwent cecal ligation and puncture (CLP) or sham operation.\nSome WT mice were injected intraperitoneally with d-chlorpheniramine and famotidine\n60 min before CLP to block H1- and H2-receptors, respectively.\nResults: In mice rendered septic by CLP, tissue histamine levels were elevated in\nassociation with increased HDC expression. Sepsis-induced abnormal cytokine\nproduction and multiple organ injury (lung, liver, and kidney) were significantly\nless pronounced in HDCâË?â??/âË?â?? mice as compared with WT controls, and HDC deficiency\nhad improved survival in sepsis. This benefit corresponded with a significant reduction\nin activation levels of the nuclear factor (NF)-Ã?ºB signaling pathway. H1RâË?â??/âË?â??/H2RâË?â??/âË?â?? mice\napparently behaved similar to HDC knockout mice in reducing sepsis-related pathological\nchanges. Pharmacological interventions with H1- and H2-receptor antagonists indicated\nthat both H1- and H2-receptors were involved in septic lung and liver injury, whereas only\nH2-receptors contributed to septic kidney injury.\nConclusions: In the setting of sepsis, histamine, through activation of H1- and H2-\nreceptors, serves as an aggravating mediator to contribute to the development of\nsepsis-driven major end-organ failure.
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