Critical role of endogenous histamine in promoting end-organ tissue injury in sepsis

BACKGROUND: 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. METHODS: Histidine decarboxylase (HDC) gene knockout (HDC(−/−)) mice, histamine H(1)-/H(2)-receptor gene-double knockout (H(1)R(−/−)/H(2)R(−/−)) 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 H(1)- and H(2)-receptors, respectively. RESULTS: 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. H(1)R(−/−)/H(2)R(−/−) mice apparently behaved similar to HDC knockout mice in reducing sepsis-related pathological changes. Pharmacological interventions with H(1)- and H(2)-receptor antagonists indicated that both H(1)- and H(2)-receptors were involved in septic lung and liver injury, whereas only H(2)-receptors contributed to septic kidney injury. CONCLUSIONS: In the setting of sepsis, histamine, through activation of H(1)- and H(2)-receptors, serves as an aggravating mediator to contribute to the development of sepsis-driven major end-organ failure. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40635-016-0109-y) contains supplementary material, which is available to authorized users.