Background: Histamine assumes a critical role as a major mediator of many disorders with inflammation and immune reactions. However, direct evidence has not been provided showing the involvement of histamine in the development of multiple organ dysfunction or failure in sepsis. The goal of the present study was to assess the response to sepsis caused by cecal ligation and puncture (CLP) in histamine decarboxylase knockout (HDC-/-) mice and histamine H1-/H2- receptor double knockout (H1R-/-/H2R-/-) mice.
Materials and Methods: H1R-/-/H2R-/- mice were generated by crossbreeding H1-receptor null mice and H2-receptor null mice. Polymicrobial sepsis was induced by CLP in HDC-/- mice, H1R-/-/H2R-/- mice, and their littermate wild type (WT) mice.
Results: Knockout mice of histamine-related gene showed lower levels of serum aminotransferase activity, serum creatinine, and serum and tissue pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, and MCP-1) than WT mice when the animals were rendered septic by CLP. Histopathological examinations showed significantly reduced acute lung, liver, and kidney injury after CLP in HDC-/- and H1R-/-/H2R-/- mice. The histamine-mediated development of major end-organ injury was associated with an increase in the nuclear factor-kB signaling pathway.
Conclusions: These results establish that endogenous histamine acting on H1- and H2- receptors is identified as an aggravating mediator to contribute to the development of major end-organ injury in sepsis. These results also suggest that the validity and feasibility of the use of histamine receptor antagonists to septic organ injury.

Histamine has a contributory role in promoting organ injury in sepsis: experimental studies using knockout mice of histamine-related genes