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 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.


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. 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.


CONCLUSIONS
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.
Department of Anesthesiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
Mizuki
M
Hattori
Department of Anesthesiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
Mitsuaki
M
Yamazaki
Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
Wakana
W
Ohashi
Department of Immunobiology, Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
Satoshi
S
Tanaka
Department of Anesthesiology and Pain Relief Center, The University of Tokyo Hospital, Tokyo, Japan.
Kohshi
K
Hattori
Department of Analytical and Bio-Analytical Chemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
Kenichiro
K
Todoroki
Department of Anesthesiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
Toshio
T
Fujimori
Department of Applied Quantum Medical Engineering, School of Engineering, Tohoku University, Sendai, Japan.
Hiroshi
H
Ohtsu
Department of Emergency and Critical Care Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Naoyuki
N
Matsuda
Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan. yhattori@med.u-toyama.ac.jp.
Yuichi
Y
Hattori
Histamine; Histidine decarboxylase; Organ injury; Sepsis