Published online Jan 28, 2008. doi: 10.3748/wjg.14.547
Revised: September 28, 2007
Published online: January 28, 2008
AIM: To explore the effects of CO-releasing molecules [tricarbonyldichlororuthenium (II) dimer, CORM-2]-liberated CO on attenuation of inflammatory responses in liver of an experimental animal model of thermal injury and to investigate the associated potential mechanisms.
METHODS: Thirty-six mice were assigned to three groups in three respective experiments. In each experiment, mice in sham group (n = 4) received sham thermal injury, whereas mice in burn group (n = 4) received a 15% of total body surface area (TBSA) full-thickness thermal injury, and mice in burn + CORM-2 group (n = 4) received the same thermal injury with immediate administration of CORM-2 (8 mg/kg, iv). Hepatic tissue sections were stained with hematoxylin and eosin and examined under a light microscope. Levels of aminotransferases (ALT and AST) and nitric oxide (NO) were measured by biochemical methods. Tumor necrosis factor-α (TNF-α) and interleukin (IL-1β) activity, and the protein expression of iNOS and HO-1 in serum and tissue homogenates were assessed. In in vitro experiments, Kupffer cells were stimulated with LPS (10 &mgr;g/mL) for 4 h in the presence or absence of CORM-2 (10-100 &mgr;mol/L). Subsequently, the expression levels of TNF-α and NO production were assessed.
RESULTS: Pro-inflammatory mediators (TNF-α, IL-1β, NO) in serum and liver homogenates of thermally injured mice were significantly reduced by CORM-2 administration. This was accompanied by a decrease in the expression of iNOS while an increase in the expression of HO-1 in the liver tissue. In parallel, the concentrations of TNF-α and NO in supernatants of LPS-stimulated Kupffer cells co-incubated with CORM-2 (10-100 &mgr;mol/L) were also markedly decreased. Histological examination demonstrated that CORM-2 could attenuate the leukocytes infiltration to the liver tissue.
CONCLUSION: CORM-released CO modulates liver inflammation and significantly protects liver injury in burn mice by inhibiting the expression of iNOS and NO production, down-regulating the expression of pro-inflammatory mediators (TNF-α, IL-1β).