Carbon monoxide (CO) can exert potent anti-inflammatory effects in animal and cell culture models of
sepsis, despite well-known lethal effects at high concentration. Endogenous
biological CO arises from the enzymatic degradation of
haem, mainly from haemoglobin turnover, catalysed by
haem oxygenases (HO). The inducible form of HO,
haem oxygenase 1 (HO-1) participates in endogenous cellular defence against oxidative stress. HO-1 confers cytoprotection in many models of organ and tissue injury where inflammatory processes are implicated, including
sepsis. When applied exogenously at low concentration, CO mimics the cytoprotective potential of HO-1 induction in these models. CO confers protection against
endotoxin shock in vitro and in vivo by inhibiting the production of pro-inflammatory
cytokines, in a mechanism involving the modulation of
p38 mitogen activated protein kinase. CO protection against
vascular injury may involve both anti-inflammatory and antiproliferative effects. The protection afforded by CO against
liver failure and inflammatory
lung injury was associated with the modulation of
inducible nitric oxide synthase. Recent in vitro studies indicate that CO inhibits proinflammatory signalling by differentially inhibiting the trafficking of
toll-like receptors (TLRs) to
lipid rafts. Additional candidate mechanisms in anti-inflammatory effects of CO include the increased expression of
heat shock proteins and the tumour suppressor
protein caveolin 1.