Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway

Abstract

The stress-inducible protein heme oxygenase-1 provides protection against oxidative stress. The anti-inflammatory properties of heme oxygenase-1 may serve as a basis for this cytoprotection. We demonstrate here that carbon monoxide, a by-product of heme catabolism by heme oxygenase, mediates potent anti-inflammatory effects. Both in vivo and in vitro, carbon monoxide at low concentrations differentially and selectively inhibited the expression of lipopolysaccharide-induced pro-inflammatory cytokines tumor necrosis factor-alpha, interleukin-1beta, and macrophage inflammatory protein-1beta and increased the lipopolysaccharide-induced expression of the anti-inflammatory cytokine interleukin-10. Carbon monoxide mediated these anti-inflammatory effects not through a guanylyl cyclase-cGMP or nitric oxide pathway, but instead through a pathway involving the mitogen-activated protein kinases. These data indicate the possibility that carbon monoxide may have an important protective function in inflammatory disease states and thus has potential therapeutic uses.

Adenovirus-mediated transfer of heme oxygenase-1 cDNA attenuates severe lung injury induced by the influenza virus in mice

“…Consistent with this observation, neutrophil migration into the lung following an intratracheal challenge of LPS was attenuated when animals breathed air containing CO, but that was not attenuated in animals lacking p38 MAPK. 28,30 Inoue et al 34 have also demonstrated that neutrophil migration to the lung following LPS inhalation was markedly attenuated by pre-administration of an endogenous HO-1 inducer, hemin, or an Ad expressing HO-1 in mice, and further demonstrated that IL-10 overproduction by macrophages was essential for suppressed neutrophilic inflammation. Together, these data suggest that overexpression of HO-1 results in CO production, which modifies cytokine profiles within both inflammatory and respiratory epithelial cells, thus suppressing neutrophil migration into the lung in response to LPS.…”

“…39,40 Similarly, CO, a by-product of HO-1-mediated heme degradation, has been shown in vitro to stimulate p38 MAPK, a molecule pivotal in the expression of various cytokines. [22][23][24]30 In this regard, Otterbein et al 28,30 have demonstrated that macrophages cultured in air containing CO showed an increase in IL-10, as well as a decrease in TNF-␣ and IL-1␤ production. Consistent with this observation, neutrophil migration into the lung following an intratracheal challenge of LPS was attenuated when animals breathed air containing CO, but that was not attenuated in animals lacking p38 MAPK.…”

“…27 CO has been demonstrated to raise intracellular cyclic GMP levels, prevent apoptosis, and downregulate proinflammatory cytokine expression by modulating the p38MAPK activity in vitro. [28][29][30] The pharmacological upregulation of endogenous HO-1 has been shown to resolve acute inflammatory reactions in experimental models by increasing survival rate of animals under LPSinduced shock, and attenuating neutrophil migration into the pleural cavity following carragenin injection. 31,32 It has also been demonstrated that overexpression of exogenously inserted HO-1 cDNA in gene transfer vectors confer therapeutic benefit on a murine model of hyperoxia 33 or LPS induced lung injury.…”

Heme-oxygenase-1-induced protection against hypoxia/reoxygenation is dependent on biliverdin reductase and its interaction with PI3K/Akt pathway

“…The cytoprotective properties of HO-1 have traditionally been attributed to the by-products of heme degradation, namely bilirubin and carbon monoxide (CO). Indeed, within a narrow therapeutic range, these catalytic by-products exert powerful antioxidant [15,31], antiinflammatory [32] and anti-apoptotic effects [33][34][35], leading to reduced infarct size [16,17,[36][37]. However, emerging evidence, suggests that HO-1 may also exert cytoprotective effects, independent of heme breakdown [38] by interacting with survival signaling pathways such as PI3K-Akt and p38.…”

A cell penetrating heme oxygenase protein protects heart graft against ischemia/reperfusion injury

“…9,10 There are various forms of stress or tissue injury that can induce the expression of HO-1. Copious studies show that HO-1 and its products can maintain cellular homeostasis based on its anti-inflammatory, 11 antioxidative 12,13 and/or antiapoptotic 14,15 properties. In different models of transplantation, induction of HO-1 can protect grafts from I/R injury, [16][17][18] acute 14,19 and chronic rejection.…”