Heme oxygenase-1 and carbon monoxide in pulmonary medicine

Abstract

Heme oxygenase-1 (HO-1), an inducible stress protein, confers cytoprotection against oxidative stress in vitro and in vivo. In addition to its physiological role in heme degradation, HO-1 may influence a number of cellular processes, including growth, inflammation, and apoptosis. By virtue of anti-inflammatory effects, HO-1 limits tissue damage in response to proinflammatory stimuli and prevents allograft rejection after transplantation. The transcriptional upregulation of HO-1 responds to many agents, such as hypoxia, bacterial lipopolysaccharide, and reactive oxygen/nitrogen species. HO-1 and its constitutively expressed isozyme, heme oxygenase-2, catalyze the rate-limiting step in the conversion of heme to its metabolites, bilirubin IXalpha, ferrous iron, and carbon monoxide (CO). The mechanisms by which HO-1 provides protection most likely involve its enzymatic reaction products. Remarkably, administration of CO at low concentrations can substitute for HO-1 with respect to anti-inflammatory and anti-apoptotic effects, suggesting a role for CO as a key mediator of HO-1 function. Chronic, low-level, exogenous exposure to CO from cigarette smoking contributes to the importance of CO in pulmonary medicine. The implications of the HO-1/CO system in pulmonary diseases will be discussed in this review, with an emphasis on inflammatory states.

Figure 1

Role of heme oxygenase and carbon monoxide in lung diseases. Heme oxygenase (HO) generates biliverdin IXα, ferrous iron, and carbon monoxide (CO) from the oxidation of heme. Exhaled CO reflects active heme metabolism. Inflammation, oxidative stress, and apoptosis represent an axis of disease, against which both endogenous HO activity and exogenous CO exert protective effects. CO may inhibit both inflammation and apoptosis. The toxicological properties of CO imply increased pro-oxidant activity; however, the pro-oxidant/and antioxidant consequences of CO in the physiological range remain unclear. The bile pigments biliverdin IXα and bilirubin IXα have demonstrated antioxidant properties, though their prospective roles in modulation of inflammation and apoptosis are currently under investigation. Iron (Fe) released from HO activity returns to a transient chelatable pool, where it may potentially promote oxidative stress and apoptosis. Induction of ferritin synthesis and sequestration of the released iron into ferritin may represent one possible detoxification pathway that limits the potential of iron in pro-apoptotic and pro-oxidative processes.

Figure 2

Possible mechanism(s) of carbon monoxide action. Endogenous carbon monoxide (CO) arises principally as a product of heme metabolism, from the action of heme oxygenase enzymes, although a portion may arise from environmental sources such as pharmacological administration or accidental exposure, or other endogenous processes such as drug and lipid metabolism. The vasoregulatory properties of CO, including its effects on cellular proliferation, platelet aggregation, and vasodilation, have been largely ascribed to the stimulation of guanylate cyclase by direct heme binding, leading to the generation of cyclic GMP. The anti-inflammatory properties of CO are associated with the downregulation of proinflammatory cytokine production, dependent on the selective modulation of mitogen-activated protein kinase (MAPK), such as the 38 kilodalton protein (p38MAPK). In addition to these two mechanisms, CO may potentially interact with any hemoprotein target, though the functional consequences of these interactions with respect to cellular signaling remain poorly understood.