Carbon Monoxide and Bilirubin

Abstract

Heme oxygenase (HO)-1, an inducible, low-molecular-weight stress protein, confers cellular and tissue protection in multiple models of injury and disease, including oxidative or inflammatory lung injury, ischemia/reperfusion (I/R) injuries, and vascular injury/disease. The tissue protection provided by HO-1 potentially relates to the endogenous production of the end products of its enzymatic activity: namely, biliverdin (BV)/bilirubin (BR), carbon monoxide (CO), and iron. Of these, CO and BV/BR show promise as possible therapeutic agents when applied exogenously in models of lung or vascular injury. CO activates intracellular signaling pathways that involve soluble guanylate cyclase and/or p38 mitogen-activated protein kinase. Although toxic at elevated concentrations, low concentrations of CO can confer antiinflammatory, antiapoptotic, antiproliferative, and vasodilatory effects. BV and BR are natural antioxidants that can provide protection against oxidative stress in cell culture and in plasma. Application of BV or BR protects against I/R injury in several organ models. Recent evidence has also demonstrated antiinflammatory and antiproliferative properties of these pigments. To date, evidence has accumulated for salutary effects of CO, BV, and/or BR in lung/vascular injury models, as well as in models of transplant-associated I/R injury. Thus, the exogenous application of HO end products may provide an alternative to pharmacologic or gene therapy approaches to harness the therapeutic potential of HO-1.

The Ability of Bilirubin in Identifying Smokers with Higher Risk of Lung Cancer: A Large Cohort Study in Conjunction with Global Metabolomic Profiling

“…Of the 29 metabolites with significant trends, bilirubin caught our most interest given its potent endogenous cytoprotective properties and more importantly, its inverse association with cardiovascular disease and respiratory disease in previous reports (24–27). Therefore, we selected bilirubin and λ-glutamylalanine, which showed the most significant trend from metabolomic profiling and after Bonferroni correction for further validation.…”

“…Elevated levels of serum bilirubin have been associated with a lower risk of respiratory diseases and lung cancer (24, 27). The mechanism of this association was credited to the antioxidant and anti-inflammatory properties of bilirubin.…”

Heme oxygenase-1 regulates mitochondrial quality control in the heart

“…Biliverdin is immediately converted into bilirubin by biliverdin reductase, while iron is oxidized (to Fe 3+ ) and sequestered by ferritin. The protective properties of HO-1 expression can be attributed to both the degradation of heme as well as the production of these cytoprotective byproducts, which possess antioxidant, antiinflammatory, and antiapoptotic properties (10–14). …”

Combined Effects of Smoking and Bilirubin Levels on the Risk of Lung Cancer in Korea: The Severance Cohort Study

“…From cross-sectional and longitudinal studies, serum bilirubin has inverse associations with the risk of cardiovascular disease (CVD), stroke, metabolic syndrome and cancers such as colorectal cancer and breast cancer [8]–[12]. An experimental study using animal models support a protective effect of increased bilirubin against respiratory injury by environmental stressors [13]. Given the remarkable antioxidant, cytoprotective, and antiinflammatory properties of bilirubin, and the critical role of oxidative stress, we hypothesized that higher baseline bilirubin level is associated with lower risk of lung cancer.…”