Therapeutic Potential of Heme Oxygenase-1 and Carbon Monoxide in Acute Organ Injury, Critical Illness, and Inflammatory Disorders

Abstract

Heme oxygenase-1 (HO-1) is an inducible stress protein that catalyzes the oxidative conversion of heme to carbon monoxide (CO), iron, and biliverdin (BV), the latter of which is converted to bilirubin (BR) by biliverdin reductase. HO-1 has been implicated as a cytoprotectant in various models of acute organ injury and disease (i.e., lung, kidney, heart, liver). Thus, HO-1 may serve as a general therapeutic target in inflammatory diseases. HO-1 may function as a pleiotropic modulator of inflammatory signaling, via the removal of heme, and generation of its enzymatic degradation-products. Iron release from HO activity may exert pro-inflammatory effects unless sequestered, whereas BV/BR have well-established antioxidant properties. CO, derived from HO activity, has been identified as an endogenous mediator that can influence mitochondrial function and/or cellular signal transduction programs which culminate in the regulation of apoptosis, cellular proliferation, and inflammation. Much research has focused on the application of low concentration CO, whether administered in gaseous form by inhalation, or via the use of CO-releasing molecules (CORMs), for therapeutic benefit in disease. The development of novel CORMs for their translational potential remains an active area of investigation. Evidence has accumulated for therapeutic effects of both CO and CORMs in diseases associated with critical care, including acute lung injury/acute respiratory distress syndrome (ALI/ARDS), mechanical ventilation-induced lung injury, pneumonias, and sepsis. The therapeutic benefits of CO may extend to other diseases involving aberrant inflammatory processes such as transplant-associated ischemia/reperfusion injury and chronic graft rejection, and metabolic diseases. Current and planned clinical trials explore the therapeutic benefit of CO in ARDS and other lung diseases.

Significance of Heme and Heme Degradation in the Pathogenesis of Acute Lung and Inflammatory Disorders

“…The potential targets of CO binding are, in principle, represented by cellular hemoproteins that utilize heme for catalytic activity. In this regard, CO may compete for oxygen binding to hemoglobin (with an affinity ~245 times that of oxygen), inhibit cytochrome c oxidase activity, and modulate the enzymatic activity of select hemoproteins, with sGC being the classic example [ 51 , 52 , 53 ]. CO was implicated as an anti-inflammatory effector molecule in macrophages based on p38 MAPK-dependent downregulation of pro-inflammatory cytokines and upregulation of the anti-inflammatory cytokine IL-10 [ 48 ].…”

“…CO was also characterized as an antiapoptotic molecule based on initial observations of inhibition of TNF-α-mediated endothelial cell apoptosis [ 50 ]. Further, evidence has accumulated that CO, when applied exogenously at low concentrations in the ppm range (i.e., 250 ppm), can confer cyto- and tissue protection in inflammatory disease models in effect by influencing inflammation, apoptosis, and cell proliferation programs [ 51 , 52 , 53 ]. The molecular and cellular effects of exogenous CO application as a therapeutic agent in animal models of injury and disease have been reviewed extensively elsewhere [ 51 , 52 , 53 ].…”

“…Heme-derived CO, generated endogenously by HO activity, or applied at low concentrations designed to mimic biological production, may impact cellular functions by affecting endogenous signal transduction pathways [ 51 , 52 ]. Specifically, these effects include the modulation of apoptosis and other regulated forms of cell death, inflammation, cell proliferation, autophagy and other biological processes [ 51 , 52 , 53 ]. Collectively, these studies establishing cellular effects of CO served as the basis for widespread development of CO releasing molecules (CORMs) and organic CO-donor compounds, as potential candidates for therapeutic application [ 54 , 55 ].…”

Dual Acting Carbon Monoxide Releasing Molecules and Carbonic Anhydrase Inhibitors Differentially Modulate Inflammation in Human Tenocytes

“…Under oxidative stress and inflammation, Nrf2 directly transcribes for heme oxygenase-1 (HO-1), which produces carbonic monoxide (CO) along with ferrous iron and biliverdin as a crucial cellular stress response that repairs damage and restores cellular homeostasis [ 7 ]. The therapeutic significance of a controlled carbon monoxide (CO) delivery at low doses has recently gained reliability being sustained by a broad amount of literature [ 8 , 9 ]. It has been reported that CO administered at low doses can mimic many of the beneficial effects exerted by HO-1 in several experimental models such as inflammatory conditions [ 10 ].…”

Hydrogen Sulfide and Carbon Monoxide Tolerance in Bacteria

“…CO has potential for therapeutic applications through three modes of delivery: induction of genes encoding heme oxygenases; inhalation of gaseous CO; and use of CO-releasing molecules (CORMs) [ 7 ]. CORMs exhibit vasodilatory, regulation of mitochondrial respiration, anti-inflammatory, anti-apoptotic, anti-ischemic, and cardioprotective properties [ 8 , 9 ].…”