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

Stefan Ryter

doi:10.3390/antiox9111153

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.

Highlights

Heme oxygenase-1, a vital heme degradative enzyme and inducible stress protein
Application of Inhaled Carbon Monoxide (iCO) during pneumonia-infection reduced pro-inflammatory urinary cysteinyl leukotrienes and improved levels of circulating specialized pro-resolving mediators (SPMs), including eicosapentaenoic acid-derived E-series resolvins (RvE) and lipoxins [70]. These results suggested that altered SPM profiles during pneumonia can be partially restored with iCO therapy [70]
The Heme oxygenase-1 (HO-1) field continues to draw worldwide interest, with a multiplicity of biological roles recognized for Heme oxygenase (HO)-1 and its reaction products, from regulation of inflammation to immune system modulation

Summary

Introduction

Heme oxygenase-1, a vital heme degradative enzyme and inducible stress protein. Heme oxygenase (HO; E.C. 1:14:99:3) is a metabolic enzyme system first described in the late 1960s which provides the rate-limiting step in the oxidative degradation of heme [1,2]. The upregulation of mtROS by low concentration CO was associated with inhibition of cytochrome c oxidase, which promoted anti-inflammatory effects via p38 MAPK signaling These studies reported a stabilizing effect of CO on cellular ATP production and ∆Ψm [75]. Elevation of mtROS in macrophages by low-dose CO was shown to trigger adaptive cellular signaling through upregulation of peroxisome proliferator-activated receptor-γ (PPAR-γ) reduced expression of the pro-inflammatory factor early growth response-1. CORM-3 prevented mitochondrial function stimulated activation ofofmitochondrial biogenesis in septic mice [85]. decline and activation of mitochondrial biogenesis in septic [85]. biogenesis in septic mice [85]

Representative

Protective

Therapeutic Modulation of HO-1 in Human Disease

Findings

Conclusions