The social network of carbon monoxide in medicine

Abstract

Networking between cells is critical for proper functioning of the cellular milieu and is mediated by cascades of highly regulated and overlapping signaling molecules. The enzyme heme oxygenase-1 (HO-1) generates three separate signaling molecules through the catalysis of heme - carbon monoxide (CO), biliverdin, and iron - each of which acts via distinct molecular targets to influence cell function, both proximally and distally. This review focuses on state-of-the art developments and insights into the impact of HO-1 and CO on the innate immune response, the effects of which are responsible for an ensemble of functions that help regulate complex immunological responses to bacterial sepsis and ischemia/reperfusion injury. HO-1 exemplifies an evolutionarily conserved system necessary for the cellular milieu to adapt appropriately, function properly, and ensure survival of the organism.

Figure I

Catabolism of Heme by HO-1

Figure I

Catabolism of Heme by HO-1

Figure 1. Social Networking of Heme Oxygenase-1 and Carbon Monoxide in Innate Immunity

Carbon monoxide (CO), generated by HO-1 or provided as an exogenous gas, is depicted here as an umbrella representing the very broad effects of CO as it regulates many aspects of the innate immune response to stressors. Inhaled CO imparts potent salutary effects against both pathogenic (bacterial sepsis) and sterile inflammatory (chemical-induced, e.g., acetaminophen-induced liver injury) sequelae and functions homeodynamically to restore basal cellular function. CO functions in a manner that befits the need of the cell to ensure the optimal probability for survival.

Figure 2. Signaling Pathways of Carbon Monoxide in the Cells of the Innate Immune System

Comparativeresponse of a cell to stress or injury is dependent on the time of CO application administered pre or post insult. Signaling molecules and pathways that are induced by pretreatment with CO lead to the establishment of a protective barrier to prevent an inflammatory response (left panels). Essentially, CO conditions the cell to be tolerant of subsequent stressors. If, however, the cell is exposed to the stress prior to CO exposure (right panels), CO amplifies the response in a highly controlled fashion to more rapidly restore homeostasis and ensure survival. ROS, Reactive Oxygen Species; MAPK, Mitogen Activated Protein Kinase; NOS, Nitric Oxide Synthase; HIF1α, Hypoxia Inducible Factor 1α; PPARγ, Peroxisome Proliferating-Activated Receptor-γ.