Cytoprotection by Carbon Monoxide In Sepsis and Lung Injury

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Carbon monoxide (CO) has been regarded as an environmental pollutant and noxious health hazard from industrial exposure. Counter to this established toxicity of CO, this laboratory and others have established a cyto- and tissue protective function of low dose of CO, endogenously derived from the heme oxygenase system. In preclinical models of tissue injury. Despite indications that the therapeutic effects of CO in preventing tissue injury may involve anti-inflammatory, anti-apoptotic, and anti-proliferative effects, the mechanism(s) by which CO impacts cellular homeostasis remains incompletely understood. Furthermore, while preclinical studies have established CO cytoprotection, few studies have addressed the therapeutic potential of CO in human disease, in particular acute lung injury (ALI). Autophagy has gained recent attention as a fundamental cellular homeostatic process which facilitates cellular survival by recycling endogenous cellular macromolecules through lysosomal-dependent degradation. Autophagy was originally characterized in yeast, but recent characterization in mammals has raised intense interest in its biological significance. The function of autophagy in ALI has not been explored and nothing is known of how CO may regulate this process. Thus, the delineation of mechanisms by which CO could regulate autophagy and its relationship to tissue protection is a highly novel concept, with far-reaching implications on how inhaled CO could be translated to use in patients with ALI. To examine these relationships, we propose the following hypothesis: CO confers cyto- and tissue protection in ALI and IVIODS through activation of autophagydependent suppression of infiammasome pathway. Furthermore, the proof of concept "first in ALI" Phase I safety CO trial will provide the groundwork for a Phase ll/lll CO intervention trial in human ALI. To address this hypothesis we will examine the following Specific Aims: Specific Aim 1: To determine the regulation and function of CO-induced autophagy in mediating the cytoprotective effects of CO in experimental sepsis and ALI Specific Aim 2: To determine the mechanism by which CO dampens the inflammasome pathway in experimental sepsis and ALI Specific Aim 3: To perform proof of concept "flrst in ALI" Phase I safety CO trial in humans