Carbon monoxide in acute lung injury.
ABSTRACT Despite modern clinical practice in critical care medicine, acute lung injury still causes unacceptably high rates of morbidity and mortality. Therefore, the challenge today is to identify new and effective strategies in order to improve the outcome of these patients. Carbon monoxide, endogenously produced by the heme oxygenase enzyme system, has emerged as promising gaseous therapeutic that exerts protective effects against inflammation, oxidative and mechanical stress, and apoptosis, thus potentially limiting acute lung injury. In this review we discuss the effects of inhaled carbon monoxide on acute lung injury that results from ischemia-reperfusion, transplantation, sepsis, hyperoxia, or mechanical ventilation, the latter referred to as ventilator-induced lung injury. Multiple investigations using in vivo and in vitro models have demonstrated anti-inflammatory, anti-apoptotic, and anti-proliferative properties of carbon monoxide in the lung when applied at low dose prior to or during stressful stimuli. The molecular mechanisms that are modulated by carbon monoxide exposure are still not fully understood. Carbon monoxide mediated lung protection involves several signaling pathways including mitogen activated protein kinases, nuclear factor-κB, activator protein-1, Akt, peroxisome proliferating- activated receptor-γ, early growth response-1, caveolin-1, hypoxia-inducible factor-1α, caspases, Bcl-2-family members, heat shock proteins, or molecules of the fibrinolytic axis. At present, clinical trials on the efficacy and safety of CO investigate whether the promising laboratory findings might be translatable to humans.
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ABSTRACT: Significance. Many reports have underscored the importance of the heme degradation pathway regulated by heme oxygenase (HO). This reaction releases bile pigments and carbon monoxide (CO), which are important antioxidant and signaling molecules. Thus the reaction of HO-1 would have significant cytoprotective effects. Nevertheless, the importance of this protein goes beyond its enzymatic action. New evidence outlines significant effects of inactive forms of the HO-1 protein Recent Advances. In fact, the role of the HO protein on cellular signaling including transcription factor activation, binding to proteins, phosphorylation and modulation of protein function, amongst others, has begun to be elucidated. The mechanism by which the inducible form HO-1 in particular, can migrate to various cellular compartments to mediate important signaling or how and why it binds to key transcription factors and other proteins that are important in DNA repair is also described in several physiologic systems. Critical Issues. The signaling functions of HO-1 may have particular relevance in clinical circumstances including cancer since redistribution of HO-1 into the nuclear compartment is observed with cancer progression and metastasis. In addition, with oxidative stress, the pleiotropic functions of HO-1 modulate antioxidant defense. In organ transplantation, HO and its byproducts suppress rejection at multiple levels and in sepsis induced pulmonary dysfunction, inhaled CO or modulation of HO activity can change the course of the disease in animals. Future Directions. It is hoped that a more detailed understanding of the various signaling functions of HO will guide therapeutic approaches for complex diseases.Antioxidants & Redox Signaling 11/2013; · 8.20 Impact Factor