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Gaseous Therapeutics in Acute Lung Injury

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Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) remain major causes of morbidity and mortality in critical care medicine despite advances in therapeutic modalities. ALI can be associated with sepsis, trauma, pharmaceutical or xenobiotic exposures, high oxygen therapy (hyperoxia), and mechanical ventilation. Of the small gas molecules (NO, CO, H2S) that arise in human beings from endogenous enzymatic activities, the physiological significance of NO is well established, whereas that of CO or H2S remains controversial. Recent studies have explored the potential efficacy of inhalation therapies using these small gas molecules in animal models of ALI. NO has vasoregulatory and redox‐active properties and can function as a selective pulmonary vasodilator. Inhaled NO (iNO) has shown promise as a therapy in animal models of ALI including endotoxin challenge, ischemia/reperfusion (I/R) injury, and lung transplantation. CO, another diatomic gas, can exert cellular tissue protection through antiapoptotic, anti‐inflammatory, and antiproliferative effects. CO has shown therapeutic potential in animal models of endotoxin challenge, oxidative lung injury, I/R injury, pulmonary fibrosis, ventilator‐induced lung injury, and lung transplantation. H2S, a third potential therapeutic gas, can induce hypometabolic states in mice and can confer both pro‐ and anti‐inflammatory effects in rodent models of ALI and sepsis. Clinical studies have shown variable results for the efficacy of iNO in lung transplantation and failure for this therapy to improve mortality in ARDS patients. No clinical studies have been conducted with H2S. The clinical efficacy of CO remains unclear and awaits further controlled clinical studies in transplantation and sepsis. © 2011 American Physiological Society. Compr Physiol 1:105‐121, 2011.

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Figure 1. Figure 1.

Endogenous production of gaseous signaling molecules. (A) Nitric oxide is synthesized from l‐arginine by the action of nitric oxide synthase enzymes. (B) Carbon monoxide is generated from the oxidative catabolism of heme by the action of heme oxygenase enzymes. (C) H2S is synthesized from l‐cysteine. Simplified reaction catalyzed by cystathionine‐γ‐lyase is shown.

Figure 2. Figure 2.

Rationale for therapeutic application of carbon monoxide (CO). CO can provide tissue protection dependent largely on antiapoptotic, anti‐inflammatory, and antiproliferative properties. Additional systemic effects that can promote tissue protection include inhibition of microvascular leakage and inhibition of thrombosis. The molecular mechanisms for these effects are not entirely clear, but several candidate biochemical targets/pathways have been described. Finally, the therapeutic application of low‐concentration CO may have limitations, including inhibition of alveolar fluid clearance, unclear neurotoxicity, carboxyhemoglobinemia, and systemic/extrapulmonary effects.

Figure 1.

Endogenous production of gaseous signaling molecules. (A) Nitric oxide is synthesized from l‐arginine by the action of nitric oxide synthase enzymes. (B) Carbon monoxide is generated from the oxidative catabolism of heme by the action of heme oxygenase enzymes. (C) H2S is synthesized from l‐cysteine. Simplified reaction catalyzed by cystathionine‐γ‐lyase is shown.

Figure 2.

Rationale for therapeutic application of carbon monoxide (CO). CO can provide tissue protection dependent largely on antiapoptotic, anti‐inflammatory, and antiproliferative properties. Additional systemic effects that can promote tissue protection include inhibition of microvascular leakage and inhibition of thrombosis. The molecular mechanisms for these effects are not entirely clear, but several candidate biochemical targets/pathways have been described. Finally, the therapeutic application of low‐concentration CO may have limitations, including inhibition of alveolar fluid clearance, unclear neurotoxicity, carboxyhemoglobinemia, and systemic/extrapulmonary effects.

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Stefan W. Ryter, Augustine M. K. Choi. Gaseous Therapeutics in Acute Lung Injury. Compr Physiol 2010, 1: 105-121. doi: 10.1002/cphy.c090003