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 MODS through activation of autophagy-dependent 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 "first in ALI" Phase I safety CO trial in humans.

Public Health Relevance

The mechanism by which low dose carbon monoxide provides cytoprotection in sepsis and acute lung injury is poorly understood. Carbon monoxide induced autophagy may mediate its cytoprotection in sepsis and acute lung injury via its anti-inflammatory effects. An improved understanding on how carbon monoxide mediates its'cytoprotection will assist in the proof of concept studies in humans to examine whether inhaled carbon monoxide can be a potential therapy in human sepsis and acute lung injury.

National Institute of Health (NIH)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brigham and Women's Hospital
United States
Zip Code
Beitler, Jeremy R; Schoenfeld, David A; Thompson, B Taylor (2014) Preventing ARDS: progress, promise, and pitfalls. Chest 146:1102-13
Siempos, Ilias I; Lam, Hilaire C; Ding, Yan et al. (2014) Cecal ligation and puncture-induced sepsis as a model to study autophagy in mice. J Vis Exp :e51066
Suliman, Hagir B; Piantadosi, Claude A (2014) Mitochondrial biogenesis: regulation by endogenous gases during inflammation and organ stress. Curr Pharm Des 20:5653-62
Agrawal, Pankaj B; Pierson, Christopher R; Joshi, Mugdha et al. (2014) SPEG interacts with myotubularin, and its deficiency causes centronuclear myopathy with dilated cardiomyopathy. Am J Hum Genet 95:218-26
Nakahira, Kiichi; Cloonan, Suzanne M; Mizumura, Kenji et al. (2014) Autophagy: a crucial moderator of redox balance, inflammation, and apoptosis in lung disease. Antioxid Redox Signal 20:474-94
Schumacker, Paul T; Gillespie, Mark N; Nakahira, Kiichi et al. (2014) Mitochondria in lung biology and pathology: more than just a powerhouse. Am J Physiol Lung Cell Mol Physiol 306:L962-74
Colas, Romain A; Shinohara, Masakazu; Dalli, Jesmond et al. (2014) Identification and signature profiles for pro-resolving and inflammatory lipid mediators in human tissue. Am J Physiol Cell Physiol 307:C39-54
Shinohara, Masakazu; Kibi, Megumi; Riley, Ian R et al. (2014) Cell-cell interactions and bronchoconstrictor eicosanoid reduction with inhaled carbon monoxide and resolvin D1. Am J Physiol Lung Cell Mol Physiol 307:L746-57
Ryter, Stefan W; Koo, Ja Kun; Choi, Augustine M K (2014) Molecular regulation of autophagy and its implications for metabolic diseases. Curr Opin Clin Nutr Metab Care 17:329-37
Kraft, Bryan D; Piantadosi, Claude A; Benjamin, Ashlee M et al. (2014) Development of a novel preclinical model of pneumococcal pneumonia in nonhuman primates. Am J Respir Cell Mol Biol 50:995-1004

Showing the most recent 10 out of 26 publications