CO has been regarded by the scientific community as an environmental pollutant, asphyxiant and noxious health hazard from occupational or industrial exposure. Counter to this established toxicity and popular view of CO as a lethal substance, this laboratory and others have established a cyto- and tissue protective function of low concentrations of CO in cell culture and animal models of cell and tissue injury. While preliminary studies have established an anti-inflammatory effect of CO in rodents, less is known of the therapeutic potential of CO against polymicrobial sepsis. Furthermore, few studies have addressed this therapeutic potential in higher organisms such as non-human primates or humans. Despite indications that the therapeutic effects of CO in preventing tissue injury involve anti-inflammatory, anti-apoptotic, and anti-proliferative effects, the molecular mechanisms by which CO impacts cellular homeostasis remain incompletely understood. (Macro)-autophagy has gained recent attention as a fundamental cellular homeostatic mechanism which facilitates cellular survival under adverse conditions by recycling endogenous cellular macromolecules through lysosomal-dependent degradation. Autophagy was originally characterized in yeast, but the recent characterization of this process in mammals has raised intensive interest in its biological significance and potential as a therapeutic target. The endogenous regulation of autophagy as a either a protagonist or adaptive mechanism during disease pathogenesis is not well understood. Furthermore, nothing is known of how gaseous mediators such as CO may regulate this process. Thus, the characterization of mechanisms by which gaseous molecules such as CO could regulate autophagy and its relationship to tissue protection is a highly novel concept, with far-reaching implications on how CO could be adapted to clinical therapies. To examine these relationships, we propose the following hypothesis: CO confers cyto- and tissue protection in endotoxemia/sepsis by preserving cellular homeostasis and promoting bacterial clearance through molecular regulation and activation of the autophagic pathway. To address this hypothesis will we 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 sepsis Specific Aim 2: To determine the mechanism by which CO-induced autophagic pathway mediates cytoprotection in experimental sepsis Specific Aim 3: To perform proof-of-concept studies for biomarker detection and therapeutic efficacy to assist in the planning of Phase 1/Phase IIa trial for therapeutic efficacy of CO in human sepsis

Public Health Relevance

!##$%&'( ! #$!%$&#'()*%!+,!-#)&#!./-!0/*$!&'1+/(!%/(/2)0$!31/4)0$*!&,5/31/5$&5)/(!)(! *$3*)*!)*!3//1.,!6(0$1*5//07!!8'1+/(!%/(/2)0$!)(06&$0!'65/3#'9,!%',!%$0)'5$!)5*! &,5/31/5$&5)/(!)(!*$3*)*7!!:(!)%31/4$0!6(0$1*5'(0)(9!/(!#/-!&'1+/(!%/(/2)0$! )(06&$*!'65/3#'9,!-)..!'**)*5!6*!5/!0$4)*$!(/4$.!5#$1'3,!)(!#6%'(!*$3*)*!)(!5#$! ;6561$7!

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Harabin, Andrea L
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
Ryter, Stefan W; Choi, Augustine M K (2016) Targeting heme oxygenase-1 and carbon monoxide for therapeutic modulation of inflammation. Transl Res 167:7-34
Lee, Seonmin; Suh, Gee-Young; Ryter, Stefan W et al. (2016) Regulation and Function of the Nucleotide Binding Domain Leucine-Rich Repeat-Containing Receptor, Pyrin Domain-Containing-3 Inflammasome in Lung Disease. Am J Respir Cell Mol Biol 54:151-60
Cloonan, Suzanne M; Choi, Augustine M K (2016) Mitochondria in lung disease. J Clin Invest 126:809-20
Nakahira, Kiichi; Pabon Porras, Maria Angelica; Choi, Augustine M K (2016) Autophagy in Pulmonary Diseases. Am J Respir Crit Care Med 194:1196-1207
Moon, Jong-Seok; Nakahira, Kiichi; Chung, Kuei-Pin et al. (2016) NOX4-dependent fatty acid oxidation promotes NLRP3 inflammasome activation in macrophages. Nat Med 22:1002-12
Zhang, Ruoyu; Nakahira, Kiichi; Guo, Xiaoxian et al. (2016) Very Short Mitochondrial DNA Fragments and Heteroplasmy in Human Plasma. Sci Rep 6:36097
Cloonan, Suzanne M; Glass, Kimberly; Laucho-Contreras, Maria E et al. (2016) Mitochondrial iron chelation ameliorates cigarette smoke-induced bronchitis and emphysema in mice. Nat Med 22:163-74
Nakahira, Kiichi; Choi, Augustine M K (2015) Carbon monoxide in the treatment of sepsis. Am J Physiol Lung Cell Mol Physiol 309:L1387-93
Lee, So-Young; Choi, Mary E (2015) Urinary biomarkers for early diabetic nephropathy: beyond albuminuria. Pediatr Nephrol 30:1063-75
Zhong, Huiqin; Yin, Huiyong (2015) Role of lipid peroxidation derived 4-hydroxynonenal (4-HNE) in cancer: focusing on mitochondria. Redox Biol 4:193-9

Showing the most recent 10 out of 76 publications