Carbon monoxide (CO) has been regarded by the scientific community as an environmental pollutant and noxious health hazard from occupational or industrial exposure. Counter to this established toxicity of CO as a lethal substance, this laboratory and others have established a cyto- and tissue protective function of CO at low concentrations in cell culture and animal models of cell and tissue injury. Despite ample reports that the therapeutic effects of CO involve anti-inflammatory, anti-apoptotic, and anti-proliferative effects, the molecular mechanisms by which CO confers these effects remain incompletely understood. The seminal discovery of Toll-like receptors (TLR) playing critical roles in the host's innate immune responses to extracellular signals unraveled a major avenue of research in biomedical research. Intriguingly, recent reports reveal the existence of NOD-like receptors (NLR), which are critical intracellular recognition receptors responding to cellular stress signals. Members of NLRs family and apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) form a multi-protein complex called the """"""""inflammasome"""""""", which activates caspase-1. Activated caspase-1 then initiates the secretion of downstream pro-inflammatory cytokines such as IL-18, IL- 33, and IL-12. These cytokines are central to the propagation of acute inflammatory responses, independent of the TLR driven NF-?B dependent TNF-a1 expression and secretion. Little or nothing is known on the regulation and function of inflammasomes and its regulated pro-inflammatory cytokines in human lung disease including ALI/ARDS. Our current preliminary data demonstrate an intriguing role of inflammasomes in the pathogenesis of experimental ALI and human ALI/ARDS, and that CO significantly inhibits inflammasomes and their regulated pro-inflammatory cytokines. Furthermore, we have observed that inflammasomes and their regulated cytokines are associated with severity and mortality in human ALI/ARDS. Hence we hypothesize that CO confers cyto- and tissue protection in ALI by supression of inflammasome signaling. Furthermore, inflammasomes can potentially serve as diagnostic biomarker in predicting severity of human ALI/ARDS. To address this hypothesis will we examine three Specific Aims:
Specific Aim #1 : To determine the regulation and function of inflammasome complex formation and its regulated pro-inflammatory cytokines in experimental ALI.
Specific Aim #2 : To determine the mechanism(s) by which cytoprotective CO molecule inhibits inflammasome complex and its downstream pro-inflammatory cytokines in experimental ALI Specific.
Aim #3 : To determine whether inflammasome complexes and/or its regulated pro-inflammatory cytokines can serve as biomarkers to predict disease severity and mortality in human ALI/ARDS

Public Health Relevance

The mechanism by which low dose carbon monoxide provides cytoprotection in acute lung injury is poorly understood. An improved understanding on how carbon monoxide inhibits inflammasomes and its inflammatory cytokines will assist us to devise novel therapies in acute lung injury in the future.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL055330-17
Application #
8775917
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Harabin, Andrea L
Project Start
1996-07-01
Project End
2016-05-31
Budget Start
2013-12-12
Budget End
2014-05-31
Support Year
17
Fiscal Year
2013
Total Cost
$214,502
Indirect Cost
$87,952
Name
Weill Medical College of Cornell University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
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
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
Moon, Jong-Seok; Lee, Seonmin; Park, Mi-Ae et al. (2015) UCP2-induced fatty acid synthase promotes NLRP3 inflammasome activation during sepsis. J Clin Invest 125:665-80
Jung, Sung-Soo; Moon, Jong-Seok; Xu, Jin-Fu et al. (2015) Carbon monoxide negatively regulates NLRP3 inflammasome activation in macrophages. Am J Physiol Lung Cell Mol Physiol 308:L1058-67
Moon, Jong-Seok; Hisata, Shu; Park, Mi-Ae et al. (2015) mTORC1-Induced HK1-Dependent Glycolysis Regulates NLRP3 Inflammasome Activation. Cell Rep 12:102-15
Choi, Alexander J S; Ryter, Stefan W (2014) Inflammasomes: molecular regulation and implications for metabolic and cognitive diseases. Mol Cells 37:441-8
Mizumura, Kenji; Cloonan, Suzanne M; Nakahira, Kiichi et al. (2014) Mitophagy-dependent necroptosis contributes to the pathogenesis of COPD. J Clin Invest 124:3987-4003

Showing the most recent 10 out of 91 publications