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 #
2R01HL055330-15A1
Application #
8236801
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
2012-08-01
Budget End
2013-05-31
Support Year
15
Fiscal Year
2012
Total Cost
$449,362
Indirect Cost
$176,054
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Cloonan, Suzanne M; Lam, Hilaire C; Ryter, Stefan W et al. (2014) "Ciliophagy": The consumption of cilia components by autophagy. Autophagy 10:532-4
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
Ryter, Stefan W; Choi, Augustine M K; Kim, Hong Pyo (2014) Profibrogenic phenotype in caveolin-1 deficiency via differential regulation of STAT-1/3 proteins. Biochem Cell Biol 92:370-8
Rogers, Angela J; McGeachie, Michael; Baron, Rebecca M et al. (2014) Metabolomic derangements are associated with mortality in critically ill adult patients. PLoS One 9:e87538
Lee, Seonmin; Lee, Seon-Jin; Coronata, Anna A et al. (2014) Carbon monoxide confers protection in sepsis by enhancing beclin 1-dependent autophagy and phagocytosis. Antioxid Redox Signal 20:432-42
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
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
Ryter, Stefan W; Nakahira, Kiichi; Haspel, Jeffrey A et al. (2012) Autophagy in pulmonary diseases. Annu Rev Physiol 74:377-401
Tanaka, Akihiko; Jin, Yang; Lee, Seon-Jin et al. (2012) Hyperoxia-induced LC3B interacts with the Fas apoptotic pathway in epithelial cell death. Am J Respir Cell Mol Biol 46:507-14
Xu, Jin-Fu; Washko, George R; Nakahira, Kiichi et al. (2012) Statins and pulmonary fibrosis: the potential role of NLRP3 inflammasome activation. Am J Respir Crit Care Med 185:547-56

Showing the most recent 10 out of 68 publications