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-1. These cytokines are central to the propagation of acute inflammatory responses, independent of the TLR driven NF-?B dependent TNF-? 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
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.
| Ma, Kevin C; Schenck, Edward J; Pabon, Maria A et al. (2018) The Role of Danger Signals in the Pathogenesis and Perpetuation of Critical Illness. Am J Respir Crit Care Med 197:300-309 |
| Schenck, Edward J; Oromendia, Clara; Torres, Lisa K et al. (2018) Rapidly Improving ARDS in Therapeutic Randomized Controlled Trials. Chest : |
| Schenck, Edward J; Ma, Kevin C; Murthy, Santosh B et al. (2018) Danger Signals in the ICU. Crit Care Med 46:791-798 |
| Ryter, Stefan W; Ma, Kevin C; Choi, Augustine M K (2018) Carbon monoxide in lung cell physiology and disease. Am J Physiol Cell Physiol 314:C211-C227 |
| Harrington, John S; Schenck, Edward J; Oromendia, Clara et al. (2018) Acute respiratory distress syndrome without identifiable risk factors: A secondary analysis of the ARDS network trials. J Crit Care 47:49-54 |
| Siempos, Ilias I; Ma, Kevin C; Imamura, Mitsuru et al. (2018) RIPK3 mediates pathogenesis of experimental ventilator-induced lung injury. JCI Insight 3: |
| Finkelsztein, Eli J; Jones, Daniel S; Ma, Kevin C et al. (2017) Comparison of qSOFA and SIRS for predicting adverse outcomes of patients with suspicion of sepsis outside the intensive care unit. Crit Care 21:73 |
| Lee, Seonmin; Nakahira, Kiichi; Dalli, Jesmond et al. (2017) NLRP3 Inflammasome Deficiency Protects against Microbial Sepsis via Increased Lipoxin B4 Synthesis. Am J Respir Crit Care Med 196:713-726 |
| 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 |
| 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 |
Showing the most recent 10 out of 113 publications
