Inflammasomes: Regulation and Function in Acute Lung Injury

Brigham And Women'S Hospital, Boston MA

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Abstract

DESCRIPTION (provided by applicant): 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