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Cigarette Smoke-Derived Electrophilic Aldehydes and Airway Inflammation

Principal Investigator: Albert Van der Vliet

Funding Mechanism: National Institutes of Health- Grant

ID number: 1R01ES021476-01

Award Date: 7/30/2012

Institution: University of Vermont and State Agriculture College

While cigarette smoking is generally associated with chronic inflammation, it also possesses immunosuppressive properties that result in increased sensitivity to respiratory bacterial or viral infection. Exposure to acrolein and other related unsaturated aldehydes that are thiol-reactive agents in cigarette smoke inhibits respiratory immune response, but the mechanisms mediating its toxic effects in the respiratory tract are not well understood. Acrolein exposure also mimics some of the effects of cigarette smoking on asthma development and severity by promoting allergic sensitization and suppressing allergic inflammation. The goals of this research effort are to study how acrolein alters innate macrophage and epithelial immune responses and allergic inflammation using in vivo mouse models of acute lung injury and allergic asthma, and to identify enzymatic and metabolic systems that mediate detoxification of acrolein to determine whether changes in these systems alter acrolein susceptibility. Study aims are: (1) to determine the importance of direct protein modifications in acrolein-induced suppression of innate immune responses; (2) to explore the effects of acrolein exposure on allergic inflammation and sensitization; and (3) to explore the importance of GSTP1 and CBS/H2S in modulating acrolein-induced alterations in immune responses. To achieve Aim 1, investigators will evaluate acute mechanisms by which acrolein alters macrophage and epithelial responses to LPS by conducting in vitro studies with mouse (alveolar) macrophages and tracheal epithelial cells. The investigators will use newly-developed proteomic approaches to determine direct protein modifications in proteins of interest (e.g., RelA, JNK2, TrxR), and will explore the functional importance of these modifications. To achieve Aim 2, investigators will explore the effects of in vivo acrolein inhalation on allergic airway inflammation in sensitized mice and on allergic sensitization; these effects will be analyzed in the context of alterations in inflammatory cytokine profiles and changes in epithelial barrier function and mediator production, in association with direct alkylation or relevant target proteins. To achieve Aim 3, investigators will use siRNA approaches or cells from transgenic/knockout mice to explore the impact of these metabolic systems on acrolein-mediated alterations of macrophage/epithelial responses and on acrolein-mediated allergic sensitization. Collectively, these studies will provide further insight into the importance of acrolein in the development of respiratory disease associated with smoking and will help determine factors that may contribute to susceptibility to cigarette smoking-induced respiratory infections and allergic airway disease.

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