Browsing by Author "Romer, Eric"

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    Enhanced Platelet-activating Factor synthesis facilitates acute and delayed effects of ethanol intoxicated thermal burn injury
    (Elsevier, 2018) Harrison, Kathleen A.; Romer, Eric; Weyerbacher, Jonathan; Ocana, Jesus A.; Sahu, Ravi P.; Murphy, Robert C.; Kelly, Lisa E.; Smith, Townsend A.; Rapp, Christine M.; Borchers, Christina; Cool, David R.; Li, Gengxin; Simman, Richard; Travers, Jeffrey B.; Pharmacology and Toxicology, School of Medicine
    Thermal burn injuries in patients alcohol intoxicated result in greater morbidity and mortality. Murine models combining ethanol and localized thermal burn injury reproduce the systemic toxicity seen in human subjects, which consists of both acute systemic cytokine production with multiple organ dysfunction, as well as a delayed systemic immunosuppression. However, the exact mechanisms for these acute and delayed effects are unclear. These studies sought to define the role of the lipid mediator Platelet-activating factor (PAF) in the acute and delayed effects of intoxicated burn injury. Combining ethanol and thermal burn injury resulted in increased enzymatic PAF generation in a keratinocyte cell line in vitro, human skin explants ex vivo, as well as in murine skin in vivo. Further, the acute increase in inflammatory cytokines such as IL-6, and the systemic immunosuppressive effects of intoxicated thermal burn injury, were suppressed in mice lacking PAF receptors. Together, these studies provide a potential mechanism and novel treatment strategies for the augmented toxicity and immunosuppressive effects of thermal burn injury in the setting of acute ethanol exposure, which involves the pleotropic lipid mediator PAF.
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    Platelet-Activating Factor-Induced Reduction in Contact Hypersensitivity Responses Is Mediated by Mast Cells via Cyclooxygenase-2-Dependent Mechanisms
    (American Association of Immunologists, 2018-06-15) Ocana, Jesus A.; Romer, Eric; Sahu, Ravi; Pawelzik, Sven-Christian; FitzGerald, Garret A.; Kaplan, Mark H.; Travers, Jeffrey B.; Pharmacology and Toxicology, School of Medicine
    Platelet-activating factor (PAF) stimulates numerous cell types via activation of the G protein-coupled PAF receptor (PAFR). PAFR activation not only induces acute proinflammatory responses, but it also induces delayed systemic immunosuppressive effects by modulating host immunity. Although enzymatic synthesis and degradation of PAF are tightly regulated, oxidative stressors, such as UVB, chemotherapy, and cigarette smoke, can generate PAF and PAF-like molecules in an unregulated fashion via the oxidation of membrane phospholipids. Recent studies have demonstrated the relevance of the mast cell (MC) PAFR in PAFR-induced systemic immunosuppression. The current study was designed to determine the exact mechanisms and mediators involved in MC PAFR-mediated systemic immunosuppression. By using a contact hypersensitivity model, the MC PAFR was not only found to be necessary, but also sufficient to mediate the immunosuppressive effects of systemic PAF. Furthermore, activation of the MC PAFR induces MC-derived histamine and PGE2 release. Importantly, PAFR-mediated systemic immunosuppression was defective in mice that lacked MCs, or in MC-deficient mice transplanted with histidine decarboxylase- or cyclooxygenase-2-deficient MCs. Lastly, it was found that PGs could modulate MC migration to draining lymph nodes. These results support the hypothesis that MC PAFR activation promotes the immunosuppressive effects of PAF in part through histamine- and PGE2-dependent mechanisms.