title: Increased susceptibility to bladder inflammation in smokers: targeting the PAF-PAF receptor interaction to manage inflammatory cell recruitment.
abstract: Chronic bladder inflammation can result in a significant reduction in quality of life. Smoking remains a leading preventable risk factor in many diseases. Despite the large amount of evidence supporting the risks of smoking, roughly 45 million people in the United States remain smokers. The impact of cigarette smoking on inflammation is well established, but how smoking promotes bladder inflammation is currently unknown. The aim of this study was to determine if cigarette smoke exposure impacts inflammatory cell adherence to bladder endothelial cells and if targeting the platelet-activating factor (PAF)-PAF receptor (PAFR) interaction could be beneficial in managing bladder inflammation. In response to cigarette smoke extract (CSE) incubation, bladder endothelial cells from human or mouse displayed increased PAF accumulation, decreased PAF-AH activity, and increased inflammatory cell adherence. Inhibition of endothelial cell calcium-independent phospholipase A2β (iPLA2β) with (S)-BEL, to block PAF production, prevented adherence of inflammatory cells. Pretreatment of inflammatory cells with PAFR antagonists, ginkgolide B or WEB2086 significantly reduced the number of adhered cells to bladder endothelium. Wild-type mice exposed to cigarette smoke displayed increased presence of inflammatory infiltration which was absent in iPLA2β(-/-) mice and those exposed to room air. In conclusion, cigarette smoke exposure increases endothelial cell PAF accumulation and increased inflammatory cell adherence. Inhibition of PAF accumulation or PAFR antagonism markedly attenuated inflammatory cell adherence to bladder endothelial cells. The results detailed in this study highlight to potential therapeutic targets for managing bladder inflammation.
authors.affiliation: Department of Pathology, Saint Louis University School of Medicine, St. Louis, Missouri.
authors.forename: John
authors.initials: J
authors.lastname: Marentette
authors.affiliation: Department of Pathology, Saint Louis University School of Medicine, St. Louis, Missouri.
authors.forename: Grant
authors.initials: G
authors.lastname: Kolar
authors.affiliation: Department of Pathology, Saint Louis University School of Medicine, St. Louis, Missouri mchowaj@slu.edu.
authors.forename: Jane
authors.initials: J
authors.lastname: McHowat
keywords: Endothelium; inflammation; interstitial cystitis; smoking