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 A2 β (iPLA 2 β) 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 iPLA 2 β −/− 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.

Cigarette smoke‐induced urothelial cell damage: potential role of platelet‐activating factor

“…To date, the mechanism underlying cigarette smoke-induced bladder pain has not been elucidated. In a recent study (Marentette et al 2015), we showed that cigarette smoking was associated with increased PAF production and adherence of inflammatory cells to the bladder endothelium. Additionally, mice exposed to cigarette smoking for 4 weeks showed increased accumulation of inflammatory cells in the bladder wall (Marentette et al 2015).…”

“…; Marentette et al. ). However, increased PAF in response to smoking can be inhibited by treatment with inhibitors of iPLA 2 β , the predominant PLA 2 isoform responsible for PAF production in endothelial (McHowat et al.…”

“…Additionally, mice exposed to cigarette smoking for 4 weeks showed increased accumulation of inflammatory cells in the bladder wall (Marentette et al. ).…”

“…Bottom panels: Bladder sections from iPLA 2 b À/À female mice exposed to room air (left) or 6 months cigarette smoke (right). Three animals in each group inhibition of PAF acetylhydrolase, resulting in increased PAF content (Balsinde and Dennis 1996a;McHowat and Creer 1998;Sharma et al 2010;Marentette et al 2015). However, increased PAF in response to smoking can be inhibited by treatment with inhibitors of iPLA 2 b, the predominant PLA 2 isoform responsible for PAF production in endothelial (McHowat et al 1993a(McHowat et al , 1997Cummings et al 2000) and epithelial cells (Balsinde and Dennis 1996a).…”

A new player in interstitial cystitis/bladder pain syndrome: platelet-activating factor - PAF and its connection to smoking

“…Histological evaluation of the bladder revealed denudation and thinning of the urothelium, and results from a previous study indicated infiltration of inflammatory cells into the bladder wall (Marentette et al. ), in wild‐type mice but not in iPLA 2 β −/− mice. Interestingly, the expression of PAF and its receptor was elevated in the urothelium of the wild type mice but not of the iPLA 2 β −/− mice exposed to smoke.…”