Extracorporeal shockwave against inflammation mediated by GPR120 receptor in cyclophosphamide-induced rat cystitis model

Yi-Ling Chen,Cheuk-Kwan Sun,Yen-Ta Chen,Hon-Kan Yip,Tien-Hung Huang,Yuan-Ping Lin

doi:10.1186/s10020-018-0062-1

Abstract

BackgroundWe tested the hypothesis that extracorporeal shockwave treatment (ESWT) can abolish inflammation and restore urothelial barrier integrity in acute interstitial cystitis by upregulating the fatty acid receptor GPR120.MethodsA total of 30 female Sprague-Dawley rats were categorized into five groups: (1) sham-operated rats (SC); (2) rats treated with ESWT (SC + ESWT); (3) rats with bladder irritation using 150 mg/kg cyclophosphamide through intraperitoneal injection; (4) cyclophosphamide rats treated with ESWT (cyclophosphamide+ESWT); (5) cyclophosphamide rats treated with GPR120 agonist (cyclophosphamide+GW9508).ResultsOn Day 3, urine and bladder specimens were collected for biochemical, histopathological, immunological, and immunoblotting analysis. Following stimulation with cyclophosphamide, the inhibition of the elevated levels of TAK1/NF-κB and phospho-TAK1/NF-κB by ESWT and GPR120 agonists in RT4 cells was associated with a suppression of NF-κB translocation from the cytosol to the nucleus. Accordingly, this anti-inflammatory effect was abolished by GPR120 antagonist and knockdown of GPR120. Histologically, bladder inflammation in cyclophosphamide-treated rats was suppressed by GW9508 or ESWT. Masson’s trichrome and Sirius red staining revealed that cyclophosphamide treatment enhanced synthesis of extracellular matrix in rats that was reversed by GW9508 or ESWT. Upregulated pro-inflammatory mediators and cytokines in the cyclophosphamide-treated rats were also suppressed in the GW9508- or ESWT-treated rats. The significantly increased inflammatory cell infiltration as well as the impaired urothelial integrity of the bladder after cyclophosphamide treatment were reversed by treatment with GW9508 or ESWT.ConclusionsThese findings suggest that GPR120, the sensing receptor for ESWT, may be useful in the treatment of interstitial cystitis by inhibiting inflammatory response in bladder cells.

Highlights

Interstitial cystitis (IC) is a clinical syndrome characterized by urinary frequency, nocturia, and pelvic pain with unknown etiology
The other aim of the current study is to investigate the role of extracorporeal shock wave treatment (ESWT) in the anti-inflammatory effect of GPR120 in an experimental setting of IC
Anti-GPR120 antibody was purchased from Santa Cruz Biotechnology (Dallas, TX, USA); anti-Bax, anti-Inducible nitric oxide synthase (iNOS), anti-Monocyte chemoattractant protein-1 (MCP-1), anti-Nuclear factor transcription factor (NF-κB) antibodies were from Abcam (Cambridge, UK)

Summary

Introduction

Interstitial cystitis (IC) is a clinical syndrome characterized by urinary frequency, nocturia, and pelvic pain with unknown etiology. The etiology of IC is unknown, numerous theories defining the pathology of IC have been proposed, including altered barrier lining, afferent and/or central nervous system abnormalities, possible contribution of inflammatory or bacterial infection and abnormal urothelial signaling (Wang et al 2016; Lazzeri et al 2016; Regauer 2016; Gonzalez et al 2014). There is still no simple treatment that can eliminate the signs and symptoms of IC. G protein-coupled receptors (GPCRs) constitute a family of seven transmembrane proteins that mediate many cellular processes. We tested the hypothesis that extracorporeal shockwave treatment (ESWT) can abolish inflammation and restore urothelial barrier integrity in acute interstitial cystitis by upregulating the fatty acid receptor GPR120

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