P2X7 Receptor Blockade Protects Against Acrolein-Induced Bladder Damage: A Potential New Therapeutic Approach for the Treatment of Bladder Inflammatory Diseases.

Zhinoos Taidi,Kate H Moore,Kylie J Mansfield,Lu Liu,Tommy Zhou

doi:10.3389/fphar.2021.682520

Zhinoos Taidi, Kate H Moore + Show 3 more

Open Access

https://doi.org/10.3389/fphar.2021.682520

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Abstract

Inflammatory conditions of the urinary bladder have been shown to be associated with urothelial damage and loss of function. The purinergic P2X7 receptor has been implicated in several inflammatory conditions. The aim of this study was to investigate the role of the P2X7 receptor in acrolein-induced inflammatory damage using the porcine urinary bladder. For this purpose, an ex-vivo model of porcine urothelial damage induced by direct instillation of acrolein into the whole bladder lumen was used. To determine the role of the P2X7 receptor, the bladders were pre-incubated with a selective P2X7 receptor antagonist, A804598 (10 μM), for 1 h. The effects of the acrolein-induced urothelial damage on the bladder’s function were assessed by examining the bladder wall contractile response, structure changes, apoptosis, and oxidative stress in the bladder tissues. The acrolein treatment led to significant damage to the urothelium histology, tight junction expression, and contractile responses. Acrolein also induced apoptosis in the mucosa layer. All these acrolein-induced responses were attenuated by pre-treatment with the P2X7 receptor antagonist A804598. Acrolein also significantly induced DNA oxidation in the submucosal layer; however, the P2X7 receptor antagonism did not show any protective effect towards the acrolein-induced oxidative stress. These findings suggested that the P2X7 receptor is involved in the acrolein-induced damage to the urothelium; therefore, the P2X7 receptor antagonists may be a new therapeutic option for the treatment of bladder inflammation.

Highlights

Cyclophosphamide is an anti-neoplastic agent, mostly used to treat different types of cancers such as breast cancer, ovarian cancer, and lymphoma (Emadi et al, 2009)
Hemorrhagic cystitis is believed to be the direct effect of acrolein (Haldar et al, 2014), a highly toxic urinary metabolite of cyclophosphamide that concentrates in the bladder lumen (Cox, 1979) and damages the bladder lining, the urothelium
We have investigated the effects of acrolein on the structure, apoptosis, and oxidative stress, as well as the expression of tight junction protein zona occludens-1 (ZO-1) and contractile protein, alpha smooth muscle actin (α-SMA) in the mucosa layer of the porcine bladder tissues

Summary

Introduction

Cyclophosphamide is an anti-neoplastic agent, mostly used to treat different types of cancers such as breast cancer, ovarian cancer, and lymphoma (Emadi et al, 2009). The therapeutic use of cyclophosphamide is limited due to side effects (Stillwell and Benson, 1988), including severe urinary bladder cystitis leading to hemorrhagic cystitis (bleeding and inflammation associated with bladder filling). The patients who receive treatment with the antineoplastic agent cyclophosphamide suffer from hemorrhagic cystitis of the bladder in 2–40% of cases, which is characterized by bleeding and inflammation associated with bladder filling (Stillwell and Benson, 1988). Hemorrhagic cystitis is believed to be the direct effect of acrolein (Haldar et al, 2014), a highly toxic urinary metabolite of cyclophosphamide that concentrates in the bladder lumen (Cox, 1979) and damages the bladder lining, the urothelium. Acrolein is an alkylating agent which causes highly toxic effects on the cells by several mechanisms such as protein or DNA adduction as well as induction of oxidative stress, leading to apoptosis and cell death (Moghe et al, 2015)

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