Repeated Low-Dose Acrolein Triggers Irreversible Lamina Propria Edema in Urinary Bladder, Transient Voiding Behavior and Widening of Eyes to Mechanical Stimuli

Sanghee Lee,Tony Yaksh,Jaebeom Lee,Shelle Malkmus,George Chiang,Jiwoo Lee,Michael Albo,Chandresh Khimji

doi:10.3390/cells10123477

Sanghee Lee, Tony Yaksh + Show 6 more

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https://doi.org/10.3390/cells10123477

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Abstract

Acrolein is a metabolite of cyclophosphamide (CYP), an alkylating agent used for a wide range of benign and malignant diseases. CYP treatments are known to trigger hemorrhagic cystitis in patients and animals. Significant effort has been made to prevent CYP/acrolein-induced cystitis, while still maintaining its therapeutic benefits. As a result, supplementary therapeutic options to mediate the protective role against CYP/acrolein and lower doses of CYP are currently given to targeted patients, as compared to past treatments. There is still a need to further study the effects of the repeated low-dose CYP/acrolein on the pathophysiology of the urinary bladder. In our study, a one-time treatment of acrolein and repeated low-dose acrolein triggered the thickening of the smooth muscle and lamina propria in the urinary bladder of C57BL/6J mice, respectively. The first dose of acrolein did not trigger voiding dysfunction, but the second dose triggered high-volume low-frequency voiding. Interestingly, our new scoring criteria and concurrent behavioral assessment revealed that mice with repeated low-dose acrolein had a wider opening of eyes in response to mechanical stimuli. Our study suggests that clinical symptoms among patients undergoing prolonged low-dose CYP may differ from previously reported symptoms of CYP-induced hemorrhagic cystitis.

Highlights

The alkylating agent cyclophosphamide (CYP) is a therapeutic option used for the treatment of certain non-neoplastic and a wide range of malignant diseases [1,2,3]
Lamina propria edema in urinary bladder was observed in acrolein mice on day 1 pi and this histopathological abnormality was irreversible until day 30 pi, which is the time point after 15 days of the acrolein instillation-free period (Figure 2C)
We demonstrated that no significant difference in phosphate-buffered saline (PBS) vs. acrolein mice was observed, as determined by the conventional assessment of pain, von Frey application method and the grimace score system

Summary

Introduction

The alkylating agent cyclophosphamide (CYP) is a therapeutic option used for the treatment of certain non-neoplastic and a wide range of malignant diseases [1,2,3]. In parallel with its intended therapeutic effect, the urinary bladder is at most risk of CYP-induced urothelial cell damage due to the nature that acrolein, a metabolite of CYP, is a cytotoxic component stored in the urinary bladder until urine is voided. In 1988, Stillwell et al reported that 100 patients with CYP (average dose of 4600 cGy)-induced hemorrhagic cystitis developed gross hematuria (78%), irritative voiding symptoms (45%), microhematuria (93%) and bladder cancer (5%) [4]. Mesna (2-mercaptoethanesulfonic acid) is given to patients and murine models that received CYP treatments resulting in a significant decrease in the incidence of hemorrhagic cystitis and its secondary effect [10,11,12]. We established a murine model recapitulating in vivo changes in the urinary bladder among patients that have received a low dose of CYP. The goal of this study was to focus on behavior changes in mice repeatedly taking low-dose acrolein

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