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

Cells. 2021 Dec 9;10(12):3477. doi: 10.3390/cells10123477.


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.

Keywords: acrolein; cyclophosphamide (CYP); repeated low-dose acrolein model; urinary bladder; voiding dysfunction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrolein / adverse effects
  • Acrolein / pharmacology
  • Alkylating Agents / adverse effects
  • Alkylating Agents / pharmacology
  • Animals
  • Antineoplastic Agents, Alkylating / adverse effects
  • Antineoplastic Agents, Alkylating / pharmacology
  • Cyclophosphamide / adverse effects
  • Cyclophosphamide / pharmacology
  • Cystitis / chemically induced
  • Cystitis / drug therapy
  • Cystitis / pathology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Edema / chemically induced
  • Edema / pathology
  • Edema / prevention & control*
  • Hemorrhage / chemically induced
  • Hemorrhage / drug therapy
  • Hemorrhage / pathology
  • Hemorrhage / prevention & control*
  • Humans
  • Mice
  • Mucous Membrane / drug effects*
  • Mucous Membrane / pathology
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / pathology
  • Urinary Bladder / drug effects*
  • Urinary Bladder / pathology


  • Alkylating Agents
  • Antineoplastic Agents, Alkylating
  • Acrolein
  • Cyclophosphamide