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Radiation cystitis modeling: A comparative study of bladder fibrosis radio-sensitivity in C57BL/6, C3H, and BALB/c mice.

ABSTRACT: A subset of patients receiving radiation therapy for pelvic cancer develop radiation cystitis, a complication characterized by mucosal cell death, inflammation, hematuria, and bladder fibrosis. Radiation cystitis can reduce bladder capacity, cause incontinence, and impair voiding function so severely that patients require surgical intervention. Factors influencing onset and severity of radiation cystitis are not fully known. We tested the hypothesis that genetic background is a contributing factor. We irradiated bladders of female C57BL/6, C3H, and BALB/c mice and evaluated urinary voiding function, bladder shape, histology, collagen composition, and distribution of collagen-producing cells. We found that the genetic background profoundly affects the severity of radiation-induced bladder fibrosis and urinary voiding dysfunction. C57BL/6 mice are most susceptible and C3H mice are most resistant. Irradiated C57BL/6 mouse bladders are misshapen and express more abundant collagen I and III proteins than irradiated C3H and BALB/c bladders. We localized Col1a1 and Col3a1 mRNAs to FSP1-negative stromal cells in the bladder lamina propria and detrusor. The number of collagen I and collagen III-producing cells can predict the average voided volume of a mouse. Collectively, we show that genetic factors confer sensitivity to radiation cystitis, establish C57BL/6 mice as a sensitive preclinical model, and identify a potential role for FSP1-negative stromal cells in radiation-induced bladder fibrosis.

SUBMITTER: Zwaans BMM

PROVIDER: S-EPMC7048381 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Radiation cystitis modeling: A comparative study of bladder fibrosis radio-sensitivity in C57BL/6, C3H, and BALB/c mice.

Zwaans Bernadette M M BMM Wegner Kyle A KA Bartolone Sarah N SN Vezina Chad M CM Chancellor Michael B MB Lamb Laura E LE

Physiological reports 20200201 4

A subset of patients receiving radiation therapy for pelvic cancer develop radiation cystitis, a complication characterized by mucosal cell death, inflammation, hematuria, and bladder fibrosis. Radiation cystitis can reduce bladder capacity, cause incontinence, and impair voiding function so severely that patients require surgical intervention. Factors influencing onset and severity of radiation cystitis are not fully known. We tested the hypothesis that genetic background is a contributing fact ...[more]

PMID: 32109348

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Project description:PurposeFor decades, Dr. John Moulder has been a leading radiation biologist and one of the few who consistently supported the study of normal tissue responses to radiation. His meticulous modeling and collaborations across the field have offered a prime example of how research can be taken from the bench to the bedside and back, with the ultimate goal of providing benefit to patients. Much of the focus of John's work was on mitigating damage to the kidney, whether as the result of accidental or deliberate clinical exposures. Following in his footsteps, we offer here a brief overview of work conducted in the field of radiation-induced bladder injury. We then describe our own preclinical experimental studies which originated as a response to reports from a clinical genome-wide association study (GWAS) investigating genomic biomarkers of normal tissue toxicity in prostate cancer patients treated with radiotherapy. In particular, we discuss the use of Renin-Angiotensin System (RAS) inhibitors as modulators of injury, agents championed by the Moulder group, and how RAS inhibitors are associated with a reduction in some measures of toxicity. Using a murine model, along with precise CT-image guided irradiation of the bladder using single and fractionated dosing regimens, we have been able to demonstrate radiation-induced functional injury to the bladder and mitigation of this functional damage by an inhibitor of angiotensin-converting enzyme targeting the RAS, an experimental approach akin to that used by the Moulder group. We consider our scientific trajectory as a bedside-to-bench approach because the observation was made clinically and investigated in a preclinical model; this experimental approach aligns with the exemplary career of Dr. John Moulder.ConclusionsDespite the differences in functional endpoints, recent findings indicate a commonality between bladder late effects and the work in kidney pioneered by Dr. John Moulder. We offer evidence that targeting the RAS pathway may provide a targetable pathway to reducing late bladder toxicity.

Project description:Purpose of the Meeting:Bladder pain syndrome/interstitial cystitis is a prevalent but underserved disease. At the Global Interstitial Cystitis/Bladder Pain Syndrome Society (GIBS) meeting, the organization and participants were committed to delivering word-class expertise and collaboration in research and patient care. Under the umbrella of GIBS, leading research scholars from different backgrounds and specialties, as well as clinicians, from across the globe interested in the science and art of practice of Bladder Pain Syndrome (BPS)/Interstitial Cystitis (IC) were invited to deliberate on various dimensions of this disease. The meeting aimed to have global guidelines to establish firm directions to practicing clinicians and patients alike on the diagnosis and treatment of this disease entity. Chronic Pelvic Pain Syndrome (CPPS) is defined by pain in the pelvic area that can have different etiologies. This can be due to urologic, gynecologic, musculoskeletal, gastrointestinal, neurologic, and autoimmune or rheumatologic diseases. At the GIBS meeting held in Mumbai, India, in August 2019, a multidisciplinary expert panel of international urologists, gynecologists, pain specialists, and dietitians took part in a think tank to discuss the development of evidence-based diagnostic and treatment algorithms for BPS/IC. Summary of Presented Findings:The diagnosis of BPS/IC is difficult in daily clinical practice. Patients with BPS/IC present with a variety of signs and symptoms and clinical test results. Hence, they might be misdiagnosed or underdiagnosed, and the correct diagnosis might take a long time. A good history and physical examination, along with cystoscopy, is a must for the diagnosis of IC/BPS. For the treatment, besides lifestyle management and dietary advice, oral medication and bladder instillation therapy, botulinum toxin, and sacral neuromodulation were discussed. The innovation in bladder instillation applicators, as well as battery-free neuromodulation through the tibial nerve, was discussed, as well. Recommendation for Future Research:As BPS/IC is complex, for many patients, several treatments are necessary at the same time. This was presented at GIBS 2019 as the piano model. In this way, a combination of treatments is tailored to an individual patient depending on the symptoms, age, and patients' characteristics. In the art of medicine, especially when dealing with BPS/IC patients, pressing the right key at the right time makes the difference.

Dataset Information

Radiation cystitis modeling: A comparative study of bladder fibrosis radio-sensitivity in C57BL/6, C3H, and BALB/c mice.

Publications

Radiation cystitis modeling: A comparative study of bladder fibrosis radio-sensitivity in C57BL/6, C3H, and BALB/c mice.

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