Molecular Mechanisms and Key Processes in Interstitial, Hemorrhagic and Radiation Cystitis

Brossard, Clément; Lefranc, Anne-Charlotte; Pouliet, Anne-Laure; Simon, Jean‐Marc; Benderitter, Marc; Milliat, Fabien; Chapel, Alain

doi:10.3390/biology11070972

Cited by 8 publications

(7 citation statements)

References 106 publications

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“…Cytochrome c release is an early trigger of apoptosis and leads to caspase activation, typically caused by the permeabilization of the outer membrane of the mitochondria by proapoptotic stimuli. Previous studies have demonstrated that radiation results in thinning of the urothelium; thus, these findings may indicate that radiation causes significant DNA or cell damage leading to rapid loss of cells through apoptosis [ 7 , 13 , 16 , 17 ].…”

Section: Discussionmentioning

confidence: 99%

“…RC is a chronic, often irreversible bladder condition characterized by bladder fibrosis and vascular damage. Tissue remodeling, neovascularization, and angiogenesis coincides with RC symptoms such as frequency, nocturia, pelvic pain, incontinence, and hematuria, which can range from microscopic to gross hematuria with blood clots [ 7 ]. The presence of blood clots can cause bladder obstruction and block urine outflow.…”

Section: Introductionmentioning

confidence: 99%

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Identification of Molecular Mechanisms in Radiation Cystitis: Insights from RNA Sequencing

Mota,

Ward,

Bartolone

et al. 2024

IJMS

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Pelvic cancer survivors who were treated with radiation therapy are at risk for developing (hemorrhagic) radiation cystitis (RC) many years after completion of radiation therapy. Patients with RC suffer from lower urinary tract symptoms, including frequency, nocturia, pelvic pain, and incontinence. In advanced stages, hematuria can occur, potentially escalating to life-threatening levels. Current therapeutic options for RC are limited, partly due to ethical concerns regarding bladder biopsy in patients with fragile bladder tissue. This study aimed to leverage our established preclinical model to elucidate the molecular pathways implicated in radiation-induced tissue changes in the bladder. Female C57Bl/6 mice received a single dose of 40 Gy using CT-guided imaging and a two-beam irradiation approach using the SARRP irradiator. Bladders from irradiated and age-matched littermate controls were harvested at 1 week [n = 5/group] or 6 months [n = 5/group] after irradiation, RNA was harvested, and mRNA sequencing was performed at paired-end 150bp on the Illumina NovaSeq6000 with a target of 30 million reads per sample. Following RNA sequencing, thorough bioinformatics analysis was performed using iPathwayGuide v2012 (ADVAITA Bioinformatics). Findings of the RNA sequencing were validated using qPCR analysis. At 1 week post-irradiation, altered gene expression was detected in genes involved in DNA damage response, apoptosis, and transcriptional regulation. By 6 months post-irradiation, significant changes in gene expression were observed in inflammation, collagen catabolism, and vascular health. Affected pathways included the p53, JAK-STAT, and PI3K-Akt pathways. These findings were validated in vivo in bladder tissues from our preclinical model. This is the first study to determine the molecular changes in the bladder in response to radiation treatment. We have successfully pinpointed several pathways and specific genes that undergo modification, thereby contributing to the progression of radiation cystitis. These insights enhance our understanding of the pathophysiology of radiation cystitis and may ultimately pave the way to the identification of potential new therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of Molecular Mechanisms in Radiation Cystitis: Insights from RNA Sequencing

Mota,

Ward,

Bartolone

et al. 2024

IJMS

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“…MSC treatment of radiation cystitis, on the other hand, has not yet been studied. However, the similar mechanisms of these pathologies favor a protective effect of MSCs on the chronic evolution of radiation cystitis [5]. Interstitial cystitis (IC) is an idiopathic disease which affects over one million people worldwide [6,7].…”

Section: Introductionmentioning

confidence: 99%

“…Its loss of impermeability leads to deep damage to the bladder wall. Imperfect repair of the urothelium leads to long-term damage, which is responsible for the chronic phases of cystitis [5]. Lesions of the urothelium are mainly due to decreased uroplakin expression and hyperplasia, both of which promote a loss of impermeability of the urothelium [19,20].…”

Section: Introductionmentioning

confidence: 99%

Mesenchymal stem cells limit vascular and epithelial damage and restore the impermeability of the urothelium in chronic radiation cystitis

et al. 2023

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Background Cellular therapy seems to be an innovative therapeutic alternative for which mesenchymal stem cells (MSCs) have been shown to be effective for interstitial and hemorrhagic cystitis. However, the action of MSCs on chronic radiation cystitis (CRC) remains to be demonstrated. The aim of this study was to set up a rat model of CRC and to evaluate the efficacy of MSCs and their mode of action. Methods CRC was induced by single-dose localized irradiation of the whole bladder using two beams guided by tomography in female Sprague–Dawley rat. A dose range of 20–80 Gy with follow-up 3–12 months after irradiation was used to characterize the dose effect and the kinetics of radiation cystitis in rats. For the treatment, the dose of 40 Gy was retained, and in order to potentiate the effect of the MSCs, MSCs were isolated from adipose tissue. After expansion, they were injected intravenously during the pre-chronic phase. Three injections of 5 million MSCs were administered every fortnight. Follow-up was performed for 12 months after irradiation. Results We observed that the intensity and frequency of hematuria are proportional to the irradiation dose, with a threshold at 40 Gy and the appearance of bleeding from 100 days post-irradiation. The MSCs reduced vascular damage as well as damage to the bladder epithelium. Conclusions These results are in favor of MSCs acting to limit progression of the chronic phase of radiation cystitis. MSC treatment may afford real hope for all patients suffering from chronic radiation cystitis resistant to conventional treatments.

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“…Hemorrhagic cystitis (HC) is a diffuse inflammatory disease of the bladder with sustained hematuria and lower urinary tract symptoms (e.g., incontinence, dysuria, frequency, and urgency) in the absence of other conditions, such as active tumor, vaginal bleeding, or bleeding diathesis [ 1 , 2 ].…”

Section: Introductionmentioning

confidence: 99%

Intravesical liposomal tacrolimus for hemorrhagic cystitis: a phase 2a multicenter dose-escalation study

Hafron,

Breyer,

Joshi

et al. 2023

Int Urol Nephrol

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Background Hemorrhagic cystitis (HC) is an inflammatory disease of the bladder with sustained hematuria for which there is currently no approved drug treatment. We evaluated a liposomal tacrolimus preparation (LP-10) in patients with refractory moderate to severe sterile HC. Methods This phase 2a dose-escalation study assessed the safety and efficacy of up to 2 intravesical instillations of LP-10 (2, 4, or 8 mg tacrolimus) in 13 patients with HC. Primary efficacy outcomes were changes from baseline in the number of bleeding sites on cystoscopy, microscopic urine analysis for red blood cells (RBCs), and hematuria on dipstick. Additional efficacy measures included urinary incontinence, frequency, and urgency on a 3-day diary and cystoscopy global response assessment (GRA). Blood samples for pharmacokinetic (PK) assessment were obtained in all patients. Results Intravesical LP-10 was well tolerated, with no treatment-related severe or serious adverse events (AEs) and only 3 drug-related AEs (artificial urinary sphincter malfunction, dysuria, and bladder spasms). LP-10 blood levels showed short durations of minimal systemic uptake. Treatment resulted in significant improvements in bleeding on cystoscopy, RBC counts in urine, hematuria on dipstick, and urinary incontinence. Bleeding on cystoscopy and urinary incontinence showed dose-dependent improvements that were more pronounced in the 4 mg and 8 mg dose groups. All dose groups showed a significant improvement in cystoscopy GRA. Conclusion LP-10 was well tolerated, with clinically relevant efficacy seen in improvements in cystoscopic bleeding, hematuria, and urinary incontinence. The benefit-risk profile supports the further clinical development of LP-10 at a tacrolimus dose of 4 mg.

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Molecular Mechanisms and Key Processes in Interstitial, Hemorrhagic and Radiation Cystitis

Cited by 8 publications

References 106 publications

Identification of Molecular Mechanisms in Radiation Cystitis: Insights from RNA Sequencing

Identification of Molecular Mechanisms in Radiation Cystitis: Insights from RNA Sequencing

Mesenchymal stem cells limit vascular and epithelial damage and restore the impermeability of the urothelium in chronic radiation cystitis

Intravesical liposomal tacrolimus for hemorrhagic cystitis: a phase 2a multicenter dose-escalation study

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