Fibrosis and the bladder, implications for function ICI‐RS 2017

Fry, Christopher; Kitney, Darry G.; Paniker, Jalesh; Drake, Marcus; Andersson, Karl Erik

doi:10.1002/nau.23725

Cited by 41 publications

(44 citation statements)

References 51 publications

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“…These changes are consistent with a functional decrease in bladder capacity. RC patients also have diminished bladder capacity, which is believed to occur as a result of fibrosis (Fry et al, 2018). We used two different histological methods to quantify radiation-induced fibrosis in the bladder: Masson's trichrome and Picrosirius Red F I G U R E 5 Collagen I and collagen III accumulate in C57BL/6 mice in response to radiation.…”

Section: Discussionmentioning

confidence: 99%

“…One major culprit is the progressive buildup of fibrotic tissue, a process that is addressed by existing therapies. Bladder fibrosis has an inverse relationship with bladder compliance, and patients with a fibrotic bladder suffer from lower urinary tract symptoms such as increased urinary frequency and nocturia (Fry et al, ). Fibrosis is caused by an imbalance between extracellular matrix production and breakdown.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…MMPs and their inhibitors (TIMPs) are known to be involved in the breakdown and remodeling of the extracellular matrix and overexpression or imbalance of MMPs and TIMPs have been reported in various conditions . An upregulation of TIMPs is known to generate fibrosis with an increased deposition of collagens as well as an increase of interstitial cells that include fibroblasts and myofibroblasts . The relationship between bladder outlet obstruction and increased extracellular matrix deposition leading to bladder wall thickening and decreased compliance has been evidenced since the early 1990s .…”

Section: Discussionmentioning

confidence: 99%

“…19 An upregulation of TIMPs is known to generate fibrosis with an increased deposition of collagens as well as an increase of interstitial cells that include fibroblasts and myofibroblasts. 20 The relationship between bladder outlet obstruction and increased extracellular matrix deposition leading to bladder wall thickening and decreased compliance has been evidenced since the early 1990s. 21 To our knowledge, only two study examined the role of extracellular matrix metabolism in spina bifida NLUTD.…”

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confidence: 99%

Urinary TIMP‐2 and MMP‐2 are significantly associated with poor bladder compliance in adult patients with spina bifida

Peyronnet

Richard

Bendavid

et al. 2019

Neurourology and Urodynamics

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Aims To assess the predictive values of six urinary markers (nerve growth factor [NGF], brain‐derived neurotrophic factor [BDNF], matrix metalloproteinase 2 [MMP‐2], tissue inhibitor metalloproteinase 2 [TIMP‐2], transformation growth factor β‐1 [TGF‐B1], and prostaglandin 2 [PGE2]) for adverse urodynamic features and for upper urinary tract damage in adult patients with spina bifida. Materials and methods A single‐center prospective trial was conducted from March 2015 to March 2017 including all consecutive adult patients with spina bifida seen for urodynamic testing. The urine was collected and stored at −80°C. A urodynamic and an upper urinary tract were systematically performed. At the end of the inclusion period, urines were defrosted and urinary nerve growth factor, BDNF, TIMP‐2, and TGF‐B1 were assessed using validated ELISA kits. The urinary markers levels were adjusted on the urinary creatinine level. Urinary MMP‐2 levels were assessed by zymography. Results Fourty patients were included. Only TIMP‐2 and MMP‐2 were significantly associated with poor bladder compliance (P = .043 and P = .039, respectively). TIMP‐2 was also the only urinary marker significantly associated with upper urinary tract damage on imaging (OR = 19.81; P = .02). Of all urodynamic parameters, bladder compliance and maximum detrusor pressure were the only ones associated with upper urinary tract damage on imaging (P = .01 and P = .02), The diagnostic performances of urinary TIMP‐2 for upper urinary tract damage were slightly superior to PdetMax and bladder compliance with an area under the curve of 0.72. Conclusion Urinary TIMP‐2 and MMP‐2 were significantly associated with poor bladder compliance and urinary TIMP‐2 was significantly associated with upper urinary tract damage. These findings support a pathophysiological role of extracellular matrix remodeling in poor bladder compliance of adult patients with spina bifida.

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“…hypertension, liver disease or diabetes), and subsequent repetitive need for tissue repair, can result in excessive accumulation of ECM, leading to tissue fibrosis. In the bladder, fibrosis thickens the bladder wall and alters its urodynamic compliance [ 23 ]. We identified increased levels of three proteins (PAI 1, TIMP1 and TIMP2) that can support a pro-fibrotic environment.…”

Section: Discussionmentioning

confidence: 99%

Prostate cancer survivors with symptoms of radiation cystitis have elevated fibrotic and vascular proteins in urine

et al. 2020

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Radiation for pelvic cancers can result in severe bladder damage and radiation cystitis (RC), which is characterized by chronic inflammation, fibrosis, and vascular damage. RC development is poorly understood because bladder biopsies are difficult to obtain. The goal of this study is to gain understanding of molecular changes that drive radiation-induced cystitis in cancer survivors using urine samples from prostate cancer survivors with history of radiation therapy. 94 urine samples were collected from prostate cancer survivors with (n = 85) and without (n = 9) history of radiation therapy. 15 patients with radiation history were officially diagnosed with radiation cystitis. Levels of 47 different proteins were measured using Multiplex Luminex. Comparisons were made between non-irradiated and irradiated samples, and within irradiated samples based on radiation cystitis diagnosis, symptom scores or hematuria. Statistical analysis was performed using Welch’s t-test. In prostate cancer survivors with history of radiation therapy, elevated levels of PAI 1, TIMP1, TIMP2, HGF and VEGF-A were detected in patients that received a radiation cystitis diagnosis. These proteins were also increased in patients suffering from hematuria or high symptom scores. No inflammatory proteins were detected in the urine, except in patients with gross hematuria and end stage radiation cystitis. Active fibrosis and vascular distress is detectable in the urine through elevated levels of associated proteins. Inflammation is only detected in urine of patients with end-stage radiation cystitis disease. These results suggest that fibrosis and vascular damage drive the development of radiation cystitis and could lead to the development of more targeted treatments.

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Fibrosis and the bladder, implications for function ICI‐RS 2017

Abstract: The conclusion that reduced bladder contractile function with increased fibrosis is due largely to the replacement of detrusor with ECM offers a way forward for future research to consider approaches that will restore bladder function by reducing ECM deposition.

Cited by 41 publications

References 51 publications

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

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

Urinary TIMP‐2 and MMP‐2 are significantly associated with poor bladder compliance in adult patients with spina bifida

Prostate cancer survivors with symptoms of radiation cystitis have elevated fibrotic and vascular proteins in urine

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