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Macrophage-secreted TGF-?1 contributes to fibroblast activation and ureteral stricture after ablation injury.

ABSTRACT: Iatrogenic injury to the healthy ureter during ureteroscope-guided ablation of malignant or nonmalignant disease can result in ureteral stricture. Transforming growth factor (TGF)-?1-mediated scar formation is considered to underlie ureteral stricture, but the cellular sources of this cytokine and the sequelae preceding iatrogenic stricture formation are unknown. Using a swine model of ureteral injury with irreversible electroporation (IRE), we evaluated the cellular sources of TGF-?1 and scar formation at the site of injury and examined in vitro whether the effects of TGF-?1 could be attenuated by pirfenidone. We observed that proliferation and ?-smooth muscle actin expression by fibroblasts were restricted to injured tissue and coincided with proliferation of macrophages. Collagen deposition and scarring of the ureter were associated with increased TGF-?1 expression in both fibroblasts and macrophages. Using in vitro experiments, we demonstrated that macrophages stimulated by cells that were killed with IRE, but not LPS, secreted TGF-?1, consistent with a wound healing phenotype. Furthermore, using 3T3 fibroblasts, we demonstrated that stimulation with paracrine TGF-?1 is necessary and sufficient to promote differentiation of fibroblasts and increase collagen secretion. In vitro, we also showed that treatment with pirfenidone, which modulates TGF-?1 activity, limits proliferation and TGF-?1 secretion in macrophages and scar formation-related activity by fibroblasts. In conclusion, we identified wound healing-related macrophages to be an important source of TGF-?1 in the injured ureter, which may be a paracrine source of TGF-?1 driving scar formation by fibroblasts, resulting in stricture formation.

SUBMITTER: Ueshima E

PROVIDER: S-EPMC6692725 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Macrophage-secreted TGF-β<sub>1</sub> contributes to fibroblast activation and ureteral stricture after ablation injury.

Ueshima Eisuke E Fujimori Masashi M Kodama Hiroshi H Felsen Diane D Chen Jie J Durack Jeremy C JC Solomon Stephen B SB Coleman Jonathan A JA Srimathveeravalli Govindarajan G

American journal of physiology. Renal physiology 20190424 7

Iatrogenic injury to the healthy ureter during ureteroscope-guided ablation of malignant or nonmalignant disease can result in ureteral stricture. Transforming growth factor (TGF)-β<sub>1</sub>-mediated scar formation is considered to underlie ureteral stricture, but the cellular sources of this cytokine and the sequelae preceding iatrogenic stricture formation are unknown. Using a swine model of ureteral injury with irreversible electroporation (IRE), we evaluated the cellular sources of TGF-β< ...[more]

PMID: 31017012

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Project description:BackgroundBalloon dilation is a commonly used minimally invasive endourological treatment of ureteral stricture, but the postoperative recurrence rate is relatively high. And factors contributing to recurrence after treatment are poorly understood. Herein, we sought to develop a novel clinical nomogram to predict ureteral stricture-free survival in patients suffering from ureter stricture and performed balloon dilation.MethodsThe nomogram was established based on a retrospective analysis of 321 patients who received endoscopic balloon dilation alone for ureter strictures from January 2016 to January 2020 in Sun Yat-sen Memorial Hospital using the Cox regression model. Perioperative clinical data and disease outcomes were analyzed. The primary endpoint was the onset of ureteral re-stricture after ureter balloon dilation. Discrimination of the nomogram was assessed by the concordance index (C-index) and the calibration curve. The results were internally validated using bootstrap resampling.ResultsOverall, 321 patients with a median follow-up of 590 days were enrolled in the study, among which 97 patients (30.2%) developed recurrence of ureteral stricture during follow-up. Five variables remained significant predictors of ureteral re-stricture after multivariable analyses: stricture nature (P < 0.001), urinary nitrite (P = 0.041), CKD (P = 0.005), stent retention time (P < 0.001), and balloon size (P = 0.029). The calibration craves for the probability of 1-, 3-, and 5-years stricture-free survival (SFS) presented satisfied with the consistency of nomogram prediction and actual observation. The C-index of the model was 0.74 (95% CI 0.70-0.79).ConclusionsOur study developed the first nomogram to effectively predict stricture-free survival in patients suffering from ureter stricture after balloon dilation. It is helpful to identify the optimal patients with ureter stricture for balloon dilation and improve treatment outcomes. However, further external validation of the nomogram is warranted.

Project description:Chronic HIV infection leads to the development of cognitive impairments, designated as HIV-associated neurocognitive disorders (HAND). The secretion of soluble neurotoxic factors by HIV-infected macrophages plays a central role in the neuronal dysfunction and cell death associated with HAND. One potentially neurotoxic protein secreted by HIV-1 infected macrophages is cathepsin B. To explore the potential role of cathepsin B in neuronal cell death after HIV infection, we cultured HIV-1(ADA) infected human monocyte-derived macrophages (MDM) and assayed them for expression and activity of cathepsin B and its inhibitors, cystatins B and C. The neurotoxic activity of the secreted cathepsin B was determined by incubating cells from the neuronal cell line SK-N-SH with MDM conditioned media (MCM) from HIV-1 infected cultures. We found that HIV-1 infected MDM secreted significantly higher levels of cathepsin B than did uninfected cells. Moreover, the activity of secreted cathepsin B was significantly increased in HIV-infected MDM at the peak of viral production. Incubation of neuronal cells with supernatants from HIV-infected MDM resulted in a significant increase in the numbers of apoptotic neurons, and this increase was reversed by the addition of either the cathepsin B inhibitor CA-074 or a monoclonal antibody to cathepsin B. In situ proximity ligation assays indicated that the increased neurotoxic activity of the cathepsin B secreted by HIV-infected MDM resulted from decreased interactions between the enzyme and its inhibitors, cystatins B and C. Furthermore, preliminary in vivo studies of human post-mortem brain tissue suggested an upregulation of cathepsin B immunoreactivity in the hippocampus and basal ganglia in individuals with HAND. Our results demonstrate that HIV-1 infection upregulates cathepsin B in macrophages, increases cathepsin B activity, and reduces cystatin-cathepsin interactions, contributing to neuronal apoptosis. These findings provide new evidence for the role of cathepsin B in neuronal cell death induced by HIV-infected macrophages.

Project description:BackgroundTraditional ureteral stricture balloon dilation was performed with fluoroscopic assistance. The use of a C-arm X-ray machine delivered hazardous radiation to both surgeons and patients. In attempt to eliminate the radiation hazard, we developed a F4.5/6.5 ureteroscope assisted intraoperative X-ray free balloon dilation surgical approach to treat ureteral stricture and to verify its safety and efficacy. Specifically, this method had not been previously reported in the literature.MethodsWe demonstrated an intraoperative X-ray free balloon dilation with detailed step-by-step procedures description and video illustration. Clinical data of patients undergoing minimally invasive endourological treatment for ureteral stricture between February 2015 and November 2019 were retrospectively analyzed. All steps of X-ray free balloon dilation were carried out under direct vision of a ureteroscope, and two indwelling F7 ureteral stents were used for 3 months postoperatively. Preoperative, intraoperative, and postoperative clinical data were evaluated, and follow-up results were reported. Successful outcome was defined as disappearance of preoperative symptoms, relief of hydronephrosis and stable of renal function. Univariate and multivariate prognostic analyses were performed.ResultsWe identified 109 patients who received endourological treatment for ureteral stricture in our hospital's medical database. After excluding patients undergone simple catheter dilation, endoureterotomy and other treatment method, 76 patients received balloon dilation without intraoperative fluoroscopic guidance were included in our study. 4/76 patients report a grade II complication (urinary tract infections, UTIs) according to Clavien Dindo classification. In the 22.5 months median follow-up time, the one-year cumulative success rate and two-year cumulative success rate were 85.9% and 80.2% (61/76), respectively, and the majority (13/15, 86.7%) recurrence of ureteral stricture or hydronephrosis deterioration were found within two years after surgery. The longer stenotic lesion length (>5 mm) or multiple ureter stenosis and compromised blood supply of ureter were significantly associated with postoperative stenosis recurrence.ConclusionsX-ray free endoscopic balloon dilation is a safe and effective procedure that could be performed on patients with ureteral stenosis.

Dataset Information

Macrophage-secreted TGF-?1 contributes to fibroblast activation and ureteral stricture after ablation injury.

Publications

Macrophage-secreted TGF-β<sub>1</sub> contributes to fibroblast activation and ureteral stricture after ablation injury.

Similar Datasets

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