期刊
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
卷 317, 期 1, 页码 F52-F64出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00260.2018
关键词
fibroblast; iatrogenic injury; macrophage; obstructive uropathy; transforming growth factor-beta(1); ureteral stricture
资金
- Thompson Family Foundation
- Society of Interventional Radiology Ernest Ring Award
- National Cancer Institute (NCI) [U54-CA-137788/U54-CA-132378]
- NCI [P30-CA-008748]
- Frederick J. and Theresa Dow Wallace Fund of the New York Community Trust
Iatrogenic injury to the healthy ureter during ureteroscope-guided ablation of malignant or nonmalignant disease can result in ureteral stricture. Transforming growth factor (TGF)-beta(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-beta(1) and scar formation at the site of injury and examined in vitro whether the effects of TGF-beta(1) could be attenuated by pirfenidone. We observed that proliferation and a-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-beta(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 TOF-beta(1), consistent with a wound healing phenotype. Furthermore, using 3T3 fibroblasts. we demonstrated that stimulation with paracrine TGF-beta(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-beta(1) activity, limits proliferation and TGF-beta(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-beta(1) in the injured ureter, which may be a paracrine source of TGF-beta(1) driving scar formation by fibroblasts, resulting in stricture formation.
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