Macrophage-secreted TGF-β(1) contributes to fibroblast activation and ureteral stricture after ablation injury Journal Article
| Authors: | Ueshima, E.; Fujimori, M.; Kodama, H.; Felsen, D.; Chen, J.; Durack, J. C.; Solomon, S. B.; Coleman, J. A.; Srimathveeravalli, G. |
| Article Title: | Macrophage-secreted TGF-β(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)-β1-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-β1 and scar formation at the site of injury and examined in vitro whether the effects of TGF-β1 could be attenuated by pirfenidone. We observed that proliferation and α-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-β1 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-β1, consistent with a wound healing phenotype. Furthermore, using 3T3 fibroblasts, we demonstrated that stimulation with paracrine TGF-β1 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-β1 activity, limits proliferation and TGF-β1 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-β1 in the injured ureter, which may be a paracrine source of TGF-β1 driving scar formation by fibroblasts, resulting in stricture formation. |
| Keywords: | fibroblast; macrophage; transforming growth factor-β; iatrogenic injury; obstructive uropathy; ureteral stricture |
| Journal Title: | American Journal of Physiology - Renal Physiology |
| Volume: | 317 |
| Issue: | 1 |
| ISSN: | 1931-857X |
| Publisher: | American Physiological Society |
| Date Published: | 2019-07-01 |
| Start Page: | F52 |
| End Page: | F64 |
| Language: | English |
| DOI: | 10.1152/ajprenal.00260.2018 |
| PUBMED: | 31017012 |
| PROVIDER: | scopus |
| PMCID: | PMC6692725 |
| DOI/URL: | |
| Notes: | Source: Scopus |
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