緩釋型細胞因子受體結合阻斷之胜肽緩解小鼠膀胱阻塞導致之纖維化

許軒豪^1,2, 石宏仁^3,4, 黃俊仁^1,4,5, 張肇源⁴

¹臺北醫學大學臨床醫學研究所,²臺北市立萬芳醫院泌尿科,³彰化基督教醫院泌尿科

⁴臺北醫學大學醫學系,⁵臺北市立萬芳醫院麻醉科

Continuous cytokine-receptor binding blockings mediated by controlled release of peptide can alleviate outlet obstruction-induced bladder fibrosis in mice

Syuan-Hao Syu^1,2, Hung-Jen Shih ^3,4*, Chun-Jen Huang^1,4,5* ,Chao-Yuan Chang ⁴

¹ Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan,² Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

³ Division of Urology, Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan

⁴ Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, ⁵ Department of Anesthesiology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

Purpose:

Bladder outlet obstruction (BOO) induces tissue injury, remodeling, fibrosis, and eventually bladder dysfunction. We hypothesized that inhibition of the crucial mechanism chronic inflammation can alleviate BOO-induced bladder fibrosis in adult male mice.

Materials and Methods:

In this study, we established a BOO mice model to observate the bladder fibrosis condition due to chronic inflammation. To inhibit chronic inflammation becoming bladder fibrosis, we developed a therapy that can continuously block cytokine-receptor bindings mediated by a hydrogel-conjugated peptide KCF-18, a novel peptide that can block bindings of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 to their cognate receptors and simultaneously inhibit TNF-α, IL-1β, and IL-6.

Results:

The numbers of micturition increase and volume voided per micturition decrease since the 7^th day after BOO and progressive decrease bladder function was noted. Bladder fibrosis demonstrated by masson’s trichrome assay and fibrosis related markers of bladder wall revealed that the severity of fibrosis of bladder wall was progression in time dependent manner. Furthermore, the inflammatory markers of BOO groups were significantly elevation compare to sham group. A novel therapy, hydrogel-conjugated peptide KCF-18, was demonstrated that can effectively block bindings of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 to their cognate receptors and simultaneously inhibit TNF-α, IL-1β, and IL-6 expression in bladder tissues for 1 week. The weekly subcutaneous injection of KCF-18 loaded hydrogel was used since BOO 7^th, 14^th and 28^th day. The inflammatory markers were decrease in KCF-18 loaded hydrogel therapy groups compare to BOO group. Furthermore, the KCF-18 loaded hydrogel can mitigate the severity of fibrosis in bladder tissue and fibrosis-related markers. However, the therapeutic effect was significant in KCF-18 loaded hydrogel therapy since BOO 7^th group.

Conclusion: