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<p>Radiation-induced fibrosis is a progressive late effect of radiotherapy characterized by chronic inflammation, extracellular matrix accumulation, and functional tissue contracture. We evaluated whether delayed local hyaluronidase treatment attenuates established radiation-induced skin fibrosis in mice. Male C57BL/6 mice underwent localized hind-limb irradiation (60&#xa0;Gy total, 30&#xa0;Gy × 2). After a 28-day fibrosis-development period, irradiated mice received saline, topical 0.1% triamcinolone acetonide, or hyaluronidase every 2&#xa0;days for 2&#xa0;weeks and non-irradiated mice served as normal controls. Outcomes included hind-limb mobility, skin thickness, collagen burden, inflammatory-cell infiltration, nitrite/NO level, cytokines, and fibrosis-related gene expression. At day 56&#xa0;after treatment initiation, hyaluronidase increased hind-limb passive extension from 2.19 ± 0.37&#xa0;cm in irradiated controls to 3.53 ± 0.04&#xa0;cm and increased joint angle from 81.40 ± 9.62° to 102.00 ± 6.09°. Total skin thickness decreased from 472.3 ± 50.4&#xa0;μm to 308.8 ± 18.7&#xa0;μm, collagen area from 37.8 ± 4.7% to 20.9 ± 1.7%, hydroxyproline content from 91.6 ± 3.8 to 17.6 ± 1.6&#xa0;μg/mg, inflammatory-cell count from 88.5 ± 11.8 to 13.6 ± 1.2 cells/HPF, and nitrite/NO level from 46.9 ± 5.8 to 27.6 ± 2.0&#xa0;μM. Hyaluronidase also reduced TNF-α, IL-6, MCP-1, and IL-1β levels and downregulated <i>Tgfb1</i>, <i>Acta2</i>, <i>Col1a1</i>, <i>Il4</i>, <i>Il13</i>, and <i>Il31</i> expression. Local hyaluronidase treatment attenuated functional, histologic, inflammatory, and molecular features of radiation-induced skin fibrosis.</p> Graphical Abstract <p></p>

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Hyaluronidase attenuates radiation-induced skin fibrosis through extracellular matrix remodeling and suppression of inflammatory-profibrotic signaling

  • 期刊论文

  • 发表日期：

    2026年7月21日

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  • Caijun Jin,
  • Linh Thi Thuy Le,
  • Thuy-Tien Thi Trinh,
  • Hee Eun Kim,
  • Zhiyuan Ding,
  • Yongxun Jin,
  • Nguyen Ngan Giang,
  • Keonwoo Choi,
  • Vo Tien Huy,
  • Pham Ngoc Chien,
  • Chan Yeong Heo

摘要

Radiation-induced fibrosis is a progressive late effect of radiotherapy characterized by chronic inflammation, extracellular matrix accumulation, and functional tissue contracture. We evaluated whether delayed local hyaluronidase treatment attenuates established radiation-induced skin fibrosis in mice. Male C57BL/6 mice underwent localized hind-limb irradiation (60 Gy total, 30 Gy × 2). After a 28-day fibrosis-development period, irradiated mice received saline, topical 0.1% triamcinolone acetonide, or hyaluronidase every 2 days for 2 weeks and non-irradiated mice served as normal controls. Outcomes included hind-limb mobility, skin thickness, collagen burden, inflammatory-cell infiltration, nitrite/NO level, cytokines, and fibrosis-related gene expression. At day 56 after treatment initiation, hyaluronidase increased hind-limb passive extension from 2.19 ± 0.37 cm in irradiated controls to 3.53 ± 0.04 cm and increased joint angle from 81.40 ± 9.62° to 102.00 ± 6.09°. Total skin thickness decreased from 472.3 ± 50.4 μm to 308.8 ± 18.7 μm, collagen area from 37.8 ± 4.7% to 20.9 ± 1.7%, hydroxyproline content from 91.6 ± 3.8 to 17.6 ± 1.6 μg/mg, inflammatory-cell count from 88.5 ± 11.8 to 13.6 ± 1.2 cells/HPF, and nitrite/NO level from 46.9 ± 5.8 to 27.6 ± 2.0 μM. Hyaluronidase also reduced TNF-α, IL-6, MCP-1, and IL-1β levels and downregulated Tgfb1, Acta2, Col1a1, Il4, Il13, and Il31 expression. Local hyaluronidase treatment attenuated functional, histologic, inflammatory, and molecular features of radiation-induced skin fibrosis.

Graphical Abstract