Nintedanib Attenuates Epidural Fibrosis after Laminectomy in Rats

Epidural fibrosis (EF) is a major contributor to postoperative morbidity following laminectomy (LAM). This study investigated the antifibrotic, anti-inflammatory, and anti-angiogenic effects of nintedanib (NIN), a multi-tyrosine kinase inhibitor, in a rat model of post-LAM EF.

Twenty-one male Wistar albino rats were assigned to three groups : control, LAM, and LAM + NIN. The LAM procedure was performed at the L3 level. NIN administration, following LAM, was administered orally at a dose of 50 mg/kg/day for 28 days. Histopathological evaluations included Hematoxylin & Eosin staining for dura mater thickness and fibroblast density, and Masson's trichrome staining for collagen deposition and adhesion grading. α-smooth muscle actin (α-SMA) expression was evaluated using immunohistochemistry and reverse transcription-quantitative polymerase chain reaction. Gene expression of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), vascular endothelial growth factor (VEGF), platelet-derived growth factor receptor (PDGFR), and transforming growth factor-β1 (TGF-β1) was quantified to characterize inflammatory, angiogenic, and fibrogenic responses. Statistical comparisons were conducted using one-way analysis of variance or Kruskal-Wallis tests with appropriate post hoc analyses.

The LAM group exhibited marked post-LAM changes, including increased dura mater thickness (8.20±0.23 vs. 3.93±0.08 μm in controls, p<0.0001), elevated fibroblast density (p=0.0006), severe collagen deposition, and high-grade epidural adhesions (grade 3, p=0.0006). NIN treatment attenuated these alterations, reducing dura mater thickness (4.80±0.20 μm; p<0.0001 vs. LAM), fibroblast density (p<0.01), and adhesion grade (grade 1, p=0.0012). α-SMA immunoreactivity was high in LAM (grade 3, p<0.0001), whereas NIN significantly suppressed myofibroblast activation (grade 1, p=0.0012). NIN also significantly downregulated inflammatory mediators TNF-α (p<0.001) and IL-1β (p<0.001), as well as angiogenic markers VEGF (p<0.001) and PDGFR (p<0.001), and fibrogenic mediators TGF-β1 (p<0.001) and α-SMA (p<0.01). These findings indicate that NIN suppresses fibroblast activation, extracellular matrix accumulation, and myofibroblast differentiation, thereby limiting epidural adhesion and scar maturation.

Nintedanib effectively mitigated epidural fibrosis after LAM through combined antifibrotic, anti-inflammatory, and anti-angiogenic actions. By improving the dural structure and reducing key molecules that contribute to scar formation, NIN shows significant promise as a treatment to prevent postoperative epidural adhesions. Future studies with extended follow-up may help clarify its clinical relevance.