吡非尼酮治疗声门狭窄：博来霉素大鼠模型中的局部给药与全身给药比较

文献信息

中文摘要

目的： 喉狭窄是一种由创面愈合失调和胶原过度沉积引起的纤维炎性疾病，目前缺乏有效的药物预防手段。吡非尼酮是一种抗纤维化药物。我们在博来霉素诱导的大鼠模型中比较了局部给药与全身给药吡非尼酮预防声门狭窄的效果。
方法： 30只雄性Wistar大鼠接受内镜下博来霉素诱导的声门及声门下损伤，并随机分为局部吡非尼酮组（每次10 mg；第0、3、7、14天）、全身吡非尼酮组（40 mg/kg/天口服，共14天）或未治疗对照组。4周后，取喉组织，由两名设盲观察者进行宏观狭窄分级，并进行半定量（0-3）组织病理学和免疫组织化学评分。组间比较采用Fisher精确检验和Kruskal-Wallis检验。
结果： 25只动物（对照组n=7；全身组n=9；局部组n=9）完成了研究。5只死亡（对照组3只，每个治疗组各1只；log-rank p=0.386）。各组间宏观狭窄存在差异（p=0.015），与对照组相比，全身组（p=0.014）和局部组（p=0.010）均减轻，两种给药途径之间无差异（p=0.531）。将死亡动物归为最差结局的敏感性分析（n=30）得出相同结果（p=0.011）。黏膜下纤维化（p=0.005）和胶原-1（p=0.001）总体存在差异；仅全身组与对照组之间的两两比较显示显著降低。上皮损伤、炎症、TGF-β1、α-SMA和CD4无显著差异。
结论： 两种给药途径均显著减轻宏观声门狭窄，且两者之间无显著差异，而其对纤维化和胶原-1的抗纤维化作用仅限于全身给药。局部吡非尼酮值得进一步研究。
证据等级： 不适用（基础科学/临床前动物研究）。

英文摘要

OBJECTIVE: Laryngeal stenosis is a fibroinflammatory disease of dysregulated wound healing and excessive collagen deposition lacking effective pharmacological prophylaxis. Pirfenidone is an antifibrotic agent. We compared topical versus systemic pirfenidone for preventing glottic stenosis in a bleomycin-induced rat model.
METHODS: Thirty male Wistar rats underwent endoscopic bleomycin-induced glottic and subglottic injury and were randomized to topical pirfenidone (10 mg per application; Days 0, 3, 7, 14), systemic pirfenidone (40 mg/kg/day orally, 14 days), or untreated control. After 4 weeks, larynges were harvested for macroscopic stenosis grading by two blinded observers and semi-quantitative (0-3) histopathological and immunohistochemical scoring. Groups were compared with Fisher's exact and Kruskal-Wallis tests.
RESULTS: Twenty-five animals (control n = 7; systemic n = 9; topical n = 9) completed the study. Five died (3 control, 1 per treated group; log-rank p = 0.386). Macroscopic stenosis differed among groups (p = 0.015), being reduced in systemic (p = 0.014) and topical (p = 0.010) groups versus control, with no difference between routes (p = 0.531). A sensitivity analysis assigning the deaths the worst outcome (n = 30) gave the same result (p = 0.011). Submucosal fibrosis (p = 0.005) and collagen-1 (p = 0.001) differed overall; pairwise reductions were significant only for systemic versus control. Epithelial damage, inflammation, TGF-β1, α-SMA, and CD4 did not differ significantly.
CONCLUSION: Both routes significantly reduced macroscopic glottic stenosis, with no significant difference between them, whereas antifibrotic effects on fibrosis and collagen-1 were confined to systemic administration. Topical pirfenidone warrants further study.
LEVEL OF EVIDENCE: N/A (basic science/preclinical animal study).