Article record

mTORC1作为减轻损伤后气道狭窄发生的治疗靶点

mTORC1 as a Therapeutic Target to Mitigate Development of Airway Stenosis in Response to Injury.

基础研究咽喉科IF 2.3Q2

文献信息

PMID	42838622
原文	在 PubMed 查看原文 ↗
发表日期	2026
作者	Julia Hermann 查看其他 6 位作者 Beth Osterbauer；Charmi Dedhia；Laura Perin；Elizabeth P Henske；Wei Shi；Christian Hochstim
作者单位	Keck School of Medicine of USC, Los Angeles, California, USA. 查看其他 5 条单位信息 Division of Otolaryngology - Head and Neck Surgery, Children's Hospital Los Angeles, Los Angeles, California, USA.；The GOFARR Laboratory, Division of Urology, Children's Hospital Los Angeles, Los Angeles, California, USA.；Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.；Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.；Caruso Department of Otolaryngology - Head and Neck Surgery, Keck School of Medicine of USC, Los Angeles, California, USA.
期刊	The Laryngoscope
SCI 分区	Q2
IF	2.3
研究类型	基础研究 · 基础／转化
所属专科	咽喉科

中文摘要

目的： 气道狭窄是一种影响发声、呼吸和吞咽的高致病性疾病。其病因涉及气管插管或其他机械性损伤，但潜在的分子机制尚未完全阐明。新出现的证据提示mTOR复合物1（mTORC1）在喉气管狭窄（LTS）发病机制中发挥作用，并且雷帕霉素（一种mTOR抑制剂）可以减轻LTS的发生。在本研究中，我们在损伤诱导的气管狭窄小鼠模型中对mTORC1进行了基因和药理学靶向。
方法： 对人气管组织进行磷酸化核糖体蛋白S6激酶（pS6K，mTORC1激酶活性的下游靶点）免疫染色，以评估mTORC1激活。在多西环素诱导的Rptor敲除小鼠（Tbx4-rtTA/Tet-On-Cre/Rptorfl/fl）的气管间充质中基因消融mTORC1，并与野生型对照进行比较，两者均接受气管损伤。损伤后第21天，采集气管并测量气管固有层厚度（LPT）。药理学消融采用早期（损伤后第0-7天）和晚期（损伤后第8-21天）全身雷帕霉素治疗。
结果： 与假手术对照相比，气管损伤增加了LPT。基因消融mTORC1消除了这一效应，突变小鼠的LPT与突变假手术对照相比无变化，且显著低于损伤的野生型同窝对照。与早期载体对照相比，早期雷帕霉素显著降低了损伤气管LPT的预期增加，而晚期雷帕霉素与晚期载体对照相比没有影响。
结论： 这些结果表明，气管间充质内的mTORC1活性是损伤后气管狭窄形成所必需的，并且是一个重要的治疗靶点。
证据等级： 不适用。

英文摘要

OBJECTIVES: Airway stenosis is a morbid health condition impacting the voice, breathing, and swallowing. Etiology involves endotracheal intubation or other mechanical injury, but the underlying molecular mechanisms are not fully understood. Emerging evidence suggests a role for mTOR complex 1 (mTORC1) in the pathogenesis of laryngotracheal stenosis (LTS) and that rapamycin, an mTOR inhibitor, can mitigate development of LTS. In the present study, mTORC1 was targeted genetically and pharmacologically in an injury-induced tracheal stenosis mouse model.
METHODS: Human tracheal tissues were immunostained for phosphorylated ribosomal protein S6 kinase (pS6K), a downstream target of mTORC1 kinase activity, to assess mTORC1 activation. mTORC1 was genetically ablated in tracheal mesenchyme of doxycycline-inducible Rptor knockout mice (Tbx4-rtTA/Tet-On-Cre/Rptorfl/fl) and compared to wildtype controls, both subjected to tracheal injury. On Day 21 post injury, tracheas were harvested and tracheal lamina propria thickness (LPT) was measured. Pharmacological ablation was performed with early (Day 0-7 post injury) and late (Day 8-21 post injury) systemic rapamycin treatment.
RESULTS: Tracheal injury increased LPT compared to sham control. This effect was eliminated by genetic ablation of mTORC1, with mutant mice having no change in LPT compared to mutant sham control and significantly lower LPT than injured wildtype littermate controls. Early rapamycin significantly reduced the expected increase in injured tracheal LPT compared to early vehicle control, while late rapamycin had no effect compared to late vehicle control.
CONCLUSION: These results indicate that mTORC1 activity within tracheal mesenchyme is required for tracheal stenosis formation following injury and is an important therapeutic target.
LEVEL OF EVIDENCE: N/A.