Targeting pathologic macrophage activation through inhibition of MyD88 to attenuate laryngotracheal stenosis

通过抑制 MyD88 靶向病理性巨噬细胞激活以减轻喉气管狭窄

基本信息

  • 批准号:
    10644555
  • 负责人:
  • 金额:
    $ 19.76万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-03-01 至 2028-02-29
  • 项目状态:
    未结题

项目摘要

Project Summary: Laryngotracheal Stenosis (LTS) is the pathologic narrowing of the larynx, subglottis, and trachea secondary to mucosal injury from prolonged intubation. This narrowing leads to dyspnea, dysphonia, and can rapidly progress to airway compromise. Therapeutic interventions for the management of LTS are limited to serial dilation, tracheal resection, or permanent tracheostomy which further impairs communication. Medical therapies for LTS are limited by our poor understanding of LTS pathogenesis. Improved understanding of the mechanisms promoting LTS is needed to improve treatment of this debilitating disease. Previous investigation has revealed that an intact immune response is critical to the development of LTS. Characterization of the immune response in LTS has demonstrated increased populations of CD4+ T-cells and macrophages. Preliminary studies in a murine LTS model reveal that depletion of the macrophage population attenuates LTS fibrosis, implicating their pathologic role. However, the local immune mediators and cell signaling pathways promoting pathologic macrophages in LTS are unknown. Macrophage activation is regulated through stimulation of Toll-like receptors (TLRs). TLRs are highly conserved receptors recognizing Pathogen or Damage Associated Molecular Patterns (PAMPs/DAMPs) and lead to downstream activation of regulatory proteins controlling phenotype. Using single cell RNA sequencing the PI has demonstrates increased expression of the TLR4-MyD88 signaling pathway in LTS macrophages. Furthermore, we have identified increased expression of the DAMP S100A8/A9 in LTS tissue. S100A8/A9 is a known activator of TLR4-MyD88 signaling, and worsens fibrosis in our murine LTS model. These findings indicate that TLR4-MyD88 signaling pathways in macrophages may be critical to LTS pathogenesis. However, the relationship between S100A8/A9, TLR4-MyD88 signaling, and pathologic macrophages has not been explored in LTS or other fibrotic diseases, and may represent a critical signaling axis driving pathologic fibrosis. For this study, we will elucidate the signaling networks promoting pathologic macrophages in laryngotracheal stenosis. In Aim 1 we will assess effect of S100A8/A9 on macrophage phenotype and function in a murine LTS model, establish that S100A8/A9s profibrotic effect is mediated by macrophages, and identify the key sources of pathologic S100A8/A9 in human LTS and a murine model. In Aim 2, we will demonstrate the critical role of TLR4-MyD88 signaling in promoting pathologic macrophages in LTS, and elucidate the role of IL1β in promoting LTS fibrosis. Finally, in Aim 3 we will assess S100A8/A9 as a candidate biomarker for the development of laryngotracheal stenosis in patients who have had prolonged intubation. Collectively, this application will lead to an in-depth understanding of the cell signaling networks promoting dysregulated macrophage mediated inflammation and subsequent fibrosis in LTS. The identification of key regulatory pathways promoting pathologic macrophages in LTS will serve as the foundation for targeted treatment strategies that attenuate fibrosis.
项目总结: 喉气管狭窄(LTS)是喉部、声门下部和气管的病理性狭窄。 继发于长时间插管引起的粘膜损伤。这种狭窄会导致呼吸困难、发音困难,并可能 迅速向呼吸道妥协发展。治疗LTS的干预措施仅限于 连续扩张、气管切除或永久性气管切开术,会进一步损害沟通。医疗 由于我们对LTS的发病机制缺乏了解,LTS的治疗受到限制。更好地理解 促进LTS的机制是改善这种衰弱疾病的治疗所必需的。 先前的研究表明,完整的免疫反应对LTS的发展至关重要。 对LTS免疫反应的表征表明,CD4+T细胞和 巨噬细胞。在小鼠LTS模型中的初步研究显示巨噬细胞群的耗尽 减轻LTS纤维化,暗示其病理作用。然而,局部免疫介质和细胞信号转导 在LTS中促进病理性巨噬细胞的途径尚不清楚。 巨噬细胞的激活是通过刺激Toll样受体(TLRs)来调节的。TLR的高度 识别病原体或损伤相关分子模式的保守受体(PAMPs/DAMPS)和 导致控制表型的调控蛋白的下游激活。使用单细胞RNA测序 PI显示TLR4-MyD88信号通路在巨噬细胞中表达增加。 此外,我们还发现DAMP基因S100A8/A9在LTS组织中的表达增加。S100A8/A9是一款 已知的TLR4-MyD88信号激活剂,并在我们的小鼠LTS模型中加重纤维化。这些发现 提示巨噬细胞中的TLR4-MyD88信号通路可能在其发病机制中起关键作用。然而, S100A8/A9、TLR4-MyD88信号与病理性巨噬细胞的关系尚不清楚 在LTS或其他纤维性疾病中被发现,并可能代表驱动病理性纤维化的关键信号轴。 在这项研究中,我们将阐明促进喉气管内病理性巨噬细胞的信号网络。 狭窄。在目标1中,我们将评估S100A8/A9对小鼠巨噬细胞表型和功能的影响 模型,建立S100A8/A9S促纤维化作用是由巨噬细胞介导的,并确定关键来源 人LTS和小鼠模型中病理S100A8/A9的表达。在目标2中,我们将演示 TLR4-MyD88信号在促进肺巨噬细胞病理性改变中的作用及IL-1β在其中的作用 这是纤维化。最后,在目标3中,我们将评估S100A8/A9作为发展的候选生物标志物 长时间插管患者的喉气管狭窄。总的来说,这一应用程序将导致 深入了解促进巨噬细胞调节失调的细胞信号网络 LTS中的炎症和随后的纤维化。促进病理变化的关键调控途径的确定 LTS中的巨噬细胞将作为减轻纤维化的靶向治疗策略的基础。

项目成果

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