Epithelial progenitor cell dysfunction in fibrotic lung disease

摘要 纤维化肺病，包括普通型间质性肺炎/特发性肺纤维化（IPF）和慢性肺 同种异体移植物功能障碍（CLAD）与上皮维持和修复缺陷有关， 不可逆转的肺功能下降和死亡。然而，很少有人知道的机制，导致缺陷 这些患者的肺组织中的上皮维持和重塑。在上一个融资周期，我们 研究表明，终末期IPF患者肺组织中肺泡2型（AT 2）细胞的丢失与 伴有远端气道基底细胞和分泌细胞增生。使用最先进的3D培养模型和基因组学 我们发现IPF患者肺中的肺泡上皮祖细胞（AT 2）减少， 集落形成和克隆形成潜力以及伴随的p53途径的上调。肺泡 在小鼠模型中发现祖细胞功能障碍是小气道基底细胞的有效调节剂， 与IPF患者肺中观察到的扩张相似。白细胞介素可激活基底细胞扩增 22，一种在肺泡损伤后诱导的细胞因子， 纤维化肺病本申请的目的是确定有助于细胞凋亡的细胞机制。 以及引导细胞沿着这两条途径中的任何一条途径的分子途径 长期以来，人们期望能够开发新的疗法来促进正常组织的修复和/或 阻断纤维化。我们的实验计划将解决的首要假设，即p53依赖性肺泡 祖细胞功能障碍通过以下机制驱动气道和实质重塑： IL 23介导的先天免疫刺激和升高的IL 22产生。这一假设将在 这两个目标将确定p53信号在调节肺泡祖细胞中的作用， 在调节基底细胞的扩张和招募到肺泡损伤区域。目标的实现将 对气道上皮祖细胞的分子调控产生新的见解， 治疗慢性肺病患者的新疗法。

ABSTRACT Fibrotic lung diseases including usual interstitial pneumonia/idiopathic pulmonary fibrosis (IPF) and chronic lung allograft dysfunction (CLAD) are associated with defects in epithelial maintenance and repair that lead to irreversible declines in lung function and death. However, little is known of mechanisms leading to defective epithelial maintenance and remodeling in lung tissue of these patients. Over the previous funding period we demonstrated that loss of alveolar type 2 (AT2) cells in lung tissue of patients with end-stage IPF is associated with distal airway basal and secretory cell hyperplasia. Using state-of-the-art 3D culture models and genomics approaches we found that alveolar epithelial progenitor (AT2) cells from lungs of IPF patients have reduced colony-forming and clonogenic potentials and accompanying upregulation of the p53 pathway. Alveolar progenitor cell dysfunction in mouse models was found to be a potent regulator of small airway basal cell expansion similar to that observed in lungs of IPF patients. Basal cell expansion could be activated by interleukin 22, a cytokine that was induced following alveolar injury and whose elevated abundance has been associated with fibrotic lung disease. Goals of the present application are to determine cellular mechanisms that contribute to either regeneration or remodeling and molecular pathways that guide cells along either of these pathways with the long-term expectation that novel therapies can be developed to promote normal tissue repair and/or block fibrosis. Our experimental plan will address the overarching hypothesis that p53-dependent alveolar progenitor cell dysfunction drives airway and parenchymal remodeling through a mechanism involving IL23-mediated innate immune stimulation and elevated IL22 production. This hypothesis will be tested in two aims that will define roles for p53 signaling in regulation of alveolar progenitor cells and define roles for IL22 in the regulation of basal cell expansion and recruitment to regions of alveolar injury. Completion of aims will yield novel insights into the molecular regulation of airway epithelial progenitor cells that will guide development of new therapies to treat patients with chronic lung disease.