Epithelial stem cell hippo signaling in pulmonary fibrosis

特发性肺纤维化（IPF）是间质性肺疾病（ILD）的常见形式，其导致肺泡炎。 肺功能重塑和进行性丧失、呼吸衰竭和死亡，通常在5年内发生 诊断. IPF发病机制包括纤维化重塑、炎症和肺结构丧失。 虽然这种疾病的根本原因仍然难以捉摸，但遗传和实验证据支持 慢性肺泡损伤和呼吸道上皮不能正确修复是IPF固有的概念 发病机理在组织学上，肺实质中的呼吸道上皮细胞表达非典型的 近端气道上皮和不确定细胞类型标志物，包括杯状细胞和基底细胞（BC） 这些特征通常限于传导气道。纤维化病变和蜂窝状结构 替换肺泡结构，后者通常由肺泡1型（AT 1）和AT 2细胞排列。全基因 来自IPF患者的肺组织和分离的上皮细胞的转录组学分析显示出显著的 纤毛细胞、基底细胞和杯状细胞相关基因表达的变化和正常肺泡上皮细胞的丧失 细胞，反映了IPF中上皮细胞分化和功能的深刻变化。一种减少 或逆转特发性肺纤维化的表现是通过内源性肺干细胞触发适当的肺泡再生。 损伤导致的细胞密度和基质硬度的变化由Hippo通路感知， 控制干细胞静止。最近的报道也表明呼吸道上皮细胞中雅普活性增加 IPF患者的肺部。细支气管炎中以异常雅普激活为特征的个体IPF上皮细胞 蜂窝状区域经常共表达AT 1、AT 2、传导气道选择性标记物，甚至 间充质或EMT标记，表明正常肺中未观察到的“不确定”分化状态 发展我们的初步研究结果表明，Hippo通路的失活损害了肺泡上皮细胞， 再生，而雅普的失活促进肺纤维化的消退。使用新的 技术和工具，我们已经产生，我们将定义的分子途径和机制， 博来霉素损伤后Hippo通路控制肺泡上皮再生。

Idiopathic pulmonary fibrosis (IPF) is a common form of interstitial lung disease (ILD) resulting in alveolar remodeling and progressive loss of pulmonary function, respiratory failure, and death often within 5 years of diagnosis. IPF pathogenesis encompasses fibrotic remodeling, inflammation, and loss of lung architecture. Although the underlying causes of the disease remain elusive, genetic and experimental evidence support the concept that chronic alveolar injury and failure to properly repair the respiratory epithelium are intrinsic to IPF disease pathogenesis. Histologically, respiratory epithelial cells in the lung parenchyma express atypical proximal airway epithelial and indeterminate cell type markers, including goblet and basal cell (BC) characteristics that are normally restricted to conducting airways. Fibrotic lesions and honeycomb structures replace alveolar structures, the latter normally lined by alveolar type 1 (AT1) and AT2 cells. Genome-wide transcriptomic analyses of lung tissue and isolated epithelial cells from IPF patients demonstrate dramatic changes in ciliated, basal, and goblet cell–associated gene expression and loss of normal alveolar epithelial cells, reflecting profound changes in epithelial cell differentiation and function in IPF. One strategy to attenuate or reverse the manifestations of IPF is to trigger proper alveolar regeneration by endogenous lung stem cells. Changes in cell density and matrix stiffness as a result of injury are sensed by the Hippo pathway, which controls stem cell quiescence. Recent reports also indicate increased YAP activity in respiratory epithelial cells in lungs of patients with IPF. Individual IPF epithelial cells that feature aberrant YAP activation in bronchiolized honeycomb regions frequently co-expressed AT1, AT2, conducting airway selective markers and even mesenchymal or EMT markers, demonstrating "indeterminate" states of differentiation not seen in normal lung development. Our preliminary findings indicate that inactivation of the Hippo pathway impairs alveolar epithelial regeneration, whereas inactivation of Yap promotes the resolution of pulmonary fibrosis. Using the new techniques and tools we have generated we will define the molecular pathways and mechanism by which the Hippo pathway controls alveolar epithelial regeneration after bleomycin injury.