Regenerative therapy for lung infection by S. pneumoniae

摘要细菌性肺炎是世界范围内死亡和发病的主要原因。即使有抗生素 尽管如此，许多患者仍然迅速发展为需要住院治疗、重症监护和 延长恢复期。细菌性肺炎的病理生物学特征是强大的宿主免疫 导致气道损伤的反应。而宿主对细菌性肺部感染的防御和免疫力 虽然已经进行了广泛的研究，但对哪些细胞受损以及组织修复和 再生在细菌性肺炎的恢复中发挥作用。使用小鼠模型进行的研究， 化学损伤表明肺实质的再生过程依赖于增殖， 局部干细胞或祖细胞的分化，包括I型（AECI）和II型（AECII）肺泡 上皮细胞和细支气管俱乐部细胞。它们再生能力的缺陷与以下因素有关： 重度慢性病理状况，包括慢性阻塞性肺疾病（COPD）、特发性 肺纤维化（IPF）和肺气肿。许多对组织生长、形成图案和 胚胎发育过程中的分化在再生过程中重新部署，以修复组织 成年人的伤害。我们先前的工作表明，miRNA 302簇促进肺细胞增殖， 上皮祖细胞在发育过程中。miRNA 302的功能部分是通过抑制 Hippo信号通路中激酶级联的关键组分（Mst 1和Last 2）， 调节参与细胞增殖、凋亡和分化的基因的表达。我们的初步 研究表明，感染肺炎链球菌（Sp）的小鼠肺部有实质性损伤 实质，随后可见肺泡上皮再生。然而，全面修复需要很长时间 时间（>30天）。我们还发现肺上皮细胞中miR 302的表达增加， 常驻AECI和AECII细胞对Sp感染引起的肺损伤的反应。此外，行政 小分子miRNA 302模拟物对SP感染的小鼠促进气道上皮再生， 改善肺功能，增强小鼠恢复和更好的存活率。根据这些结果，R21 该项目将严格测试这一假设，即靶向microRNA-Hippo通路可能提供一种新的 促进肺泡上皮再生和增强肺损伤恢复的治疗方法 是由细菌性肺炎引起的

Summary. Bacterial pneumonia is a leading cause of mortality and morbidity worldwide. Even with antibiotic treatments, many patients still rapidly progress to severe illness requiring hospitalization, intensive care, and prolonged recovery. The pathobiology of bacterial pneumonia is characterized by robust host immune responses that cause airway damages. Whereas host defense and immunity to bacterial lung infections have been extensively studied, little is known about which cells are injured and what role tissue repair and regeneration play in recovery from bacterial pneumonia. Studies using mouse models with physical and chemical injuries have shown that regenerative process in the lung parenchyma depends on proliferation and differentiation of local stem or progenitor cells, which include the type I (AECI) and type II (AECII) alveolar epithelial cells, and bronchiolar Club cells. Defects in their regenerative capacity have been implicated in severe chronic pathological conditions, including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and emphysema. Numerous pathways important for tissue growth, patterning and differentiation during embryonic development are redeployed in the process of regeneration to repair tissue injury in adults. Our previous work has shown that the miRNA302 cluster promotes proliferation of lung epithelial progenitor cells during development. The miRNA302 functions, in part, by repressing expression of key components (Mst1, and Last2) of the kinase cascade in the Hippo signaling pathway, which in turn regulates expression of genes involved in cell proliferation, apoptosis and differentiation. Our preliminary studies showed that mice infected with Streptococcus pneumoniae (Sp) had substantial injuries in the lung parenchyma followed by visible alveolar epithelial regeneration. However, full repair took an extended period of time (>30 days). We also found increased expression of miR302 in the lung epithelium and proliferation of resident AECI and AECII cells in response to lung injury from Sp infection. Furthermore, administration of small molecule miRNA302-mimics to Sp-infected mice promoted airway epithelial regeneration, resulting in improved lung function, enhanced mouse recovery and better survival. Based on these results, this R21 project will rigorously test the hypothesis that targeting microRNA-Hippo pathway may provide a novel therapeutic approach to promote alveolar epithelium regeneration and enhance recovery from lung injury caused by bacterial pneumonia.