Regenerative therapy for lung infection by S. pneumoniae

总结。细菌性肺炎是世界范围内死亡和发病的主要原因。即使使用抗生素 在接受治疗的情况下，许多患者仍然迅速发展为需要住院、重症监护和 长时间的恢复。细菌性肺炎的病理生物学特征是强健的宿主免疫。 导致呼吸道损伤的反应。而宿主对细菌性肺部感染的防御和免疫力 已经进行了广泛的研究，但对哪些细胞受到损伤以及组织修复和 再生在细菌性肺炎康复中的作用。使用小鼠模型和物理模型的研究 化学损伤表明，肺实质中的再生过程依赖于增殖和 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会细胞。他们的再生能力缺陷被认为与 严重的慢性病理情况，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、图案化和 胚胎发育过程中的分化在再生过程中被重新部署以修复组织 成年人的伤害。我们之前的工作表明，miRNA302簇促进了肺的增殖 发育中的上皮祖细胞。MiRNA302的功能部分是通过抑制 在河马信号通路中，激酶的关键成分(Mst1和Last2)级联，进而 调节细胞增殖、凋亡和分化相关基因的表达。我们的预赛 研究表明，感染肺炎链球菌(Sp)的小鼠肺部有实质性损伤 可见肺泡上皮细胞再生。然而，完全修复需要较长的时间。 时间(&gt；30天)。我们还发现miR302在肺上皮细胞中的表达增加，并促进了细胞的增殖。 居民AECI和AECII细胞对SP感染所致肺损伤的反应此外，管理 Sp感染小鼠的小分子miRNA302模拟促进呼吸道上皮再生，导致 改善肺功能，促进小鼠康复，提高存活率。基于这些结果，这款R21 项目将严格检验这一假设，即靶向microRNA-Hippo途径可能提供一种新的 促进肺泡上皮再生促进肺损伤恢复的治疗途径 由细菌性肺炎引起。

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.