Investigating the effects of airway injury on the alveolar compartment of the lung.

摘要 成年哺乳动物的肺含有多种细胞群，这些细胞在体内稳态期间协调自我更新。 并进行修复。然而，在慢性阻塞性肺病等肺部疾病中，这些过程是失调的。 疾病(慢性阻塞性肺病)、哮喘、特发性肺纤维化、新冠肺炎等。肺是由肺脏的 呼吸道和肺泡腔，两个功能截然不同的隔室。每个隔间都有一套独特的 指上皮细胞，如呼吸道中的基细胞、分泌细胞和纤毛细胞。肺泡腔，在那里气体 发生交换，由肺泡2型细胞(AT2s)和肺泡1型细胞(AT1s)排列。此外，新兴市场 研究已经检查了其他类型的细胞如免疫细胞、内皮细胞和 间充质细胞。在支持肺上皮干细胞生境的间充质细胞中，有几个群体 促进呼吸道再生的平滑肌细胞和成纤维细胞。肺泡内可见明显的成纤维细胞。 已经确定了促进肺泡再生的种群。影响特定病症的肺部不适 肺间室需要激活局部上皮-间充质相互作用才能恢复 动态平衡。然而，特定部位的肺损伤在整个组织范围内的后果还不是很清楚。在我的 在这项工作中，我建议研究呼吸道损伤对肺泡室的影响。我假设 气道损伤通过肺泡相关肺的改变来调节肺泡上皮的动态平衡 间充质的我。我将使用一种小鼠呼吸道损伤模型(萘)，它选择性地消融 气道上皮，以确定肺泡上皮或支持肺泡的间质是否在 这是一种全组织的反应。我的初步工作表明，在 呼吸道损伤反应的再生期。此外，肺的单细胞RNA测序 这些受损小鼠的间充质细胞表现出对呼吸道损伤的转录变化。 通过体内、体外和计算方法的结合，我将1)定义呼吸道的影响 肺泡上皮损伤和2)确定表达PDGFRα的肺泡成纤维细胞是一种间质 已知的支持肺泡再生的人群在呼吸道再生中发生变化。总而言之，这些研究 将为伴随着呼吸道修复的肺泡室破裂提供新的见解，推动我们的 了解复杂肺部疾病中如何发生全组织功能障碍。

Abstract The adult mammalian lung contains diverse populations of cells that coordinate self-renewal during homeostasis and repair. However, these processes are dysregulated during lung diseases like chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis, COVID-19, and more. The lungs are composed of the airways and alveolar space, two compartments with distinct functions. Each compartment contains a unique set of epithelial cells, such as basal, secretory, and ciliated cells in the airways. The alveolar space, where gas exchange occurs, is lined by alveolar type 2 cells (AT2s) and alveolar type 1 cells (AT1s). Additionally, emerging studies have examined the regulation of lung epithelium by other cell types like immune, endothelial, and mesenchymal cells. Among the mesenchymal cells that support lung epithelial stem cell niches are populations of smooth muscle cells and fibroblasts that facilitate airway regeneration. In the alveoli, distinct fibroblast populations have been identified that promote alveolar regeneration. Lung perturbations that affect specific compartments of the lung require the activation of local epithelial-mesenchymal interactions to restore homeostasis. However, the tissue-wide consequences of location-specific lung injuries is not well known. In my work, I propose to study the effects of airway injury on the alveolar compartment of the lung. I hypothesize that airway injury dysregulates homeostasis of the alveolar epithelium via alterations of the alveolar-associated lung mesenchyme. I will use a murine model of airway injury (naphthalene), which selectively ablates club cells of the airway epithelium, to determine if the alveolar epithelium or alveolar-supportive mesenchyme is dysregulated in a tissue-wide response. My preliminary work demonstrates an increase in proliferative AT2s during the regenerative phase of the airway injury response. Additionally, single cell RNA-sequencing of the lung mesenchyme from these injured mice demonstrated transcriptional changes in response to the airway injury. Through a combination of in vivo, in vitro, and computational approaches, I will 1) define the effect of airway injury on the alveolar epithelium and 2) determine if alveolar Pdgfrα-expressing fibroblasts, a mesenchymal population known to support alveolar regeneration, are altered in airway regeneration. Together, these studies will provide novel insights into alveolar compartment disruptions that accompany airway repair, advancing our understanding of how tissue-wide dysfunction occurs in complex lung diseases.