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

研究气道损伤对肺泡室的影响。

• 批准号: 10311135
• 负责人: Irene Gar-Ling Wong
• 金额: $ 3.38万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10311135
• 关键词: Adult; Affect; Alveolar; Alveolar Cell; Asthma; Bronchiolitis Obliterans; COVID-19; Cause of Death; Cell Communication; Cell Differentiation process; Cell Proliferation; Cells; Chronic Obstructive Airway Disease; Coculture Techniques; Complex; Data; Data Set; Defect; Disease; Endothelium; Epithelial; Epithelial Cells; Exhibits; Fibroblasts; Functional disorder; Gases; Genetic Transcription; Growth Factor; Homeostasis; Immune; Immunofluorescence Immunologic; In Vitro; Injury; Label; Lead; Location; Lung; Lung diseases; Mesenchymal; Mesenchyme; Mus; Naphthalene; Natural regeneration; Organ; Organoids; Patients; Phase; Platelet-Derived Growth Factor alpha Receptor; Population; Population Heterogeneity; Process; Regulation; Signal Transduction; Smooth Muscle Myocytes; Supporting Cell; System; Testing; Tissues; Work; airway epithelium; airway regeneration; alveolar epithelium; alveolar homeostasis; cell type; epithelial stem cell; idiopathic pulmonary fibrosis; improved; in vivo; injured; injured airway; insight; lung injury; mouse model; novel; pulmonary function; regenerative; repaired; response; response to injury; self renewing cell; self-renewal; single-cell RNA sequencing; stem cells

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.

摘要 成年哺乳动物的肺中含有不同的细胞群，在体内平衡过程中协调自我更新 和修复。然而，这些过程在慢性阻塞性肺疾病（如慢性阻塞性肺疾病）中失调， 疾病（COPD）、哮喘、特发性肺纤维化、COVID-19等。肺是由 气道和肺泡腔，两个功能不同的隔室。每个隔间都有一套独特的 上皮细胞，如气道中的基底细胞、分泌细胞和纤毛细胞。肺泡腔，气体 交换发生时，由肺泡2型细胞（AT 2 s）和肺泡1型细胞（AT 1 s）排列。此外，新兴 研究已经检查了其他细胞类型如免疫细胞、内皮细胞和 间充质细胞在支持肺上皮干细胞小生境的间充质细胞中， 平滑肌细胞和成纤维细胞的细胞，促进气道再生。在肺泡里，有明显的成纤维细胞 已经鉴定出促进肺泡再生的种群。影响特定 肺的隔室需要激活局部上皮-间充质相互作用以恢复 体内平衡。然而，位置特异性肺损伤的组织范围的后果并不清楚。在我 工作，我建议研究气道损伤对肺泡室的肺的影响。我假设 气道损伤通过改变肺泡相关肺改变肺泡上皮的稳态 间充质我将使用一个小鼠模型的气道损伤（萘），它选择性地消融俱乐部细胞的， 气道上皮细胞，以确定肺泡上皮细胞或肺泡支持间充质是否失调， 组织范围的反应我的初步工作表明，在治疗过程中， 气道损伤反应的再生阶段。此外，肺的单细胞RNA测序 来自这些损伤小鼠的间充质表现出响应气道损伤的转录变化。 通过体内、体外和计算方法的结合，我将1）定义气道的作用， 2）确定肺泡Pdgfrα表达成纤维细胞，间充质细胞 已知支持肺泡再生的细胞群在气道再生中发生改变。这些研究一起 将为伴随气道修复的肺泡隔室破坏提供新的见解， 了解复杂肺部疾病中组织范围的功能障碍是如何发生的。