Alveolar Tissuegenesis

描述(由申请人提供)： 急性肺损伤以弥漫性肺泡损伤为特征，伴有I型和II型肺泡上皮细胞的损伤和死亡。对II型细胞的损伤尤其严重，因为它是I型细胞的前体，也是肺内肺表面活性物质的主要来源。我们的实验室最近证实了将基因工程的肺泡巨噬细胞输送到肺泡结构的可行性。我们提供的初步数据表明，新鲜分离的II型细胞可以通过气管内输送给博莱霉素诱导的急性肺损伤小鼠。供体II型细胞可以很容易地识别，并似乎附着在肺泡壁表面。我们认为这些II型细胞随后将被移植到肺泡表面；如果成功，这可能导致肺泡结构的功能恢复。此外，我们还成功地在体外转染人肺泡上皮细胞，并表现出对博莱霉素诱导的DNA损伤和细胞损伤的抗性。这些细胞被称为“超级II型细胞”，可能代表了一群供体细胞，他们将比正常的II型细胞更成功地植入。因此，我们推测：博莱霉素性肺损伤时，肺泡上皮祖细胞向肺泡结构的呼吸道输送将导致受损的肺泡上皮的植入和替换，从而加速肺功能的恢复。这项建议的具体目的是：1)证明在博莱霉素诱导的急性肺损伤中，肺泡上皮祖细胞(II型细胞，骨髓来源的祖细胞)的气道输送将定位于肺泡结构并植入到受损的肺泡表面；2)确定成功地将肺泡上皮祖细胞植入到肺泡上皮是否会加速博莱霉素诱导的急性肺损伤的恢复；以及3)确定是否供者的II型细胞对博莱霉素毒性更具抵抗力，即“超级II型细胞”，植入更成功，并促进更快的恢复。如果成功，这种肺泡组织发生的模型将代表着修复急性肺损伤时弥漫性肺泡损伤的一种非常新的治疗方法。

DESCRIPTION (provided by applicant): Acute lung injury is characterized by diffuse alveolar damage with injury and death of type I and type II alveolar epithelial cells. Injury to the type II cell is particularly critical as it is the progenitor of the type I cell and is the major source of pulmonary surfactant in the lung. Our laboratory has recently demonstrated the feasibility of airway delivery of genetically engineered alveolar macrophages to the alveolar structures. We present preliminary data that indicate that freshly isolated type II cells can be intratracheally delivered to mice with bleomycin-induced acute lung injury. The donor type II cells can be easily identified and appear to attach to the alveolar wall surface. We propose that these type II cells will subsequently engraft to the alveolar surface; if successful, this may result in functional recovery of the alveolar structures. Furthermore, we have successfully transfected alveolar epithelial cells in vitro and demonstrated resistance to bleomycin-induced DNA damage and cell injury. These cells, referred to as "super type II cells", may represent a population of donor cells that will engraft more successfully than normal type II cells. Therefore, we hypothesize that: airway delivery of alveolar epithelial progenitor cells to the alveolar structures during bleomycin lung injury will result in engraftment and replacement of the injured alveolar epithelium and will hasten recovery of lung function. The specific aims of this proposal are: 1) to demonstrate that airway delivery of alveolar epithelial progenitor cells (type II cells, marrow-derived progenitor cells) will localize to the alveolar structures and engraft to the injured alveolar surface during bleomycin-induced acute lung injury, 2) to determine if successful engraftment of alveolar epithelial progenitor cells to the alveolar epithelium will hasten recovery from bleomycin-induced acute lung injury, and 3) to determine if donor type II cells transfected to be more resistant to bleomycin toxicity, i.e. "super type II cells", engraft more successfully and promote more rapid recovery than normal type II cells. If successful, this model of alveolar tissuegenesis will represent a highly novel therapeutic approach in repair of diffuse alveolar damage during acute lung injury.