Lung Fluid Balance and Mesenchymal Stem Cells

描述(由申请人提供)：由急性肺损伤引起的急性呼吸衰竭是一个主要的临床问题，具有相当高的死亡率和发病率。本提案的总体目标是测试间充质干细胞(MSC)细胞治疗对实验性急性肺损伤的治疗价值，以及在急性肺损伤中恢复正常肺液平衡的价值。目的1确定肺内和静脉注射间充质干细胞对临床相关的急性肺损伤小鼠模型肺水肿和存活的治疗作用。目的2将在目标1中研究的小鼠急性肺损伤所致肺水肿的临床相关模型中，评估MSC治疗有益效果的机制，特别是白介素1受体拮抗剂(IL-1ra)和白介素10的作用。目的研究同种异体人骨髓间充质干细胞在体外培养的人肺泡II型上皮细胞模型中恢复肺泡上皮液转运的治疗作用和机制。AIMS 1和AIMS 2中提出的研究将促进我们对MSCs减轻肺损伤和肺水肿的机制的理解，并促进我们对MSCs在小鼠急性肺损伤中的生物学作用的了解。目的3将通过使用极化的人肺泡上皮II型细胞的培养单层细胞和体外灌流的人肺制剂将这些发现翻译到人肺。这些实验的结果将有助于确定在急性肺损伤患者中测试MSCs是否合适。这项拟议的工作还将揭示MSC减轻急性肺损伤所致肺水肿的机制，这些见解将促进肺液平衡、肺水肿和急性肺损伤领域的研究。项目叙事。这项研究建议与急性肺损伤继发的肺水肿引起的急性呼吸衰竭的临床问题直接相关，急性肺损伤是美国发病率和死亡率的原因。该提案将测试使用细胞疗法治疗实验性急性肺损伤的新策略，包括肺损伤的小鼠模型，以及使用人类肺上皮细胞和脑死亡受试者完整的人类肺组织的创新模型。

DESCRIPTION (provided by applicant): Acute respiratory failure from acute lung injury is a major clinical problem with substantial mortality and morbidity. The overall objective of this proposal is to test the value of cell-based therapy with mesenchymal stem cells (MSC) for the treatment of experimental acute lung injury and restoring normal lung fluid balance in acute lung injury. Aim 1 is designed to determine the therapeutic effects of intrapulmonary and intravenous delivery of MSC on pulmonary edema and survival in clinically relevant mouse models of acute lung injury. Aim 2 will evaluate the mechanisms responsible for the beneficial effects of MSC treatment in the clinically relevant models of pulmonary edema from acute lung injury in mice studied in Aim 1, with a specific focus on the role of interleukin-1 receptor antagonist (IL-1ra) and interleukin-10. Aim 3 is designed to test the therapeutic and mechanistic effects of allogeneic human MSC on restoring alveolar epithelial fluid transport in an in vitro model of cultured human alveolar epithelial type II cells and in an ex vivo perfused human lung preparation. The proposed studies in Aims 1 and 2 will advance our understanding of the mechanisms by which MSCs reduce lung injury and pulmonary edema as well as advance our knowledge of the biology of MSCs in the setting of acute lung injury in mice. Aim 3 will translate these findings to the human lung by using cultured monolayers of polarized human alveolar epithelial type II cells and an ex vivo perfused human lung preparation. The results of these experiments will help make it possible to determine whether testing MSCs in patients with acute lung injury is appropriate. The proposed work will also uncover mechanisms by which MSC reduces pulmonary edema from acute lung injury, and these insights will advance the fields of lung fluid balance, pulmonary edema, and acute lung injury. PROJECT NARRATIVE. This research proposal has direct relevance to the clinical problem of acute respiratory failure from pulmonary edema secondary to acute lung injury, a cause of morbidity and mortality in the United States. The proposal will test novel strategies to use cell based therapy for the treatment of experimental acute lung injury including mouse models of lung injury as well as innovative models that use human lung epithelial cells and intact human lungs harvested from brain dead subjects.