Lung Fluid Balance and Mesenchymal Stem Cells

描述（由申请人提供）：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基于细胞的间充质干细胞（MSC）治疗实验性急性肺损伤和恢复急性肺损伤正常肺液体平衡的价值。目的1是确定肺内和静脉内递送MSC对临床相关的急性肺损伤小鼠模型中肺水肿和存活的治疗效果。目的2将评估MSC治疗在目的1中研究的小鼠急性肺损伤肺水肿临床相关模型中的有益作用的机制，特别关注白细胞介素-1受体拮抗剂（IL-1 ra）和白细胞介素-10的作用。目的3旨在测试同种异体人MSC在培养的人肺泡上皮II型细胞的体外模型和离体灌注的人肺制剂中恢复肺泡上皮液体转运的治疗和机制作用。目的1和2中的拟议研究将促进我们对MSC减少肺损伤和肺水肿的机制的理解，并促进我们对小鼠急性肺损伤背景下MSC生物学的了解。目的3将通过使用极化的人肺泡上皮II型细胞的培养单层和离体灌注的人肺制剂将这些发现转化到人肺。这些实验的结果将有助于确定在急性肺损伤患者中测试MSC是否合适。拟议的工作还将揭示MSC减少急性肺损伤引起的肺水肿的机制，这些见解将推进肺液体平衡，肺水肿和急性肺损伤领域。项目叙述。本研究提案与继发于急性肺损伤的肺水肿引起的急性呼吸衰竭的临床问题直接相关，这是美国发病率和死亡率的一个原因。该提案将测试使用基于细胞的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肺上皮细胞和从脑死亡受试者中收获的完整人肺的创新模型。

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.