Mesenchymal Stem Cells for Treatment of Acute Lung Injury

描述（由申请人提供）：这是一份K 08申请，申请人是加州大学旧金山分校弗朗西斯科的麻醉师Jae-Woo Lee，医学博士，他正在将自己确立为使用间充质干细胞（MSC）进行基于细胞的治疗以治疗急性肺损伤的研究者。该申请将为Lee博士提供必要的支持，以实现以下目标：（1）开发两种创新和协同的人类急性肺损伤模型;（2）获得分子生物学方法的专业知识，以研究MSC治疗作用的机制;以及（3）使用过表达关键可溶性因子的质粒转染的MSC开发基于细胞的治疗。为了实现这些目标，李博士成立了一个科学咨询委员会，由Michael A.他是加州大学旧金山分校心血管研究所著名的重症监护医生和急性肺损伤专家。在补助金结束时，李博士将成为一名独立的研究人员，专注于急性肺损伤领域的转化重症监护研究。 在本申请中，Lee博士将在两种人类急性肺损伤的创新模型中，通过调节促炎反应和上调保护性生长因子和抗炎细胞因子的释放来测试同种异体人间充质干细胞将恢复肺泡液体清除率并维持肺内皮通透性的假设。MSC，由于其多能性和分泌多种旁分泌因子如生长因子（KGF，HGF）和抗炎细胞因子（IL-10，IL-1 ra）的能力，可以同时治疗多种异常。在目标1中，他将确定人MSC对在Transwell板中生长的人肺泡上皮II型细胞的体外模型中肺泡上皮液体转运的机械作用，所述细胞具有被cytomix损伤的气-液界面，cytomix是在ALI肺水肿液中发现的最具生物活性的细胞因子（IL-1f 3，TNF α和IFN γ）的混合物。 在目标2中，他将测试在离体灌注的人肺制备物中建立内毒素损伤后肺内滴注人MSC对肺泡上皮液体清除和肺内皮通透性的治疗效果。在目标3中，他将确定用过表达关键可溶性因子的质粒转染同种异体人MSC是否会在两种人肺损伤模型中的肺泡液清除率和肺内皮和上皮对蛋白质的渗透性方面产生进一步的保护。从这个K 08赠款的支持将提供李博士成为一个成功的独立调查员所需的技能。 公共卫生相关性：尽管对病理生理学进行了广泛的研究，但急性呼吸窘迫综合征的死亡率仍为40%。目前的治疗选择仍然主要支持肺保护性通气和液体保守策略。需要创新疗法。

DESCRIPTION (provided by applicant): This is a K08 application from Jae-Woo Lee, MD, an anesthesiologist at the University of California, San Francisco, who is establishing himself as an investigator in the use of cell-based therapy with mesenchymal stem cells (MSC) for treatment of acute lung injury. This application will provide Dr. Lee with the support necessary to accomplish the following goals: (1) develop two innovative and synergistic human acute lung injury models; (2) obtain expertise with molecular biology methods to study the mechanism underlying the therapeutic effect of MSC; and (3) develop cell-based therapy with MSC transfected with plasmids overexpressing key soluble factors. To achieve these goals, Dr. Lee has assembled a Scientific Advisory Committee chaired by Dr. Michael A. Matthay, a renowned intensivist and expert in acute lung injury within the Cardiovascular Research Institute at UCSF. By the end of the grant, Dr. Lee will become an independent investigator focused on translational critical care research in the area of acute lung injury. In this application, Dr. Lee will test the hypothesis that allogeneic human mesenchymal stem cells will restore alveolar fluid clearance and maintain lung endothelial permeability by modulating the proinflammatory response and by up-regulating the release of protective growth factors and anti-inflammatory cytokines in two innovative models of human acute lung injury. MSC, due to its pluripotent nature and its ability to secrete multiple paracrine factors such as growth factors (KGF, HGF) and anti-inflammatory cytokines (IL-10, IL-1ra) can treat multiple abnormalities simultaneously. In Aim 1, he will determine the mechanistic effects of human MSC on alveolar epithelial fluid transport in an in vitro model of human alveolar epithelial type II cells grown in Transwell plates with an air-liquid interface that are injured by cytomix, a mixture of the most biologically active cytokines found in ALI pulmonary edema fluid (IL-1f3, TNFa and IFNv). In Aim 2, he will test the therapeutic effect of intrapulmonary instillation of human MSC on alveolar epithelial fluid clearance and lung endothelial permeability after the establishment of endotoxin injury in an ex vivo perfused human lung preparation. In Aim 3, he will determine if transfection of allogeneic human MSC with plasmids over-expressing key soluble factors will lead to further protection in terms of alveolar fluid clearance and lung endothelial and epithelial permeability to protein in both human lung injury models. The support from this K08 grant will provide Dr. Lee with the necessary skills to become a successful independent investigator. Public Health Relevance: Despite extensive research into the pathophysiology, mortality from acute respiratory distress syndrome remains at 40%. Current treatment options remain primarily supportive with lung protective ventilation and fluid conservative strategy. Innovative therapies are needed.