Mesenchymal Stem Cells for Treatment of Acute Lung Injury

描述（由申请人提供）：这是一份来自Jae-Woo Lee医学博士的K08申请，他是加州大学旧金山分校的麻醉师，他正在研究利用间充质干细胞（MSC）治疗急性肺损伤的细胞疗法。该应用程序将为李博士提供必要的支持，以实现以下目标：(1)开发两个创新和协同的人类急性肺损伤模型；(2)利用分子生物学方法获取专业知识，研究MSC治疗效果的机制；(3)利用转染过表达关键可溶性因子的质粒的MSC开发基于细胞的治疗方法。为了实现这些目标，李博士组建了一个科学咨询委员会，由UCSF心血管研究所著名的重症医师和急性肺损伤专家Michael a . Matthay博士担任主席。在资助结束时，李博士将成为一名独立研究者，专注于急性肺损伤领域的转化重症监护研究。

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.