Mesenchymal Stem Cells for Treatment of Acute Lung Injury

间充质干细胞治疗急性肺损伤

• 批准号: 7667927
• 负责人: Jae Woo Lee
• 金额: $ 12.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-04 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7667927
• 关键词: Acute Lung Injury; Adult Respiratory Distress Syndrome; Advisory Committees; Air; Allogenic; Alveolar; Anti-Inflammatory Agents; Anti-inflammatory; Area; California; Cardiovascular system; Carrier Proteins; Cell Therapy; Critical Care; Edema; Endotoxins; Environmental air flow; Epithelial; Functional disorder; Genes; Genetic Transcription; Goals; Grant; Growth Factor; Hepatocyte Growth Factor; Human; In Vitro; Individual; Inflammatory; Inflammatory Response; Injury; Innovative Therapy; Interleukin-10; Lead; Liquid substance; Lung; Membrane Protein Traffic; Mesenchymal; Mesenchymal Stem Cells; Methods; Modeling; Molecular Biology; Multiple Abnormalities; Mus; Nature; Pathogenesis; Patients; Permeability; Plasmids; Preparation; Property; Proteins; Pulmonary Edema; Recombinant Proteins; Research; Research Institute; Research Personnel; Resolution; Role; San Francisco; Severities; Small Interfering RNA; Sodium; Stem cells; Stimulus; Testing; Therapeutic; Therapeutic Effect; Transfection; Translations; Type II Epithelial Receptor Cell; Universities; Whole Blood; anakinra; base; clinically relevant; cytokine; improved; in vitro Model; in vivo; injured; innovation; insight; keratinocyte; lung injury; monolayer; mortality; overexpression; paracrine; programs; public health relevance; response; skills

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.

描述（由申请人提供）：这是来自加州大学旧金山分校麻醉师 Jae-Woo Lee 医学博士的 K08 申请，他正在将自己定位为使用间充质干细胞 (MSC) 细胞疗法治疗急性肺损伤的研究人员。该申请将为李博士实现以下目标提供必要的支持：（1）开发两种创新且协同的人类急性肺损伤模型； （2）利用分子生物学方法来研究MSC的治疗作用的机制； (3) 使用转染过表达关键可溶性因子的质粒的 MSC 开发基于细胞的疗法。为了实现这些目标，李博士组建了一个科学咨询委员会，由加州大学旧金山分校心血管研究所的著名重症监护医生和急性肺损伤专家 Michael A. Matthay 博士担任主席。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。 在此应用中，Lee 博士将测试以下假设：在人类急性肺损伤的两种创新模型中，同种异体人类间充质干细胞将通过调节促炎反应以及上调保护性生长因子和抗炎细胞因子的释放来恢复肺泡液清除率并维持肺内皮通透性。 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-1ra））的能力，可以同时治疗多种异常。在目标 1 中，他将在具有气液界面的 Transwell 板中生长的人 II 型肺泡上皮细胞体外模型中确定人 MSC 对肺泡上皮液转运的机制影响，这些细胞受到细胞混合物的损伤，细胞混合物是 ALI 肺水肿液中发现的最具生物活性的细胞因子的混合物（IL-1f3、TNFa 和 IFNv）。 在目标 2 中，他将在离体灌注人肺制剂中建立内毒素损伤后，测试肺内滴注人 MSC 对肺泡上皮液清除率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进一步保护肺泡液清除率以及肺内皮和上皮对蛋白质的渗透性。这项 K08 拨款的支持将为李博士提供成为一名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高达 40%。目前的治疗选择仍然主要是支持肺保护性通气和液体保守策略。需要创新疗法。