Cytotoxic lymphocytes in acute lung injury

急性肺损伤中的细胞毒性淋巴细胞

基本信息

批准号：
7339309
负责人：
Mitzi Nagarkatti
金额：
$ 29.72万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-03-15 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7339309
关键词：
Abbreviations Acute Acute Lung Injury Address Adoptive Transfer Adult Respiratory Distress Syndrome Affect Alveolar Antibodies Bacteremia Bacterial Toxins Binding Biological Products Biological Warfare Blood Transfusion Blood Vessels Blood capillaries Bone Marrow CD44 gene CD8B1 gene Cells Cellular Infiltration Centers for Disease Control and Prevention (U.S.)Chimera organism Chimeric Proteins Clinical Condition Cytolysis Cytotoxic T-Lymphocytes Disease Edema Endothelial Cells Epithelial Cells Exhibits Exons Exotoxins Functional disorder Green Fluorescent Proteins Hyaluronic Acid Immune Incidence Infiltration Inflammation Inflammatory Injury Interferon Type II Interleukin-2 Investigation Knockout Mice Lead Ligands Lung Lymphocyte Lymphokine-Activated Killer Cells Mediating Modeling Morbidity - disease rate Mus Natural Killer Cells Nature Newborn Respiratory Distress Syndrome Pancreatitis Pathologic Processes Patients Peptides Personal Satisfaction Play Pneumonia Production Protein Binding Protein Isoforms Public Health Pulmonary Edema Pulmonary aspiration of gastric contents RNA Splicing Range Rate Resistance Respiratory Failure Role Sepsis Small Interfering RNA Specificity Standards of Weights and Measures Staphylococcal Enterotoxin B Superantigens Syndrome T-Cell Receptor T-Lymphocyte Technology Testing Trauma Tumor Necrosis Factor-alpha Up-Regulation Variant Wild Type Mouse base biodefense capillary cell injury cytokine cytotoxic cytotoxicity human TNF protein hyaluronate in vivo inhibitor/antagonist insight killings lung injury mimetics mortality mouse model novel novel strategies prevent pulmonary function smoke inhalation staphylococcal enterotoxin

项目摘要

DESCRIPTION (provided by applicant): Acute lung injury (ALI) is characterized by pulmonary cellular infiltration and edema resulting from endothelial cell (EndoC) and epithelial cell (EpiC) injury, the mechanism of which remains unclear. ALI can also lead to acute respiratory distress syndrome (ARDS), which is often lethal. It occurs in several disorders affecting ~150,000 patients per year in US with a mortality rate of ~50%. One of the common features of ALI is the inflammation in the lungs and the production of cytokines. In the current investigation, we will use a mouse model of superantigen such as staphylococcal enterotoxin-induced ALI to delineate the immunopathogenesis mechanisms involved. Staphylococcal enterotoxins and other related exotoxins have been classified by the Center for Disease Control as potential biological warfare agents. It is well established that staphylococcal enterotoxins activate a large percentage of T cells expressing an invariant T cell receptor. Preliminary studies from our lab have demonstrated that staphylococcal enterotoxin B (SEB) treatment of mice led to marked upregulation of CD44 expression on lymphocytes, which migrate to the lungs and cause vascular leak by using CD44 as an effector molecule. We have shown that CD44 knock out (KO) mice are more resistant to SEB-induced pulmonary damage and furthermore, treatment of CD44 wild-type (WT) mice with antibodies against CD44 can effectively block SEB-mediated pulmonary injury. SEB treatment led to induction of IL-2, IFN-gamma and TNF-alpha production and increased NK and NKT cell infiltration in the lungs. Based on this, we will test the central hypothesis that SEB-mediated CD44 expression on cytolytic lymphocytes plays a critical role in lung injury. The specific aims of the current study are as follows: 1) To examine the role of SEB-reactive T cells, cytotoxic T cells, NK cells and NKT cells in CD44WT and CD44KO mice in induction of vascular leak and ALI. 2) CD44 bone marrow chimeras will be used to address the role of CD44 expression on cytotoxic lymphocytes, pulmonary EndoC and EpiC in SEB-induced ALI. 3) To determine the CD44 isoforms involved in lung injury by using siRNA technology 4) The role of CD44v6 and v7 isoforms in lung injury will be determined by using specific exon knockout mice 5) To develop strategies to prevent or treat lung injury using mimetics of CD44 or its ligand. Understanding the mechanism by which cytolytic lymphocytes cause alveolar EndoC and EpiC injury would help in developing novel strategies which could serve as potential biodefense against acute lung injury caused by bacterial toxins.

描述（申请人提供）：急性肺损伤（ALI）的特点是内皮细胞（EndoC）和上皮细胞（EpiC）损伤导致肺细胞浸润和水肿，其机制尚不清楚。 ALI 还会导致急性呼吸窘迫综合征 (ARDS)，这通常是致命的。在美国，这种疾病每年影响约 150,000 名患者，死亡率约 50%。 ALI 的共同特征之一是肺部炎症和细胞因子的产生。在当前的研究中，我们将使用超级抗原（例如葡萄球菌肠毒素诱导的 ALI）的小鼠模型来描述所涉及的免疫发病机制。葡萄球菌肠毒素和其他相关外毒素已被疾病控制中心列为潜在的生物战剂。众所周知，葡萄球菌肠毒素可激活大部分表达不变 T 细胞受体的 T 细胞。我们实验室的初步研究表明，对小鼠进行葡萄球菌肠毒素 B (SEB) 治疗后，淋巴细胞上 CD44 的表达显着上调，淋巴细胞迁移至肺部，并通过使用 CD44 作为效应分子引起血管渗漏。我们已经证明，CD44 敲除（KO）小鼠对 SEB 诱导的肺损伤具有更强的抵抗力，此外，用抗 CD44 抗体治疗 CD44 野生型（WT）小鼠可以有效阻止 SEB 介导的肺损伤。 SEB 治疗可诱导 IL-2、IFN-γ 和 TNF-α 的产生，并增加肺部 NK 和 NKT 细胞的浸润。基于此，我们将检验中心假设，即 SEB 介导的溶细胞淋巴细胞上的 CD44 表达在肺损伤中发挥关键作用。本研究的具体目的如下：1）研究CD44WT和CD44KO小鼠中SEB反应性T细胞、细胞毒性T细胞、NK细胞和NKT细胞在诱导血管渗漏和ALI中的作用。 2) CD44骨髓嵌合体将用于研究CD44表达对细胞毒性淋巴细胞、肺EndoC和EpiC在SEB诱导的ALI中的作用。 3) 使用 siRNA 技术确定参与肺损伤的 CD44 亚型 4) 使用特定的外显子敲除小鼠确定 CD44v6 和 v7 亚型在肺损伤中的作用 5) 使用模拟物制定预防或治疗肺损伤的策略CD44或其配体。了解溶细胞淋巴细胞引起肺泡 EndoC 和 EpiC 损伤的机制将有助于开发新的策略，这些策略可以作为针对细菌毒素引起的急性肺损伤的潜在生物防御。