Protective activity of the lectin-like domain of TNF in permeability edema

TNF 凝集素样结构域对通透性水肿的保护活性

• 批准号: 8487430
• 负责人: Rudolf Lucas
• 金额: $ 35.34万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8487430
• 关键词: 5 year old; Affect; Affinity Chromatography; Agonist; Alveolar; Antibiotic Therapy; Arginine; Bacterial Infections; Bacterial Pneumonia; Bacterial exotoxin; Cause of Death; Cells; Cessation of life; Child; Cholesterol; Complication; Data; Development; Disease; Down-Regulation; Edema; Elderly; Enzyme Uncoupling; Enzymes; Epithelial; Epithelial Cells; Event; Exotoxins; Functional disorder; Generations; Goals; Human; In Vitro; Infection; Influenza A virus; Knock-in Mouse; Lead; Lectin; Life; Liquid substance; Listeria monocytogenes; Listeria monocytogenes hlyA protein; Lung; Mediating; Membrane; Mus; NADPH Oxidase; Patients; Peptide N-glycohydrolase F; Peptides; Permeability; Phosphorylation; Play; Pneumonia; Production; Protein Kinase C; Research; Role; Secondary to; Small Interfering RNA; Sodium; Sodium Channel; Sterility; Streptococcus pneumoniae; Streptococcus pneumoniae plY protein; TNF gene; Testing; Tissues; Toxin; Vascular Permeabilities; Virulence Factors; Virus Diseases; Wild Type Mouse; aged; arginase; base; combat; epithelial Na+ channel; improved; in vivo; inhibitor/antagonist; mortality; mouse model; mutant; novel therapeutic intervention; novel therapeutics; patch clamp; programs; protein expression; public health relevance; rhoA GTP-Binding Protein; uptake

DESCRIPTION (provided by applicant): Severe pneumonia is the leading single cause of mortality in children aged less than five years worldwide and the sixth leading cause of death in seniors over age 65 in the US. Streptococcus pneumoniae represents the main etiological agent of the disease. Moreover, mortality after influenza A virus (IAV) infection has been suggested to be mainly due to secondary pneumoccocal infections. Intriguingly, death in pneumococcal-induced pneumonia can occur days after initiation of antibiotic therapy, when tissues are sterile and the pneumonia is clearing. This mortality correlates with the presence of pneumococcal virulence factors, the most important one of which is the pore-forming toxin pneumolysin (PLY). A major complication of severe pneumonia is permeability edema, characterized by a dramatically increased pulmonary endothelial hyperpermeability and an impaired alveolar liquid clearance (ALC). The enzyme PKC-(, which is activated by PLY-mediated Ca2+ influx, has recently been suggested to be implicated in the downregulation of the epithelial sodium channel (ENaC) expression, as well as in endothelial barrier dysfunction. Our preliminary data demonstrate that the lectin-like domain of TNF, mimicked by the TIP peptide, is able to blunt PLY-induced PKC-( activation, endothelial hyperpermeability and ALC dysfunction. Our overall hypothesis is that the lectin-like domain of TNF restores alveolar liquid clearance and improves barrier integrity during G+-infection- associated pneumonia, by means of blunting exotoxin-mediated PKC-( activation. We will test three specific aims to this purpose. First, we will unravel the mechanism by which the TIP peptide restores epithelial sodium channel activity and expression in PLY-treated alveolar epithelial cells. Second, we will determine at which step(s) in the cascade of events leading to PLY-induced endothelial dysfunction, the TIP peptide intervenes and what is the most upstream event affected by the peptide. Third, we will test the hypothesis that the lectin-like domain of TNF restores ALC and preserves pulmonary endothelial barrier integrity in PLY-treated mice, upon blunting PKC-( activation, making use of Triple mTNF knock-in mice, expressing a lectin-deficient mutant of TNF. The results of this research program can thus provide important information about mechanisms leading to permeability edema and dysfunctional ALC during bacterial pneumonia and can thus lead to the identification of novel therapeutic strategies.

描述(申请人提供)：严重肺炎是全球五岁以下儿童死亡的主要单一原因，也是美国65岁以上老年人死亡的第六大原因。肺炎链球菌是该病的主要病原体。此外，甲型流感病毒(IAV)感染后的死亡被认为主要是由于继发性肺炎肺炎感染。有趣的是，肺炎球菌引起的肺炎的死亡可能发生在抗生素治疗开始几天后，此时组织是无菌的，肺炎正在消失。这种死亡率与肺炎球菌毒力因子的存在有关，其中最重要的是致孔毒素肺炎溶血素(PLY)。重症肺炎的一个主要并发症是通透性水肿，其特征是肺内皮细胞高通透性显著增加和肺泡液体清除(ALC)受损。由PLY介导的钙内流激活的酶PKC-()最近被认为与上皮钠通道(ENaC)表达下调有关，也与内皮屏障功能障碍有关。我们的初步数据表明，TIP多肽模拟的肿瘤坏死因子的凝集素样域能够钝化PLY诱导的PKC-(激活、内皮高通透性和ALC功能障碍)。我们的总体假设是，在G+感染相关性肺炎期间，肿瘤坏死因子的凝集素样域通过钝化外毒素介导的PKC-()激活，恢复肺泡液体清除并改善屏障完整性。为此，我们将测试三个具体目标。首先，我们将揭示TIP肽在PLY处理的肺泡上皮细胞中恢复上皮钠通道活性和表达的机制。其次，我们将确定在导致PLE诱导的内皮功能障碍的级联事件中的哪一步(S)，TIP肽参与其中，以及受TIP肽影响最上游的事件是什么。第三，我们将测试假设，即在PLY处理的小鼠中，肿瘤坏死因子的凝集素样域可以恢复ALC并保护肺内皮屏障的完整性，通过钝化PKC-(利用三重mtnf敲入小鼠，表达凝集素缺乏的肿瘤坏死因子突变体)。因此，该研究项目的结果可以为细菌性肺炎期间导致通透性、水肿和ALC功能障碍的机制提供重要信息，从而有助于确定新的治疗策略。

项目成果

Alpha7 nicotinic receptors as novel therapeutic targets for inflammation-based diseases.

α7烟碱受体是基于炎症疾病的新型治疗靶标。

• DOI: 10.1007/s00018-010-0525-1
• 发表时间: 2011-03
• 期刊: CELLULAR AND MOLECULAR LIFE SCIENCES
• 影响因子: 8
• 作者: Bencherif, Merouane;Lippiello, Patrick M.;Lucas, Rudolf;Marrero, Mario B.
• 通讯作者: Marrero, Mario B.

A FIM study to assess safety and exposure of inhaled single doses of AP301-A specific ENaC channel activator for the treatment of acute lung injury.

• DOI: 10.1002/jcph.203
• 发表时间: 2014-03
• 期刊: JOURNAL OF CLINICAL PHARMACOLOGY
• 影响因子: 2.9
• 作者: Schwameis, Richard;Eder, Sandra;Pietschmann, Helmut;Fischer, Bernhard;Mascher, Hermann;Tzotzos, Susan;Fischer, Hendrik;Lucas, Rudolf;Zeitlinger, Markus;Hermann, Robert
• 通讯作者: Hermann, Robert