Molecular control of lung endothelial barrier function in ALI

ALI 中肺内皮屏障功能的分子控制

• 批准号: 9916818
• 负责人: Konstantin Birukov
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9916818
• 关键词: Acute; Acute Lung Injury; Adherens Junction; Adult Respiratory Distress Syndrome; Agonist; Animals; Anti-Inflammatory Agents; Antibiotic Therapy; Antiinflammatory Effect; Attenuated; Bacteria; Blood Vessels; Blood gas; CD47 gene; Clinical; Coagulation Process; Complex; Concentration Camps; Cyclic AMP; Deposition; Development; Disease; Endothelial Cells; Endothelium; Enzymes; Exposure to; FDA approved; Fibrin; Fibrinogen; Functional disorder; Funding; Homeostasis; ITGA5 gene; Impairment; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Integrin alpha5beta1; Intercellular Junctions; Investigation; Knowledge; Lead; Life; Link; Lung; Lung Inflammation; Maintenance; Mediating; Mediation; Modeling; Molecular; Pathologic; Pathology; Permeability; Pharmacology; Phase; Phosphodiesterase Inhibitors; Pilot Projects; Plasma; Pre-Clinical Model; Process; Prostaglandins I; Pulmonary Circulation; Pulmonary Edema; Recovery; Role; Scheme; Severities; Signal Transduction; Signaling Protein; Staphylococcus aureus; Structure; Syndrome; System; Therapeutic; Time; Vascular Endothelial Cell; Vascular Endothelium; adhesion receptor; analog; base; endothelial dysfunction; in vivo; in vivo Model; injury recovery; integrin-linked kinase; knock-down; lung development; lung injury; monolayer; mortality; particle; pathogen; pathogenic bacteria; paxillin; phosphodiesterase IV; phosphoric diester hydrolase; prognostic tool; protective effect; protein complex; recruit; restoration; septic; synergism; vascular endothelial dysfunction; vascular inflammation

PROJECT SUMMARY ALI/ARDS is a serious condition with high mortality rates, and more complete understanding of pathologic mechanisms mediating lung vascular inflammation and barrier dysfunction in ARDS is critical for development of efficient therapeutic approaches to confront this devastating disease. Previous studies by our and other groups revealed pronounced anti-inflammatory and barrier enhancing effects of cyclic AMP elevating agonists on pulmonary vascular endothelium, which accelerated ALI recovery. Endogenous cAMP levels also appear to be critical for the maintenance of endothelial cell anti-inflammatory status and barrier function. However, septic and ALI conditions lead to impairment of cAMP homeostasis, which may contribute to severity of endothelial dysfunction and lung injury in ARDS. The importance of this mechanism is supported by beneficial effects of pharmacological inhibition of cAMP hydrolyzing enzyme, phosphodiesterase (PDE) in preclinical models of septic ALI. Despite these encouraging results, precise molecular mechanisms of PDE activation in inflammatory conditions still remain to be elucidated. Coagulation and inflammation are activated by the same types of challenges and correlate both temporally and spatially in different pathologies, but mechanistic interactions between these two processes are incompletely understood. Fibrinogen is a key component of the coagulation system. Increased levels of fibrinogen and fibrin deposition are distinctive features of advanced ALI and septic syndromes. Fibrinogen directly interacts with α5β1 integrin adhesion receptor expressed by pulmonary endothelial cells. Our exciting pilot studies show that this interaction may augment EC inflammation and barrier dysfunction caused by bacterial pathogens via recruitment of PDE4 to the α5-integrin associated signaling protein complex. This proposal will investigate for the first time the molecular mechanism of synergy between ARDS-relevant coagulation component fibrinogen and lung EC inflammation caused by bacterial particles. Aim-1 will employ in vitro and in vivo models of ALI caused by Gram-positive bacterial particles to evaluate fibrinogen role in lung vascular endothelial dysfunction and severity of lung injury. Aim-2 will investigate assembly and activation of α5-integrin-ILK-paxillin signalosome and evaluate its role in the mediation of fibrinogen-induced exacerbation of endothelial dysfunction and lung inflammation. Aim-3 will study targeting of PDE4 to fibrinogen-activated α5-integrin-ILK-paxillin signalosome and its significance for PDE4- dependent suppression of intracellular cAMP and augmentation of HKSA-induced ALI.

项目摘要 急性肺损伤/急性呼吸窘迫综合征是一种严重的疾病，死亡率高， 在ARDS中，介导肺血管炎症和屏障功能障碍的机制对于发展至关重要 有效的治疗方法来对抗这种毁灭性的疾病。我们和其他人以前的研究 组显示出环AMP升高激动剂的显著抗炎和屏障增强作用， 对肺血管内皮细胞有明显的抑制作用，加速了ALI的恢复。内源性cAMP水平似乎也 对维持内皮细胞抗炎状态和屏障功能至关重要。然而，败血症 和ALI条件导致cAMP稳态受损，这可能有助于内皮细胞损伤的严重性。 功能障碍和肺损伤。这一机制的重要性得到以下有益效果的支持： cAMP水解酶磷酸二酯酶（PDE）的药理学抑制作用， 脓毒性急性肺损伤尽管有这些令人鼓舞的结果，PDE激活的精确分子机制， 炎性病症仍有待阐明。 凝血和炎症是由相同类型的挑战激活的，并且两者都相互关联。 在不同的病理中，时间和空间上，但这两个过程之间的机械相互作用， 不完全理解。纤维蛋白原是凝血系统的关键成分。增加水平的 纤维蛋白原和纤维蛋白沉积是晚期ALI和脓毒性综合征的显著特征。蛋白原 直接与肺内皮细胞表达的α5β1整合素粘附受体相互作用。整理的丰厚 初步研究表明，这种相互作用可能会增加EC炎症和屏障功能障碍， 通过将PDE 4募集到α5-整联蛋白相关信号蛋白复合物来对抗细菌病原体。这 该提案将首次研究ARDS相关药物之间协同作用的分子机制。 凝血成分纤维蛋白原和细菌颗粒引起的肺EC炎症。 Aim-1将采用革兰氏阳性细菌颗粒引起的ALI的体外和体内模型， 评估纤维蛋白原在肺血管内皮功能障碍和肺损伤严重程度中的作用。Aim-2将 研究α5-整合素-ILK-桩蛋白信号体的组装和激活，并评估其在细胞凋亡中的作用。 调解纤维蛋白原诱导的内皮功能障碍和肺部炎症的恶化。Aim-3将研究 PDE 4对纤维蛋白原激活的α5-整合素-ILK-桩蛋白信号体的靶向作用及其对PDE 4-的意义 依赖性抑制细胞内cAMP和增加HKSA诱导的ALI。

项目成果

Tuning endothelial monolayer adhesion: a neutron reflectivity study.

调节内皮单层粘附：中子反射率研究。

• DOI: 10.1152/ajplung.00160.2013
• 发表时间: 2014
• 期刊: American journal of physiology. Lung cellular and molecular physiology
• 作者: Pocivavsek,Luka;Junghans,Ann;Zebda,Noureddine;Birukov,Konstantin;Majewski,Jaroslaw
• 通讯作者: Majewski,Jaroslaw