Defining the roles of adenosine, anesthetics, and selective integrin targeting during leukocyte and platelet activation -A basis for new therapeutic strategies aiming to treat systemic inflammation, ischemia-reperfusion injury and thrombosis
定义腺苷、麻醉剂和选择性整合素靶向在白细胞和血小板活化过程中的作用——旨在治疗全身炎症、缺血再灌注损伤和血栓形成的新治疗策略的基础
基本信息
- 批准号:242031561
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:德国
- 项目类别:Research Grants
- 财政年份:2013
- 资助国家:德国
- 起止时间:2012-12-31 至 2016-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
The systemic inflammatory response syndrome (SIRS) is a major cause of morbidity and mortality in intensive care medicine. During sepsis, SIRS is caused by infectious microorganisms. SIRS can also result from non-infectious causes such as extracorporeal circulation (ECC) in cardiac surgery or organ ischemia and reperfusion. During SIRS pro-inflammatory mediators induce the activation and interaction of leukocytes, platelets and endothelium. These cellular interactions are of central importance for the maintenance of SIRS and lead to life-threatening inflammatory organ failure. Leukocyte activation is associated with increases in expression and ligand affinity of adhesion molecules, including the Mac-1 integrin receptor. Mac-1 plays a central role in leukocyte adhesion to endothelium and platelets. In contrast, the ecto-apyrase CD39 plays a crucial role in generating the anti-inflammatory molecule adenosine, which inhibits leukocyte and platelet activation. The anesthetics sevoflurane and propofol also carry anti-inflammatory potential. These agents interact with cell surface molecules and probably activate adenosine receptors. In this study we will analyze mechanisms underlying the development of SIRS with the aim to establish new pharmacological treatment strategies. For this purpose, we have identified three promising approaches to increase anti-inflammatory effects, which we will test. Ex vivo we will induce leukocyte and platelet activation using physiological agonists and simulated ECC. In vivo we will employ a murine intravital microscopy model to study leukocyte-platelet-endothelium interaction during SIRS and will investigate leukocyte and platelet activation during ischemia and reperfusion of mouse myocardium and liver. Our three approaches include: Activation-specific blockade of Mac-1, activation of adenosine receptors, and increase of adenosine production. First, to define the role of Mac-1 in leukocyte and platelet interaction we will use a KO mouse strain and analyze the effect of the single chain antibody fragment MAN-1 on leukocyte and platelet interaction. MAN-1 selectively binds to the activated conformation of Mac-1 without affecting the overall function of Mac-1 in the immune system. Second, we will use sevoflurane and propofol to induce adenosine receptor activation and evaluate the effects of these anesthetics on leukocyte and platelet activation and look at different adenosine receptor KO mice. Third, we will employ a bivalent molecule, which carries the ecto-apyrase CD39 and is targeted against the activated platelet GP IIb/IIIa receptor. Using this approach, apyrase activity can be confined to sites of platelet-leukocyte interaction to remove the prothrombotic platelet agonist ADP and to produce the anti-inflammatory agent adenosine. Pharmacological advances to prevent leukocyte and platelet activation represent a novelty in the treatment of SIRS, as it represents a major step towards symptomatic treatment.
全身炎症反应综合征(SIRS)是重症监护医学中发病和死亡的主要原因。在败血症期间,SIRS由感染性微生物引起。SIRS也可由非感染性原因引起,例如心脏手术中的体外循环(ECC)或器官缺血和再灌注。在SIRS期间,促炎介质诱导白细胞、血小板和内皮的活化和相互作用。这些细胞相互作用对于维持SIRS至关重要,并导致危及生命的炎症性器官衰竭。白细胞活化与粘附分子(包括Mac-1整联蛋白受体)的表达和配体亲和力增加相关。Mac-1在白细胞与内皮和血小板的粘附中起核心作用。相比之下,胞外三磷酸腺苷双磷酸酶CD 39在产生抗炎分子腺苷方面发挥着至关重要的作用,从而抑制白细胞和血小板活化。麻醉剂七氟烷和丙泊酚也具有抗炎潜力。这些药物与细胞表面分子相互作用,并可能激活腺苷受体。在这项研究中,我们将分析SIRS的发展机制,旨在建立新的药物治疗策略。为此,我们确定了三种有前途的方法来增加抗炎作用,我们将对其进行测试。我们将使用生理激动剂和模拟ECC体外诱导白细胞和血小板活化。在体内,我们将采用小鼠活体显微镜模型来研究SIRS期间白细胞-血小板-内皮细胞的相互作用,并将研究小鼠心肌和肝脏缺血和再灌注期间白细胞和血小板的活化。我们的三种方法包括:Mac-1的激活特异性阻断,腺苷受体的激活和腺苷产量的增加。首先,为了确定Mac-1在白细胞和血小板相互作用中的作用,我们将使用KO小鼠品系并分析单链抗体片段MAN-1对白细胞和血小板相互作用的影响。MAN-1选择性地结合Mac-1的活化构象,而不影响Mac-1在免疫系统中的整体功能。其次,我们将使用七氟烷和丙泊酚诱导腺苷受体活化,并评估这些麻醉剂对白细胞和血小板活化的影响,并观察不同的腺苷受体KO小鼠。第三,我们将采用二价分子,其携带胞外腺苷三磷酸双磷酸酶CD 39并靶向活化的血小板GP IIb/IIIa受体。使用这种方法,腺苷三磷酸双磷酸酶活性可以被限制在血小板-白细胞相互作用的位点,以去除促血栓形成血小板激动剂ADP并产生抗炎剂腺苷。预防白细胞和血小板活化的药理学进展代表了SIRS治疗的新奇,因为它代表了对症治疗的重要一步。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Adenosine Receptor Adora2b Plays a Mechanistic Role in the Protective Effect of the Volatile Anesthetic Sevoflurane during Liver Ischemia/Reperfusion
- DOI:10.1097/aln.0000000000001234
- 发表时间:2016-09-01
- 期刊:
- 影响因子:8.8
- 作者:Granja, Tiago F.;Koehler, David;Straub, Andreas
- 通讯作者:Straub, Andreas
Inhibition of Neogenin Dampens Hepatic Ischemia-Reperfusion Injury
- DOI:10.1097/ccm.0000000000000485
- 发表时间:2014-09
- 期刊:
- 影响因子:8.8
- 作者:Martin Schlegel;T. Granja;S. Kaiser;Andreas Körner;J. Henes;K. König;A. Straub;P. Rosenberger;V. Mirakaj
- 通讯作者:Martin Schlegel;T. Granja;S. Kaiser;Andreas Körner;J. Henes;K. König;A. Straub;P. Rosenberger;V. Mirakaj
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Professor Dr. Andreas Straub其他文献
Professor Dr. Andreas Straub的其他文献
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{{ truncateString('Professor Dr. Andreas Straub', 18)}}的其他基金
Trombozytenprotektion und Entzündungshemmung an der extrakorporalen Zirkulation: Entwicklung eines Therapieansatzes für den Einsatz in der Herzchirurgie
体外循环中的血小板保护和抗炎作用:开发用于心脏手术的治疗方法
- 批准号:
114810129 - 财政年份:2009
- 资助金额:
-- - 项目类别:
Research Grants
Untersuchungen zum Mechanismus der hypothermie-induzierten Thrombozytenaktivierung und Entwicklung neuer pharmakologischer Strategien zur Vermeidung von thrombembolischen Komplikationen während herzchirurgischer Operationen unter Hypothermie
低温诱导血小板活化机制的研究及低温心脏手术中预防血栓栓塞并发症的新药理学策略的开发
- 批准号:
27091590 - 财政年份:2006
- 资助金额:
-- - 项目类别:
Research Fellowships
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