Are pulmonary GABA-receptors the key for the therapy of acute pulmonary inflammation and does the link with the adenosine A2B-receptor represent the first step towards personalized medicine?

肺部 GABA 受体是治疗急性肺部炎症的关键吗？与腺苷 A2B 受体的联系是否代表着个体化医疗的第一步？

• 批准号: 398748271
• 负责人: Professorin Dr. Franziska M. Konrad
• 金额: --
• 依托单位: Klinik für Anaesthesiologie und Intensivmedizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/398748271?language=en
• 关键词: pulmonary; GABA; receptors; key; therapy

Despite decades of research, acute pulmonary inflammation (Acute Respiratory Distress Syndrom; ARDS) is still a frightened complication on intensive care units with a high mortality. The central pathomechanism in terms of pulmonary inflammation is the excessive infiltration of polymorphonuclear neutrophils (PMNs). Despite the identification of chemokine- and adenosine-receptors as key-player in terms of regulation the migration of PMNs into the lung, the detailed mechanisms still remain elusive. Therapeutic options are limited and, to date, a specific anti-inflammatory therapy does not exist. Therefore, the main focus of pulmonary inflammation research is based on the recommendation to identify subgroups of patients for a specific personalized treatment. GABA-receptors are the main inhibitory receptors in the central nervous system. Additionally, they were associated with a pivotal role in terms of central inflammation. Actual research demonstrated now, that the pulmonary epithelium expresses these GABA-receptors and secrets GABA. Present studies indicate anti-inflammatory effects of these pulmonary GABA-receptors, which are in the focus of the presented proposal and will be investigated in detail by using specific GABA-agonist/antagonist. By using a particular flowcytometry-based method, we are planning to investigate the influence of the specific GABA-receptor-agonists/antagonists on the migration of PMNs into the three compartments of the lung (attached to the endothelium, interstitial, alveolar space). These pulmonary GABA-receptors represent a new promising target in the therapy of acute pulmonary inflammation. At the same time, actual research links the mode of action of GABA-receptors with adenosine-receptors. Within the lung, the adenosine A2B-receptors plays a detrimental role in terms of inflammation. Preliminary work of the applicant detected a link between the pulmonary GABA-receptors and the A2B-receptor. This connection allows an identification of patient subgroups, where a treatment with a specific GABA-agonist would be successful. Patients on intensive care units who are particularly in risk for developing pulmonary inflammation, have sometimes altered expressions of adenosine-receptors. Therefore, the expression of the A2B-receptor should be investigated first, to define if a treatment with specific GABA-agonists would be suitable for the patient. Concordantly, the findings of this proposal represent a major step towards personalized therapy in acute pulmonary inflammation.

尽管经过几十年的研究，急性肺部炎症（急性呼吸窘迫综合征; ARDS）仍然是重症监护病房的一个可怕的并发症，死亡率很高。肺部炎症的中心病理机制是多形核中性粒细胞（PMNs）的过度浸润。尽管趋化因子受体和腺苷受体在调节中性粒细胞向肺内迁移中起着关键作用，但其详细机制仍不清楚。治疗选择是有限的，迄今为止，具体的抗炎治疗不存在。因此，肺部炎症研究的主要重点是根据建议确定特定个性化治疗的患者亚组。GABA受体是中枢神经系统中的主要抑制性受体。此外，它们与中枢炎症方面的关键作用有关。现在实际的研究表明，肺上皮细胞表达这些GABA受体并分泌GABA。目前的研究表明，这些肺GABA受体，这是在所提出的建议的重点，并将通过使用特定的GABA激动剂/拮抗剂进行详细研究的抗炎作用。通过使用特定的基于流式细胞术的方法，我们计划研究特定GABA受体激动剂/拮抗剂对PMN迁移到肺的三个隔室（附着于内皮、间质、肺泡空间）的影响。这些肺GABA受体代表了急性肺部炎症治疗的新的有前途的目标。同时，实际研究将GABA受体的作用模式与腺苷受体联系起来。在肺内，腺苷A2 B受体在炎症方面发挥着有害作用。申请人的初步工作检测到肺GABA受体和A2 B受体之间的联系。这种联系允许识别患者亚组，其中使用特定GABA激动剂的治疗将是成功的。重症监护病房的患者特别容易发生肺部炎症，有时腺苷受体的表达会改变。因此，应首先研究A2 B受体的表达，以确定用特异性GABA激动剂治疗是否适合患者。一致地，该提案的发现代表了急性肺部炎症个性化治疗的重要一步。