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?

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种可怕的并发症，死亡率很高。肺部炎症的中心病理机制是中性粒细胞(PMN)的过度渗透。尽管趋化因子和腺苷受体被认为是调节中性粒细胞向肺内迁移的关键因素，但详细的机制仍然不清楚。治疗选择有限，而且到目前为止，还不存在特定的抗炎疗法。因此，肺部炎症研究的主要重点是根据建议确定患者亚组进行特定的个性化治疗。GABA受体是中枢神经系统的主要抑制性受体。此外，它们还与中枢炎症的关键作用有关。现在的实际研究表明，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受体的抗炎作用，这是提出的建议的重点，并将通过使用特定的GABA激动剂/拮抗剂详细研究。通过一种特殊的基于流式细胞术的方法，我们计划研究特定的GABA受体激动剂/拮抗剂对中性粒细胞迁移到肺的三个部分(附着于内皮、间质和肺泡腔)的影响。这些肺内GABA受体是治疗急性肺部炎症的新靶点。与此同时，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A2B受体在炎症方面起着有害的作用。申请人的初步工作发现了肺GABA受体和A2B受体之间的联系。这种联系允许识别患者亚群，在那里用特定的GABA激动剂治疗会成功。重症监护病房的患者特别容易发生肺部炎症，有时会改变腺苷受体的表达。因此，首先应该研究A2B受体的表达，以确定特定的GABA激动剂是否适合患者。一致地，这项建议的发现代表着朝着急性肺部炎症的个性化治疗迈出了重要的一步。

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.