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?

• Applicant: Professorin Dr. Franziska M. Konrad
• Subject Area: Anaesthesiology
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 398748271

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.

• DFG Programme: Research Grants