Mechanisms of pulmonary landscape remodelling during resolution of inflammation

• Applicant: Professor Dr. Alexander Zarbock
• Subject Area: Anaesthesiology
• Term: since 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 398555373

Clearance of bacterial pathogens by immune cells is crucially needed to maintain organ homeostasis. Nonetheless, such inflammatory reaction must be controlled and limited to prevent tissue damage. In the lung, platelets actively participate in both the onset and the resolution of bacterially triggered pulmonary inflammation. Non-resolving inflammation is linked to organ fibrosis and impaired long-term organ function in the lung. Lung fibrosis has recently been described to rely on specific macrophage subsets, but their involvement in models of bacterially triggered inflammation remains unclear. Our group could previously demonstrate that platelets affect alveolar macrophages during resolution of pulmonary inflammation, but impact of platelets on pulmonary interstitial landscape is so far unclear. To define the impact of platelets on pulmonary landscape recomposition, we will now analyze in detail the molecular mechanisms of platelet-dependent macrophage-phenotype switches in lung interstitium. In addition, we will investigate the impact of macrophage and T-cell subsets on organ fibrosis following bacterial infections of the lung. Finally, to understand translational aspects of our work, we will assess presence and involvement of pulmonary platelets and macrophages during inflammation and resolution in humans. Using translational genetic knockout models derived from the obtained data, we will then demonstrate the disease relevance and possible therapeutic implications. This proposal therefore consists of three central aims in which we will investigate: 1) Changes of the pulmonary interstitial macrophage landscape following bacterial infection and functional consequences of such. 2) The origin, presence and phenotypic priming of distinct pro- and anti-resolution interstitial macrophage subsets by indirect and direct platelet-dependent processes. 3) Presence, cellular interplay and involvement of platelets and macrophages during inflammation and resolution in human ARDS patients.

• DFG Programme: Research Grants