The role of interstitial lung macrophages in the early diagnosis and treatment of chronic obstructive pulmonary disease

• Applicant: Dr. Theodore Kapellos
• Subject Area: Immunology ; General Genetics and Functional Genome Biology ; Pneumology, Thoracic Surgery
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 536665008

Chronic obstructive pulmonary disease (COPD) is a worldwide fatal disease and is characterized by small airway obstruction, alveolar wall damage and chronic inflammation. Lung macrophages orchestrate the observed pathophysiology via the imbalance in the secretion of pro-inflammatory mediators and defects in macrophage phagocytosis which result in irreversible immune cell recruitment and emphysema. Moreover, macrophage-derived reactive oxygen species predominate over endogenous antioxidant mechanisms and promote cellular senescence, mucous hypersecretion and contribute to the risk of acute exacerbations. In previous work, I investigated the functional changes in lung macrophage populations in bronchoalveolar lavage fluid from early-stage COPD patients. Single-cell transcriptomics revealed that lung macrophages are highly heterogeneous and comprise several cellular states. In COPD patients, an interstitial lung macrophage state exhibits enhanced degranulation and phagocytosis and is predicted to express protein biomarkers that are involved in blood immune cell mobilization and epithelial death. My preliminary data demonstrate that these interstitial macrophages are responsible for the lung injury in early COPD, suggesting that it could be an excellent biomarker for the early diagnosis of the disease, as well as a plausible therapeutic target. The current research project aims to extend the characterization of macrophage populations to severe-stage COPD and analyze the alveolar immune landscape in all severity stages of the disease. The interstitial lung macrophage population phenotype will be validated in bronchoscopy samples from early and severe-stage COPD with in vitro functional assays and its ligand-receptor communication patterns with other bronchoalveolar populations will be resolved with proteomics assays and state of the art computational algorithms. To better understand how interstitial macrophages are involved in lung injury, their localization in the lung tissue will be determined with cutting edge multiplexed immunofluorescence. Lastly, given their central role in COPD pathophysiology, this project will employ an in silico approach for interstitial macrophage-specific drug re-purposing. Database-deposited drug candidates that reverse interstitial macrophage inflammatory gene signatures in early COPD will be shortlisted as potential therapeutics. Their immunoregulatory effects will be validated in ex vivo macrophage cultures and immunocompetent organoids, as well as a murine model of smoke exposure. Ultimately, the project will explore the suitability of interstitial lung macrophage populations as cellular biomarkers for early diagnosis of COPD and will develop novel macrophage-based therapeutic concepts.

• DFG Programme: Research Grants