Chronic obstructive pulmonary disease (COPD) is currently the third leading cause of death worldwide and displays high regional prevalence in several European cities. The disease manifests through progressive lung function decline from mild chronic obstructive lung disease to severe airflow obstruction and features chronic inflammation, alveolar wall damage and mucous cell hyperplasia as the major pathophysiological mechanisms. Mainly triggered by smoking, chronic exposure to air pollution and occupational gases, it is now clear that the environment has strong implications on the initiation of the disease, although genetic contributions are not completely ruled out.

Macrophages - The Lungs Army against Pathogenes

The lung immune system, and particularly tissue-resident macrophages, the most abundant immune cells in the human lung, are a common denominator of COPD pathogenesis. This immune population orchestrates the inflammatory responses in the small airways. Despite the central role of lung macrophages in COPD progression, we have a very limited understanding of their diversity and functions in COPD. The lung macrophage population comprises alveolar and interstitial macrophages.

This is why we want to a) unravel the diversity and localization of lung interstitial macrophages over COPD progression with scRNA-seq and cutting-edge imaging technologies, b) characterize and experimentally validate lung interstitial macrophage inflammatory responses in COPD with ex vivo functional assays and c) harness in silico models of candidate drug prediction to propose novel interstitial macrophage-specific therapeutic strategies for COPD.

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Changing the perspective - The importance of gender in COPD

Historically, men have had higher prevalence rates than women due to higher tobacco consumption. However, recent data from developing countries suggest that sex differences in COPD prevalence have flattened, with women experiencing more severe disease. As a result, our project will take sex into consideration in its experimental design and will enroll an equal number of male and female patients in the early and severe disease cohorts. Moreover, all macrophage immunophenotyping, tissue localization and lung organoid culture experiments will be conducted in both male and female specimens to allow conclusions about the effect of sex to be drawn.

Ultimately, this project will examine the suitability of lung interstitial macrophage populations as cellular targets for COPD and will identify druggable macrophage signaling pathways for therapeutic intervention.