Lung Fibrosis . Epithelial Dysfunction . Human-Centered Disease Models 

Respiratory Research

Cellular and molecular mechanisms of inflammatory and fibrosing interstitial lung diseases (ILDs)

The core focus of our research group is to uncover the cellular and molecular drivers of chronic and fibrosing interstitial lung diseases (ILDs), with a primary emphasis on idiopathic pulmonary fibrosis (IPF) and sarcoidosis. We investigate how epithelial dysfunction, immune–mesenchymal crosstalk and aberrant tissue repair mechanisms contribute to disease initiation and progression in pulmonary fibrosis. While in sarcoidosis we are interested in multinucleated giant cell formation and how dysfunction phagosome maturation and TH17.1 cell contribute.

In IPF, our work has identified key players in this process, including alveolar macrophages (via CCL18 secretion) and reprogrammed airway basal epithelial cells (Fig.1). We also established the roles of alveolar macrophage–fibroblast signaling loops, as major contributors of the fibrotic microenvironment.

By integrating bronchoalveolar lavage (BAL) transcriptomics, single-cell analysis, spatial transcriptomics, proteomics and longitudinal clinical data, we identify molecular signatures and biomarkers that enhance our ability to stratify patients, predict disease progression, optimize therapeuthic intervention and/or transplant timing.

Innovative Human-Based Disease Modeling

To complement in vivo and in silico approaches, our group has pioneered the use of human precision-cut lung slices (PCLS) as a high-fidelity, ex vivo model of lung disease. A key innovation of our platform is the ability to maintain PCLS in culture for extended periods beyond 14 days and up to 42 days, enabling:

  • Dynamic tracking of fibrotic and immune responses over time.
  • Long-term therapeutic testing in a physiologically relevant human system.
  • Mechanistic studies of chronic disease processes in a multicellular human system that has clinical translatability.

This advancement positions PCLS as a powerful tool for drug screening, biomarker validation, mechanistic studies and personalized medicine.

Importantly, our PCLS work aligns with the FDA’s strategic roadmap to reduce animal testing, supporting the regulatory shift toward New Approach Methodologies (NAMs) that offer greater human relevance in preclinical safety and efficacy studies.

Broader Disease Focus: Sarcoidosis and COPD

Beyond IPF, our research extends to other chronic and inflammatory lung diseases, including:

  • Sarcoidosis, where we use scRNAseq, spatial transcriptomics and immunopathology to dissect granuloma-specific molecular niches. We are interested in multinucleated giant cell formation and how dysfunction phagosome maturation and C-type lectins are involved. Within a project (COMBAT-SARC) funded by the Ann Theodore Foundation we develop a new therapy based on CTL ligand coated nanoparticles inhibiting multinucleated giant cell formation.
  • Chronic Obstructive Pulmonary Disease (COPD), where we explore shared epithelial and immune mechanisms, focusing on airway remodeling and corticosteroid resistance.

Across all projects, our goal is to translate molecular insights into precision medicine strategies, grounded in human-relevant models and clinically meaningful outcomes.

 

Prasse’s work on BAL gene expression and epithelial reprogramming in IPF was featured at the Pulmonary Fibrosis Foundation Summit.

https://www.pulmonaryfibrosis.org/pff-summit

 

 

Figure 1

(Figure from Jaeger et al. Nat Commun. 2022;13:5637)

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