Late Breaking Abstract - PCLS as a human, in vitro IPF model – morphological and molecular insights

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive, life-limiting lung disease, characterized by excessive fibrotic remodeling of the parenchyma. Current therapies remain limited by the heterogeneity of IPF, inadequately modeled by traditional in vitro and in vivo models, resulting in poor translation of preclinical data (Murgo A. et al., Front Pharmacol, 2023;14:1303646). In this project human precision-cut lung slices (PCLS) are used as in vitro model for pulmonary fibrosis and in screening potential therapeutic agents. Building on our previous setup with cultivation up to 4 weeks (Preuss, E. et al., Am J Pathol, 2022;192(2):239-253) PCLS from IPF and non-IPF patients were cultivated for 3-11 weeks, stimulated with PDGF, LPA, TNF-a and TGF-b to induce fibrosis and treated with metformin. Morphological and molecular changes were analyzed at selected timepoints using 2D histopathology and 3D imaging in relation to GeoMx Digital Spatial Profiler. We observed septa thickening at 3 weeks of cultivation and fibrotic remodeling in PCLS stimulated for 11 weeks. GeoMx finds treatment-specific transcriptome alterations hinting at effective fibrotic stimulation and the inhibiting potential of metformin. We demonstrated that long term cultivation is feasible, while fibrotic stimulation models early stages of IPF. As PCLS are also suitable for therapeutic testing, they feature the potential to bridge between preclinical and clinical findings. erj;66/suppl_69/PA1902/F1 F1 F1

Authors 8

1. Birger Tielemans Aachen 1Institute of Pathology

   Universitätsklinikum Aachen

   Affiliation as printed

   1Institute of Pathology, Uniklinik RWTH Aachen, Aachen, Germany

2. Janik Riese Aachen 1Institute of Pathology

   Universitätsklinikum Aachen

   Affiliation as printed

   1Institute of Pathology, Uniklinik RWTH Aachen, Aachen, Germany

3. Saskia Von Stillfried Und Rattonitz Aachen 1Institute of Pathology

   Universitätsklinikum Aachen

   Affiliation as printed

   1Institute of Pathology, Uniklinik RWTH Aachen, Aachen, Germany

4. Holger Schlüter

   Boehringer Ingelheim (Germany)

   Affiliation as printed

   4Boehringer Ingelheim Pharma GmbH & Co. KG, Department Immunology and Respiratory Disease research, Biberach an der Riß, Germany

5. Lavinia Neubert

   Medizinische Hochschule Hannover

   Affiliation as printed

   5Institute of Pathology, Hannover Medical School, Hannover, Germany

6. Christopher Werlein

   Medizinische Hochschule Hannover

   Affiliation as printed

   5Institute of Pathology, Hannover Medical School, Hannover, Germany

7. Danny David Jonigk Aachen 1Institute of Pathology

   Universitätsklinikum Aachen

   Affiliation as printed

   1Institute of Pathology, Uniklinik RWTH Aachen, Aachen, Germany

8. Mark Kühnel Aachen 1Institute of Pathology

   Universitätsklinikum Aachen

   Affiliation as printed

   1Institute of Pathology, Uniklinik RWTH Aachen, Aachen, Germany