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Clinically validated markers of the extracellular matrix remodelling are altered by potential anti-fibrotic compounds in a human lung fibrosis ex vivo model

: Leeming, Diana Julie; Sand, Jannie M.B.; Hesse, Christina; Konzok, Sebastian; Sewald, Katherina; Rønnow, Sarah; Braun, Armin; Karsdal, Morten A.; Brockbank, Sarah; Cruwys, Simon


European Respiratory Journal 52 (2018), Supplement 62, Abstract PA5255
ISSN: 0903-1936
ISSN: 1399-3003
European Respiratory Society (ERS International Congress) <2018, Paris>
Fraunhofer ITEM ()

Background: Pulmonary fibrosis (PF) is characterized by excessive extracellular matrix (ECM) remodeling. Clinically validated ECM neoepitopes markers, related to progressive PF, may be useful for the evaluation of potential anti-fibrotic effects.
Aim: The aim was to evaluate ECM remodelling (ECMR) in a human ex vivo precision-cut lung slice (PCLS) model.
Methods: Human PF tissue was collected from two donors during lung transplantation. Within 24hours, the lungs were processed into PCLSs. The slices were cultured 2 pr/well and in triplicates for 48hours in serum free medium with 1nM-10μM nintedanib or 100pM-1µM mTOR/PI3K inhibitor omipalisib (GSK2126458). Responsiveness was tested using Lipopolysaccaride (LPS) and cytotoxicity using lactate dehydrogenase (LDH). Markers of collagen type I, III and VI formation (P1NP, PRO-C3, PRO-C6) and type III collagen degradation (C3M) were assessed in the supernatants. The subpleural and central lung regions were used and evaluated by hematoxylin and eosin staining.
Results: The tissue from both donors was responsive to LPS and no toxicity was seen with the selected compound doses using LDH. P1NP, PRO-C3, and C3M were significantly reduced by 1nM-1µM omipalisib (p<0.05-0.001) including the IC50 value around 40-50nM. Non-significant reductions of PRO-C6 were seen. Data varied depending on region and donor. Similar trends were observed for nintedanib, however no significant changes were seen in this model.
Conclusion: We found that an mTOR/PI3K inhibitor decreased markers of ECMR in a human PF ex vivo model, potential as a tool for evaluating anti-fibrotic compounds in a 3D PF structure.