B77-03 Admilparant Reduces Mediators of Fibrosis in a Novel Patient-Derived Interstitial Lung Disease Tissue Culture System

Rationale Primary lung tissue culture offers significant advantages for investigating pulmonary fibrosis because of the maintenance of extracellular matrix architecture and the capacity to study intercellular interactions within the context of native tissue. However, these benefits are often offset by the limited availability of donor lung tissue and challenges in preserving viable samples for repeated studies. Methods To address these limitations and further our understanding of pulmonary fibrosis, we established a cryobank of human lung tissue obtained from patients undergoing transplantation for interstitial lung disease. Pleura was removed from sections of explanted lung tissue, which was then minced and immersed in a DMSO-free cryoprotectant. After validation of tissue viability and fibrotic response post-cryopreservation, we utilized this platform to evaluate the antifibrotic efficacy of the lysophosphatidic acid (LPA) antagonist, admilparant, using gene expression and proteomic analysis. Results The response of cryopreserved lung tissue to pro-fibrotic stimuli was consistent with published literature. LPA stimulation of the lung tissues led to upregulation of inflammatory and pro-fibrotic pathways. Strikingly, admilparant-treated lung tissues from the same donors resulted in measurable reductions in key biomarkers involved in mediating fibrosis and inflammation, as demonstrated by both gene expression and proteomic analysis. These biomarkers included multiple collagen derived products, transforming growth factor-β-driven cytokines, and CTHRC1, a marker of pathogenic fibroblasts. Conclusions These findings indicate that cryopreserved lung tissue can be used for fibrosis research. They also indicate that LPA signaling regulates multiple fibrotic relevant pathways in human lung tissue and underscore the pivotal role of LPA in sustaining the fibrotic phenotype and potential treatment benefit of admilparant.