A translatable, human pulmonary edema model enables target and drug discovery in idiopathic pulmonary fibrosis exacerbation

Le résumé fourni par la source

Acute lung injury leads to alveolar-capillary barrier breakdown accompanied by the spillover of fluids and damage response markers. The accumulation of fluids into the alveolus hinders the gas-exchange process. In idiopathic pulmonary fibrosis (IPF), acute exacerbations (AE) result in high mortality (50%), especially in those requiring intensive care (90%). While rodent models have been used to develop drugs for acute lung injury, former concepts have not progressed into the development of effective drugs for IPF-AE mainly due to translatability issues. We developed an alveolus-on-chip model using human adult alveolar stem cells (AT2) and pulmonary microvascular endothelial cells. Under stretching conditions, AT2 cells differentiate into an AT1-like phenotype more effectively than those on inserts, highlighting the importance of mechanical cues for alveolar differentiation. While dedicated cell fate markers for capillary cell differentiation from the general capillary (gCap) into aerocytes (aCap) are missing, capillary cells enlarged time-dependently under stretching, suggesting initial cell adaptation toward the larger aerocytes. Treatment with IPF cocktail or TNFα induced permeabilization and fluid invasion, and the release of prognostic biomarkers in IPF. Clinical-stage compounds were used to assess back-translation of the system, and omics analyses were run to understand the pathway disturbances occurring upon human acute alveolar injury. This model serves as a platform to study molecular signaling in IPF-AE and to validate therapeutic concepts. The linkage to prognostic biomarkers supports human dose estimates and suggests translatability of the system.

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