Breathing-induced stretch enhances the efficacy of an inhaled and orally delivered anti-fibrosis drug in vitro

Science and Research

Mechanical forces, which are crucial for most downstream signaling pathways in lung (patho-)physiology, may also regulate the efficacy of drugs. We investigated the role of mechanical forces on the effectiveness of inhaled and systemic (oral) administration of an anti-fibrosis drug. We established an induced triple coculture fibrosis model of a tight alveolar endothelial-epithelial barrier combined with pro-fibrotically stimulated primary fibroblasts derived from healthy donors and compared it to an analogous triple coculture model with fibroblasts from idiopathic pulmonary fibrosis (IPF) patients (innate IPF model). The 3D in vitro fibrosis models were established on a biomimetic, stretchable basement (BETA) membrane and cultured at an air-liquid interface (ALI). These fibrosis models were treated with an FDA-approved anti-fibrosis drug (oral and aerosolized application of Nintedanib) under static and dynamic culture conditions – including cyclic mechanical stretch and medium-flow induced shear stress – leveraging our advanced millifluidic CIVIC mini-lung technology. Fibrosis markers were characterized by protein and immunofluorescence analysis supplemented with real-time measurement of pulmonary compliance as a functional assay. Nintedanib shows more potent anti-inflammatory (IL1