Repurposing ivacaftor to attenuate LPS-induced acute lung injury: evidence from a non-cystic fibrosis model

In this study, we explicitly evaluate the anti-inflammatory effects of ivacaftor as a route-of-delivery comparison (intraperitoneal vs. intratracheal) in a reproducible LPS-induced lung inflammation model. We evaluated the effects of ivacaftor [40 mg/kg, administered either intraperitoneally (IP) or intratracheally (IT)] on lipopolysaccharide (LPS, 8 μg)-induced lung inflammation in 8-10-week-old female C57BL/6 mice. Mice were euthanised at 24 or 72 h post-treatment, and serum, bronchoalveolar lavage fluid (BALF), and lung tissue were collected for analysis. Inflammation was assessed by measuring immune cell infiltration, fluorescence-activated cell sorting (FACS)-based leucocyte profiling, and histological changes. Ivacaftor concentrations in the samples were quantified using multiple reaction monitoring liquid chromatography-mass spectrometry (MRM-LCMS). At 24 h, both IT and IP ivacaftor significantly reduced the total BALF cell counts (∼40% reduction) and neutrophil infiltration compared to the LPS-only controls (p < 0.05). Inflammatory responses were reduced following ivacaftor treatment, as reflected by lower BALF cellularity, reduced neutrophil infiltration, and improved histological outcomes. Histological analysis showed reduced alveolar wall thickening and immune cell infiltration in ivacaftor-treated lungs. FACS confirmed lower frequencies of neutrophils and macrophages. Ivacaftor concentrations were higher in lung tissue following IT administration. Our findings indicate that ivacaftor has a potential anti-inflammatory effect, unrelated to cystic fibrosis transmembrane conductance regulator (CFTR) function, in a murine model of LPS-induced acute lung injury. These results offer insights into inflammation mechanisms and could inform future clinical treatments.