Profibrotic predictive toxicology in the lung

Pooja SinghRajesh SinhaVeena B Antony^*

• University of Alabama at Birmingham, Birmingham, United States

Fibrosis in the gossamer alveolar capillary membranes of the lung can lead to abnormalities in gas exchange, hypoxemia and death of the individual. These interstitial lung diseases (ILDs) of known or yet undefined etiologies (such as Idiopathic pulmonary fibrosis) highlight the need for predictive, physiologically relevant models for toxicity studies. Three-dimensional (3D) lung organoids derived from animal cells provide an advanced platform that replicates the structural and cellular complexity of lung tissue while reducing whole-animal use. In this study, mouse lung organoids (MiLO) were used to evaluate pulmonary toxicity caused by environmental toxicants and pharmacologic agents. Environmental toxicant (Cadmium) or drug (amiodarone or nitrofurantoin) treated organoids developed hallmark fibrotic features, including increased collagen deposition. Gene expression analyses revealed activation of the Tgfb1 signaling pathway, elevated expression of collagen synthesis and cross-linking genes (Pdgfb, Lox2), and pro-fibrotic markers (Nfkb1, Akt1) activation, accompanied by expansion of collagen-producing myofibroblasts resembling those in fibrotic lung tissue (%ZOI). These findings demonstrate that mouse lung organoids effectively recapitulate key molecular and pathological aspects of drug-and toxin-induced pulmonary fibrosis and represent a powerful model for mechanistic investigation and preclinical screening of compounds with potential pro-fibrotic effects.