Heterogenous Intrapulmonary Distribution of Aerosolized Model Compounds in Mice with Bleomycin-Induced Pulmonary Fibrosis.

Abstract

Background: A distinctive pathological feature of idiopathic pulmonary fibrosis (IPF) is the aberrant accumulation of extracellular matrix components in the alveoli in abnormal remodeling and reconstruction following scarring of the alveolar structure. The current antifibrotic agents used for IPF therapy frequently result in systemic side effects because these agents are distributed, through the blood, to many different tissues after oral administration. In contrast to oral administration, the intrapulmonary administration of aerosolized drugs is believed to be an efficient method for their direct delivery to the focus sites in the lungs. However, how fibrotic lesions alter the distribution of aerosolized drugs following intrapulmonary administration remains largely unknown. In this study, we evaluate the intrapulmonary distribution characteristics of aerosolized model compounds in mice with bleomycin-induced pulmonary fibrosis through imaging the organs and alveoli. Methods: Aerosolized model compounds were administered to mice with bleomycin-induced pulmonary fibrosis using a Liquid MicroSprayer^®. The intrapulmonary distribution characteristics of aerosolized model compounds were evaluated through several imaging techniques, including noninvasive lung imaging using X-ray computed tomography, ex vivo imaging using zoom fluorescence microscopy, frozen tissue section observation, and three-dimensional imaging with tissue-clearing treatment using confocal laser microscopy. Results: In fibrotic lungs, the aerosolized model compounds were heterogeneously distributed. In observations of frozen tissue sections, model compounds were observed only in the fibrotic foci near airless spaces called honeycombs. In three-dimensional imaging of cleared tissue from fibrotic lungs, the area of the model compound in the alveolar space was smaller than in healthy lungs. Conclusion: The intrapulmonary deposition of extracellular matrix associated with pulmonary fibrosis limits the intrapulmonary distribution of aerosolized drugs. The development of delivery systems for antifibrotic agents to improve the distribution characteristics in fibrotic foci is necessary for effective IPF therapy.