title: Alteration in Intrapulmonary Pharmacokinetics of Aerosolized Model Compounds Due to Disruption of the Alveolar Epithelial Barriers Following Bleomycin-Induced Pulmonary Fibrosis in Rats.
abstract: Idiopathic pulmonary fibrosis is a lethal lung disease that is characterized by the accumulation of extracellular matrix and a change in lung structure. In this study, intrapulmonary pharmacokinetics of aerosolized model compounds were evaluated using rats with bleomycin-induced pulmonary fibrosis. Aerosol formulations of indocyanine green, 6-carboxyfluorescein (6-CF), and fluorescein isothiocyanate dextrans (FD; 4.4, 10, 70, and 250 kDa) were administered to rat lungs using a MicroSprayer. Indocyanine green fluorescence signals were significantly weaker in fibrotic lungs than in control lungs and 6-CF and FD concentrations in the plasma of pulmonary fibrotic animals were markedly higher than in the plasma of control animals. Moreover, disrupted epithelial tight junctions, including claudins-1, -3, and -5, were observed in pulmonary fibrotic lesions using immunofluorescence microscopy. In addition, destruction of tight junctions on model alveolar epithelial cells (NCI-H441) by transforming growth factor-β1 treatment enhanced the permeability of 6-CF and FDs through NCI-H441 cell monolayers. These results indicate that aerosolized drugs are easily distributed into the plasma after leakage through damaged tight junctions of alveolar epithelium. Therefore, the development of delivery systems for anti-fibrotic agents to improve intrapulmonary pharmacokinetics may be necessary for effective idiopathic pulmonary fibrosis therapy.
authors.affiliation: Division of Pharmaceutics, Hokkaido Pharmaceutical University School of Pharmacy, Sapporo, Hokkaido 006-8590, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Togami
authors.affiliation: Division of Pharmaceutics, Hokkaido Pharmaceutical University School of Pharmacy, Sapporo, Hokkaido 006-8590, Japan.
authors.forename: Sumio
authors.initials: S
authors.lastname: Chono
authors.affiliation: Division of Pharmaceutics, Hokkaido Pharmaceutical University School of Pharmacy, Sapporo, Hokkaido 006-8590, Japan. Electronic address: h-tada@hokuyakudai.ac.jp.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Tada
mesh_terms: D000336:Aerosols / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000818:Animals; D001761:Bleomycin / Q000494:pharmacology*; D003911:Dextrans / Q000008:administration & dosage; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism*; D016650:Fluorescein-5-isothiocyanate / Q000008:administration & dosage / Q000031:analogs & derivatives; D005452:Fluoresceins / Q000494:pharmacology; D007208:Indocyanine Green / Q000008:administration & dosage; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000378:metabolism*; D051381:Rats; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D000336:Aerosols; D003911:Dextrans; D005452:Fluoresceins; D053773:Transforming Growth Factor beta1; C015219:fluorescein isothiocyanate dextran; D001761:Bleomycin; C024098:6-carboxyfluorescein; D016650:Fluorescein-5-isothiocyanate; D007208:Indocyanine Green
keywords: aerosol-based pulmonary drug delivery system; alveolar epithelial cells; anti-fibrotic agent; claudin; epithelial-mesenchymal transition; idiopathic pulmonary fibrosis; tight junction