American journal of respiratory cell and molecular biology | 2019
Bleomycin Induces Drug Efflux in Lungs: A pitfall for Pharmacological Studies of Pulmonary Fibrosis.
Abstract
RATIONALE\nATP-binding cassette (ABC) transporters are evolutionarily conserved membrane proteins that pump a variety of endogenous substrates across cell membranes. Certain subfamilies are known to interact with pharmaceutical compounds, potentially influencing drug delivery and treatment efficacy. However, the role of drug resistance-associated ABC transporters has not been examined in idiopathic pulmonary fibrosis (IPF) or its animal model: the bleomycin-induced murine model.\n\n\nOBJECTIVE\nHere we investigate the expression of two ABC transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), in human IPF lung tissue and two different bleomycin-induced mouse models of pulmonary fibrosis.\n\n\nMETHODS\nWe obtained human IPF specimens from patients during lung transplantation and administered bleomycin to male C57BL/6J mice either by oropharyngeal aspiration (1 U/kg) or subcutaneous osmotic infusion (100 U/kg over 7 days).\n\n\nRESULTS\nWe report that P-gp and BCRP expression in IPF patient lungs was comparable to controls. However, murine lungs expressed increased levels of P-gp and BCRP after oropharyngeal and subcutaneous bleomycin administration. We localized this upregulation to multiple pulmonary cell types, including alveolar fibroblasts, endothelial cells, and type-2 epithelial cells. Functionally, this effect reduced murine lung exposure to nintedanib, an FDA-approved IPF therapy known to be a P-gp substrate.\n\n\nCONCLUSION\nThe study reveals a discrepancy between IPF pathophysiology and the common animal model of lung fibrosis. Bleomycin-induced drug efflux in the murine lungs may present an uncontrolled confounding variable in the preclinical study of IPF drug candidates, and these findings will facilitate disease model validation, enhance new drug discoveries that ultimately improve patient outcomes.