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Role of ₁-Acid Glycoprotein in Therapeutic Antifibrotic Effects of Imatinib with Macrolides in Mice

¹ Department of Internal Medicine and Molecular Therapeutics, ² Support Center for Advanced Medical Sciences, and ³ Department of Molecular and Environmental Pathology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan; and ⁴ Clinical Research Center for Allergy and Rheumatology, National Kochi Hospital, Kochi, Japan

Correspondence and requests for reprints should be addressed to Yasuhiko Nishioka, M.D., Ph.D., Department of Internal Medicine and Molecular Therapeutics, Institute of Health Biosciences, University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan. E-mail: yasuhiko{at}clin.med.tokushima-u.ac.jp

Rationale: Imatinib is an inhibitor of platelet-derived growth factor receptors. We have reported that treatment with imatinib inhibited bleomycin-induced pulmonary fibrosis in mice. However, late treatment with imatinib had no effect.

Objectives: To clarify why imatinib had no antifibrotic effect when its administration was delayed, we focused on ₁-acid glycoprotein (AGP), because it was reported to bind imatinib and mediate drug resistance.

Methods: The concentration of AGP in serum of mice and patients with idiopathic pulmonary fibrosis was measured by radial immunodiffusion testing. The effects of AGP in vitro were evaluated by assaying the growth of lung fibroblasts. We examined the combined effects of erythromycin (EM) or clarithromycin (CAM) on bleomycin-induced pulmonary fibrosis in mice.

Measurements and Main Results: Addition of AGP abrogated imatinib-mediated inhibition of the growth of fibroblasts. However, treatment with EM or CAM restored the growth-inhibitory effects of imatinib. The elevated level of AGP was detected in serum and lung homogenates in bleomycin-exposed mice and reached a plateau on Day 14. Imatinib alone did not ameliorate pulmonary fibrosis when treatment was started on Day 15, whereas coadministration of imatinib and EM or CAM significantly reduced the fibrogenesis via inhibition of the growth of fibroblasts in vivo. Serum levels of AGP were higher in patients with idiopathic pulmonary fibrosis than in healthy subjects.

Conclusions: AGP is an important regulatory factor modulating the ability of imatinib to prevent pulmonary fibrosis in mice, and combined therapy with imatinib and EM or CAM might be useful for treatment of pulmonary fibrosis.

Key Words: platelet-derived growth factor • erythromycin • clarithromycin • fibroblast

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Imatinib inhibited pulmonary fibrosis using a bleomycin model in mice. However, while early treatment (Days 0 to 15) prevented pulmonary fibrosis, late treatment (Days 15 to 28) did not. What This Study Adds to the Field Coadministration of imatinib with macrolides reduced pulmonary fibrosis in mice even if started on Day 15.

 

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