Role of alpha1-acid glycoprotein in therapeutic antifibrotic effects of imatinib with macrolides in mice.
BACKGROUND
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.


OBJECTIVE
To clarify why imatinib had no antifibrotic effect when its administration was delayed, we focused on alpha(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.


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.
Azuma
Momoyo
M
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.
Nishioka
Yasuhiko
Y
Aono
Yoshinori
Y
Inayama
Mami
M
Makino
Hideki
H
Kishi
Jun
J
Shono
Masayuki
M
Kinoshita
Katsuhiro
K
Uehara
Hisanori
H
Ogushi
Fumitaka
F
Izumi
Keisuke
K
Sone
Saburo
S
D000818:Animals; D001549:Benzamides; D002478:Cells, Cultured; D017291:Clarithromycin / Q000378:metabolism; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004917:Erythromycin / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D000068877:Imatinib Mesylate; D018942:Macrolides / Q000378:metabolism*; D051379:Mice; D009961:Orosomucoid / Q000032:analysis / Q000187:drug effects / Q000502:physiology*; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy*; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology*
D001549:Benzamides; D018942:Macrolides; D009961:Orosomucoid; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D004917:Erythromycin; D000068877:Imatinib Mesylate; D017291:Clarithromycin