Role of alpha1-acid Glycoprotein in Therapeutic Antifibrotic Effects of Imatinib Plus Macrolides in Mice.

@article{citeulike:2070654, abstract = {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. OBJECTIVE: To clarify why imatinib had no antifibrotic effect when its administration was delayed, we focused on alpha1-acid glycoprotein (AGP), since 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 (IPF) 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 co-administration 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 IPF than in healthy subjects. CONCLUSIONS: These results suggest that 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.}, address = {Department of Internal Medicine and Molecular Therapeutics, University of Tokushima Graduate School, Tokushima, Japan.}, author = {Azuma, Momoyo and Nishioka, Yasuhiko and Aono, Yoshinori and Inayama, Mami and Makino, Hideki and Kishi, Jun and Shono, Masayuki and Kinoshita, Katsuhiro and Uehara, Hisanori and Ogushi, Fumitaka and Izumi, Keisuke and Sone, Saburo }, citeulike-article-id = {2070654}, doi = {http://dx.doi.org/10.1164/rccm.200702-178OC}, issn = {1535-4970}, journal = {Am J Respir Crit Care Med}, month = {August}, posted-at = {2007-12-07 03:04:22}, priority = {2}, title = {Role of {alpha}1-acid Glycoprotein in Therapeutic Antifibrotic Effects of Imatinib Plus Macrolides in Mice.}, url = {http://dx.doi.org/10.1164/rccm.200702-178OC}, year = {2007} }

TY - JOUR ID - citeulike:2070654 L3 - citeulike-article-id:2070654 TI - Role of {alpha}1-acid Glycoprotein in Therapeutic Antifibrotic Effects of Imatinib Plus Macrolides in Mice. JF - Am J Respir Crit Care Med AD - Department of Internal Medicine and Molecular Therapeutics, University of Tokushima Graduate School, Tokushima, Japan. SN - 1535-4970 N2 - 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. OBJECTIVE: To clarify why imatinib had no antifibrotic effect when its administration was delayed, we focused on alpha1-acid glycoprotein (AGP), since 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 (IPF) 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 co-administration 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 IPF than in healthy subjects. CONCLUSIONS: These results suggest that 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. AU - Azuma, Momoyo AU - Nishioka, Yasuhiko AU - Aono, Yoshinori AU - Inayama, Mami AU - Makino, Hideki AU - Kishi, Jun AU - Shono, Masayuki AU - Kinoshita, Katsuhiro AU - Uehara, Hisanori AU - Ogushi, Fumitaka AU - Izumi, Keisuke AU - Sone, Saburo PY - 2007/08/23/ UR - http://dx.doi.org/10.1164/rccm.200702-178OC ER -