Effect of SU5416 on the inflammation of pulmonary fibrosis in mice_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

LI Wancheng ¹ , LIU Weijia ² , LI Yanping ¹ , LIU Daishun ¹ , LIU Yong ¹ , WEN Fuqiang ¹ ,  FENG Yulin ¹

Department of Respiratory Medicine，West China Hospital，Sichuan University.Chengdu，Sichuan，610041，ChinaCorresponding author：FENG Yu-lin，E-mail：FengYulin1115@hotmail.com;

Corresponding author：

FENG Yulin, Email: FengYulin1115@hotmail.com

Keywords：

Vascular endothelial growth factor receptor inhibitor; SU5416; Pulmonary interstitial fibrosis; Bleomycin

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Objective To explore the effects of SU5416，a vascular endothelial growth factor receptor (VEGFR) inhibitor，on inflammation in mice with bleomycin-induced pulmonary fibrosis.Methods C57BL/6 mice were randomly divided into four groups，ie.a control group，a bleomycin-induced pulmonary fibrosis (BPF) group,early intervention with SU5416 group (days 1-14，SE)，and delayed intervention with SU5416group (days 15-28，SD).Bleomycin (10 mg/kg) was instilled into the trachea of the mice to induce pulmonary fibrosis.After the instillation，SU5416 (50 mg/kg) was injected into the peritoneal cavities of the mice twice a week.The mice treated with bleomycin alone or with bleomycin followed by SU5416 were sacrificed on the day 14 and day 28 after the instillation of bleomycin.Lung tissues were taken and processed for determination of hydroxyl proline content.Bronchoalveolar lavage fluid (BALF) was collected for total and differential cell counts and measurements of lactic dehydrogenase (LDH) levels.Results It was found that the hydroxyl proline contents，the number of macrophages，and the LDH contents from the mice treated with bleomycin alone on day 14 were greatly increased.However，only the hydroxyl proline showed a significant increase in the mice treated with bleomycin alone on day 28.The number of macrophages，LDH contents，and hydroxyl proline contents were greatly reduced in the mice treated with bleomycin and early administration of SU5416 on day 14 when compared with those treated with bleomycin alone.But there were no significant differences in the above parameters of the mice treated with bleomycin and delayed administration of SU5416 on day 14.Conclusion This study indicates that early intervention by SU5416 might attenuate the fibrosis through inhibiting early inflammation in animal model of pulmonary fibrosis induced by bleomycin.

Citation： LI Wancheng,LIU Weijia,LI Yanping,LIU Daishun,LIU Yong,WEN Fuqiang,FENG Yulin. Effect of SU5416 on the inflammation of pulmonary fibrosis in mice. Chinese Journal of Respiratory and Critical Care Medicine, 2007, 6(1): 55-59. doi: Copy

1.	朱元珏，陈文彬，主编.呼吸病学.北京：人民卫生出版社，2003.1071-1082.
2.	Bjoraker JA，Ryu JH，Edwin MK，et al.Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med，1998，157：199-203.
3.	Nicholson AG，Colby TV，du Bois RM，et al.The prognostic significance of the histologic pattern of interstitial pneumonia in patients presenting with the clinical entity of cryptogenic fibrosing alveolitis.Am J Resprit Care Med，2000，162：2213-2217.
4.	American Thoracic Society (ATS)，and the European Respiratory Society (ERS).Idiopathic pulmonary fibrosis：diagnosis and treatment.International consensus statement.Am J Respir Crit Care Med，2000，161：646-664.
5.	Okuma T，Terasaki Y，Kaikita K，et al.C-C chemokine receptor-2 (CCR2) deficiency improves bleomycin-induced pulmonary fibrosis by attenuation of both macrophage infiltration and production of macrophage-derived matrix metalloproteinases.J Pathol，2004，204：594-604.
6.	Griffioen AW，Molema G.Angiogenesis：Potentials for pharmacologic intervention in the treatment of cancer，cardiovascular diseases，and chronic inflammation.Pharmacol Rev，2000，52：237-268.
7.	Ferrara N.Vascular endothelial growth factor.Trends Cardiovasc Med，1993，3：244-250.
8.	Mendel DB，Schreck RE，West DC，et al.The angiogenesis inhibitor SU5416 has long-lasting effects on vascular endothelial growth factor receptor phosphorylation and function.Clin Cancer Res，2000，6：4848-4858.
9.	Sukbuntherng J，Cropp G，Hannah A，et al.Pharmacokinetics and interspecies scaling of a novel VEGF receptor inhibitor，SU5416.J Pharm Pharmacol，2001，53：1629-1636.
10.	Fong TA，Shawver LK，Sun L，et al.SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis，tumor vascularization，and growth of multiple tumor types.Cancer Res，1999，59：99-106.
11.	Vajkoczy P，Menger MD，Vollmar B，et al.Inhibition of tumor growth，angiogenesis，and microcirculation by the novel Flk-1 inhibitor SU5416 as assessed by intravital multi-fluorescence videomicroscopy.Neoplasia，1999，1：31-41.
12.	Maheshwari U，Gupta D，Aggarwal AN，et al.Spectrum and diagnosis of idiopathic pulmonary fibrosis.Indian J Chest Dis Allied Sci，2004，46：23-26.
13.	Davies HR，Richeldi L.Idiopathic pulmonary fibrosis：current and future treatment options.Am J Respir Med，2002，1：211-224.
14.	刘秉文，陈俊杰，主编.医学分子生物学.第2版.北京：中国协和医科大学出版社，2005.67-84.
15.	李圣青，李焕章，杨乔欣，等.TGF-βRⅡ/Fc融合蛋白在杆状病毒系统中的表达.第四军医大学学报，2003，24：323-326.
16.	Li J，Poovey HG，Rodriguez JF，et al.Effect of platelet-derived growth factor on the development and persistence of asbestos-induced fibroproliferative lung disease.J Environ Pathol Toxicol Oncol，2004，23：253-266.
17.	Yokoyama A，Kohno N，Hamada H，et al.Circulating KL-6 predicts the outcome of rapidly progressive idiopathic pulmonary fibrosis.Am J Respir Crit Care Med，1998，158：1680-1684.
18.	Defrances MC，Wolf HK，Michalopoulos GK，et al.The presence of hepatocyte growth factor in the developing rat.Development，1992，116：387-395.
19.	Zhang Y, Lee TC, Guillemin B, et al. Enhanced IL-1 beta and tumor necrosis factor-alpha release and messenger RNA expression in macrophages from idiopathic pulmonary fibrosis or after asbestos exposure. J Immunol,1993,150:4188-4196.
20.	Eubank TD，Roberts R，Galloway M，et al.GM-CSF induces expression of soluble VEGF receptor-1 from human monocytes and inhibits angiogenesis in mice.Immunity，2004，21：831-842.
21.	Zeng H，Zhao D，Mukhopadhyay D.Flt-1-mediated down-regulation of endothelial cell proliferation through pertussis toxin-sensitive G proteins，beta gamma subunits，small GTPase CDC42，and partly by Rac-1.J Biol Chem，2002，277：4003-4009.
22.	Gerber HP，McMurtrey A，Kowalski J，et al.Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3’-kinase/Akt signal transduction pathway.Requirement for Flk-1/KDR activation.J Biol Chem，1998，273：30336-30343.

1. 朱元珏，陈文彬，主编.呼吸病学.北京：人民卫生出版社，2003.1071-1082.
2. Bjoraker JA，Ryu JH，Edwin MK，et al.Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med，1998，157：199-203.
3. Nicholson AG，Colby TV，du Bois RM，et al.The prognostic significance of the histologic pattern of interstitial pneumonia in patients presenting with the clinical entity of cryptogenic fibrosing alveolitis.Am J Resprit Care Med，2000，162：2213-2217.
4. American Thoracic Society (ATS)，and the European Respiratory Society (ERS).Idiopathic pulmonary fibrosis：diagnosis and treatment.International consensus statement.Am J Respir Crit Care Med，2000，161：646-664.
5. Okuma T，Terasaki Y，Kaikita K，et al.C-C chemokine receptor-2 (CCR2) deficiency improves bleomycin-induced pulmonary fibrosis by attenuation of both macrophage infiltration and production of macrophage-derived matrix metalloproteinases.J Pathol，2004，204：594-604.
6. Griffioen AW，Molema G.Angiogenesis：Potentials for pharmacologic intervention in the treatment of cancer，cardiovascular diseases，and chronic inflammation.Pharmacol Rev，2000，52：237-268.
7. Ferrara N.Vascular endothelial growth factor.Trends Cardiovasc Med，1993，3：244-250.
8. Mendel DB，Schreck RE，West DC，et al.The angiogenesis inhibitor SU5416 has long-lasting effects on vascular endothelial growth factor receptor phosphorylation and function.Clin Cancer Res，2000，6：4848-4858.
9. Sukbuntherng J，Cropp G，Hannah A，et al.Pharmacokinetics and interspecies scaling of a novel VEGF receptor inhibitor，SU5416.J Pharm Pharmacol，2001，53：1629-1636.
10. Fong TA，Shawver LK，Sun L，et al.SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis，tumor vascularization，and growth of multiple tumor types.Cancer Res，1999，59：99-106.
11. Vajkoczy P，Menger MD，Vollmar B，et al.Inhibition of tumor growth，angiogenesis，and microcirculation by the novel Flk-1 inhibitor SU5416 as assessed by intravital multi-fluorescence videomicroscopy.Neoplasia，1999，1：31-41.
12. Maheshwari U，Gupta D，Aggarwal AN，et al.Spectrum and diagnosis of idiopathic pulmonary fibrosis.Indian J Chest Dis Allied Sci，2004，46：23-26.
13. Davies HR，Richeldi L.Idiopathic pulmonary fibrosis：current and future treatment options.Am J Respir Med，2002，1：211-224.
14. 刘秉文，陈俊杰，主编.医学分子生物学.第2版.北京：中国协和医科大学出版社，2005.67-84.
15. 李圣青，李焕章，杨乔欣，等.TGF-βRⅡ/Fc融合蛋白在杆状病毒系统中的表达.第四军医大学学报，2003，24：323-326.
16. Li J，Poovey HG，Rodriguez JF，et al.Effect of platelet-derived growth factor on the development and persistence of asbestos-induced fibroproliferative lung disease.J Environ Pathol Toxicol Oncol，2004，23：253-266.
17. Yokoyama A，Kohno N，Hamada H，et al.Circulating KL-6 predicts the outcome of rapidly progressive idiopathic pulmonary fibrosis.Am J Respir Crit Care Med，1998，158：1680-1684.
18. Defrances MC，Wolf HK，Michalopoulos GK，et al.The presence of hepatocyte growth factor in the developing rat.Development，1992，116：387-395.
19. Zhang Y, Lee TC, Guillemin B, et al. Enhanced IL-1 beta and tumor necrosis factor-alpha release and messenger RNA expression in macrophages from idiopathic pulmonary fibrosis or after asbestos exposure. J Immunol,1993,150:4188-4196.
20. Eubank TD，Roberts R，Galloway M，et al.GM-CSF induces expression of soluble VEGF receptor-1 from human monocytes and inhibits angiogenesis in mice.Immunity，2004，21：831-842.
21. Zeng H，Zhao D，Mukhopadhyay D.Flt-1-mediated down-regulation of endothelial cell proliferation through pertussis toxin-sensitive G proteins，beta gamma subunits，small GTPase CDC42，and partly by Rac-1.J Biol Chem，2002，277：4003-4009.
22. Gerber HP，McMurtrey A，Kowalski J，et al.Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3’-kinase/Akt signal transduction pathway.Requirement for Flk-1/KDR activation.J Biol Chem，1998，273：30336-30343.

Chinese Journal of Respiratory and Critical Care Medicine

Effect of SU5416 on the inflammation of pulmonary fibrosis in mice

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