HDAC8抑制剂PCI-34051对慢性支气管哮喘小鼠的治疗作用
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摘要
目的探讨组蛋白去乙酰化酶8抑制剂PCI-34051对慢性哮喘小鼠气道炎症、气道重塑和气道高反应的治疗作用。方法 BALB/C小鼠分为正常组、哮喘组、地塞米松组和PCI-34051组。测定气道阻力,BALF细胞计数和分类计数,ELISA检测IL-4、IL-5、TGF-β1和IFN-γ。HE染色观察气道炎症,AB-PAS和Masson染色测定气道重塑。Western blot测定α-SMA和TGF-β1表达。结果与哮喘组比,地塞米松组和PCI-34051组气道阻力降低,BALF中炎性细胞总数和嗜酸性粒细胞减少,IL-4、IL-5、TGF-β1表达下降。地塞米松组和PCI-34051组HE染色气道周围炎症减轻,气道平滑肌增厚减弱;AB-PAS染色杯状细胞化生减轻;Masson染色面积减少。Western blot发现地塞米松组和PCI-34051组TGF-β1表达下降,但α-SMA降低不明显。结论 PCI-34051能够缓解慢性哮喘气道炎症、气道高反应和气道重塑。
Objective To investigate the therapeutic effect of PCI-34051, a selective HDAC8 inhibitor, on the development of chronic allergic airway disease in mice with airway inflammation, airway remodeling and airway hyperresponsiveness. Methods Wildtype BALB / C mice were randomly divided into control group, asthma group, dexamethasone group and PCI-34051 group. Then we detected airway resistance, total cells and different cells, and levels of IL-4, IL-5, TGF-β1 and IFN-γ in the bronchoalveolar lavage fluid( BALF). Airway inflammation was assessed by HE staining, and airway remodeling was assessed by Alcian blue-periodic acid Schiff staining and Masson trichrome staining. Expressions of α-SMA and TGF-β1 were assessed by western blot. Results Compared with the asthma group, Dexamethasone and PCI-34051 treatment relieved airway resistance( penh), total inflammatory cells, eosinophils, and IL-4, IL-5 and TGF-β1 levels in the BALF. After treatment, inflammatory cells infiltration and smooth muscle thickening in HE staining, goblet cell metaplasia in AB-PAS staining, and subepithelial collagen deposition in Masson trichrome staining were reduced in Dexamethasone and PCI-34051 groups. Western blot found expression of decreased TGF-β1, but insignificant decrease of α-SMA in the dexamethasone group and the PCI-34051 group. Conclusion Treatment with HDAC8 inhibitors( PCI-34051) can reduce airway inflammation, airway remodeling and airway hyperresponsiveness in chronic allergic airway disease of mice.
Objective To investigate the therapeutic effect of PCI-34051, a selective HDAC8 inhibitor, on the development of chronic allergic airway disease in mice with airway inflammation, airway remodeling and airway hyperresponsiveness. Methods Wildtype BALB / C mice were randomly divided into control group, asthma group, dexamethasone group and PCI-34051 group. Then we detected airway resistance, total cells and different cells, and levels of IL-4, IL-5, TGF-β1 and IFN-γ in the bronchoalveolar lavage fluid( BALF). Airway inflammation was assessed by HE staining, and airway remodeling was assessed by Alcian blue-periodic acid Schiff staining and Masson trichrome staining. Expressions of α-SMA and TGF-β1 were assessed by western blot. Results Compared with the asthma group, Dexamethasone and PCI-34051 treatment relieved airway resistance( penh), total inflammatory cells, eosinophils, and IL-4, IL-5 and TGF-β1 levels in the BALF. After treatment, inflammatory cells infiltration and smooth muscle thickening in HE staining, goblet cell metaplasia in AB-PAS staining, and subepithelial collagen deposition in Masson trichrome staining were reduced in Dexamethasone and PCI-34051 groups. Western blot found expression of decreased TGF-β1, but insignificant decrease of α-SMA in the dexamethasone group and the PCI-34051 group. Conclusion Treatment with HDAC8 inhibitors( PCI-34051) can reduce airway inflammation, airway remodeling and airway hyperresponsiveness in chronic allergic airway disease of mice.
引文
[1]Poon AH,Eidelman DH,Martin JG,et al.Pathogenesis of severe asthma.Clin Exp Allergy.2012,42(5):625-637
[2]Dani C,Bonatto D,Salvador M,et al.Antioxidant protection of resveratrol and catechin in Saccharomyces cerevisiae.J Agric Food Chem,2008,56:4268-4272
[3]Grabiec AM,Krausz S,de Jager W,et al.Histone deacetylase inhibitors suppress inflammatory activation of rheumatoid arthritis patient synovial macrophages and tissue.J Immunol,2010,184(5):2718-2728
[4]Wang L,Tao R,Hancock WW.Using histone deacetylase inhibitors to enhance Foxp3(+)regulatory T-cell function and induce allograft tolerance.Immunol Cell Biol.2009,87:195-202
[5]Shankar S,Srivastava RK.Histone deacetylase inhibitors:mechanisms and clinical significance in cancer:HDAC inhibitor-induced apoptosis.Adv Exp Med Biol,2008,615:261-298
[6]Buggy JJ,Sideris ML,Mak P,et al.Cloning and characterization of a novel human histone deacetylase,HDAC8.Biochem J,2000,350 Pt(1):199-205
[7]Balasubramanian S,Ramos J,Luo W,et al.A novel histone deacetylase 8(HDAC8)-specific inhibitor PCI-34051induces apoptosis in T-cell lymphomas.Leukemia,2008,22(5),1026-1034
[8]Tang W,Luo T,Greenberg EF,et al.Discovery of histone deacetylase 8 selective inhibitors.Bioorg Med Chem Lett,2011,21(9):2601-2605
[9]Royce SG,Karagiannis TC.Histone Deacetylases and Their Role in Asthma.Journal of Asthma,2012,49:121-128
[10]Royce SG,Karagiannis TC.Histone deacetylases and their inhibitors:new implications for asthma and chronic respiratory conditions.Curr Opin Allergy Clin Immunol,2014,14(1):44-48
[11]Vannini A,Volpari C,Filocamo G,et al.Crystal structure of a eukaryotic zinc-dependent histone deacetylase,human HDAC8,complexed with a hydroxamic acid inhibitor.Proc Natl A cad Sci USA,2004,101(42):15064-15069
[12]Choi JH,Oh SW,Kang MS,et al.Trichostatin A attenuates airway inflammation in mouse asthma model.Clin Exp Allergy,2005,35:89-96
[13]Banerjee A,Trivedi CM,Damera G,et al.Trichostatin A abrogates airway constriction,but not inflammation in mouse and human asthma models.Am J Respir Cell Mol Biol,2012;46(2):132-138
[14]Royce SG,Dang W,Ververis K,et al.Protective effects of valproic acid against airway hyperresponsiveness and airway remodeling in a mouse model of allergic airways disease.Epienetics.2011,6(12):1463-1470
[15]Royce SG,Dang W,Gao Y,et al.Resveratrol has protective effects against airway remodeling and airway inflammation in a murine model of allergic airways disease.Pathobiol Aging Age-Related Dis 2011;1:7134
[16]Lee M,Kim S,Kwon OK,et al.Anti-inflammatory and anti-asthmatic effects of resveratrol,a polyphenolic stilbene,in a mouse model of allergic asthma.Int Immunopharmacol,2009;9(4):418-424
[17]Royce SG,Dang W,Yuan G,et al.Effects of the Histone Deacetylase Inhibitor,Trichostatin A,in a Chronic Allergic Airways Disease Model in Mice.Arch Immunol Ther Exp.2012,60(4):295-306
[2]Dani C,Bonatto D,Salvador M,et al.Antioxidant protection of resveratrol and catechin in Saccharomyces cerevisiae.J Agric Food Chem,2008,56:4268-4272
[3]Grabiec AM,Krausz S,de Jager W,et al.Histone deacetylase inhibitors suppress inflammatory activation of rheumatoid arthritis patient synovial macrophages and tissue.J Immunol,2010,184(5):2718-2728
[4]Wang L,Tao R,Hancock WW.Using histone deacetylase inhibitors to enhance Foxp3(+)regulatory T-cell function and induce allograft tolerance.Immunol Cell Biol.2009,87:195-202
[5]Shankar S,Srivastava RK.Histone deacetylase inhibitors:mechanisms and clinical significance in cancer:HDAC inhibitor-induced apoptosis.Adv Exp Med Biol,2008,615:261-298
[6]Buggy JJ,Sideris ML,Mak P,et al.Cloning and characterization of a novel human histone deacetylase,HDAC8.Biochem J,2000,350 Pt(1):199-205
[7]Balasubramanian S,Ramos J,Luo W,et al.A novel histone deacetylase 8(HDAC8)-specific inhibitor PCI-34051induces apoptosis in T-cell lymphomas.Leukemia,2008,22(5),1026-1034
[8]Tang W,Luo T,Greenberg EF,et al.Discovery of histone deacetylase 8 selective inhibitors.Bioorg Med Chem Lett,2011,21(9):2601-2605
[9]Royce SG,Karagiannis TC.Histone Deacetylases and Their Role in Asthma.Journal of Asthma,2012,49:121-128
[10]Royce SG,Karagiannis TC.Histone deacetylases and their inhibitors:new implications for asthma and chronic respiratory conditions.Curr Opin Allergy Clin Immunol,2014,14(1):44-48
[11]Vannini A,Volpari C,Filocamo G,et al.Crystal structure of a eukaryotic zinc-dependent histone deacetylase,human HDAC8,complexed with a hydroxamic acid inhibitor.Proc Natl A cad Sci USA,2004,101(42):15064-15069
[12]Choi JH,Oh SW,Kang MS,et al.Trichostatin A attenuates airway inflammation in mouse asthma model.Clin Exp Allergy,2005,35:89-96
[13]Banerjee A,Trivedi CM,Damera G,et al.Trichostatin A abrogates airway constriction,but not inflammation in mouse and human asthma models.Am J Respir Cell Mol Biol,2012;46(2):132-138
[14]Royce SG,Dang W,Ververis K,et al.Protective effects of valproic acid against airway hyperresponsiveness and airway remodeling in a mouse model of allergic airways disease.Epienetics.2011,6(12):1463-1470
[15]Royce SG,Dang W,Gao Y,et al.Resveratrol has protective effects against airway remodeling and airway inflammation in a murine model of allergic airways disease.Pathobiol Aging Age-Related Dis 2011;1:7134
[16]Lee M,Kim S,Kwon OK,et al.Anti-inflammatory and anti-asthmatic effects of resveratrol,a polyphenolic stilbene,in a mouse model of allergic asthma.Int Immunopharmacol,2009;9(4):418-424
[17]Royce SG,Dang W,Yuan G,et al.Effects of the Histone Deacetylase Inhibitor,Trichostatin A,in a Chronic Allergic Airways Disease Model in Mice.Arch Immunol Ther Exp.2012,60(4):295-306