Abstract Objective To investigate the molecular mechanism of action of BET bromodomain inhibitor JQ1 in treating airway remodeling in asthmatic mice. Methods A total of 24 mice were randomly divided into control group, ovalbumin (OVA)-induced asthma group (OVA group), and JQ1 intervention group (JQ1+OVA group), with 8 mice in each group. OVA sensitization/challenge was performed to establish a mouse model of asthma. At 1 hour before challenge, the mice in the JQ1+OVA group were given intraperitoneal injection of JQ1 solution (50 μg/g). Bronchoalveolar lavage fluid (BALF) and lung tissue samples were collected at 24 hours after the last challenge, and the total number of cells and percentage of eosinophils in BALF were calculated. Pathological staining was performed to observe histopathological changes in lung tissue. RT-PCR and Western blot were used to measure the mRNA and protein expression of E-cadherin and vimentin during epithelial-mesenchymal transition (EMT). Results Compared with the control group, the OVA group had marked infiltration of inflammatory cells in the airway, thickening of the airway wall, increased secretion of mucus, and increases in the total number of cells and percentage of eosinophils in BALF (P < 0.01). Compared with the OVA group, the JQ1+OVA group had significantly alleviated airway inflammatory response and significant reductions in the total number of cells and percentage of eosinophils in BALF (P < 0.01). Compared with the control group, the OVA group had significant reductions in the mRNA and protein expression of E-cadherin and significant increases in the mRNA and protein expression of vimentin (P < 0.01); compared with the OVA group, the JQ1+OVA group had significant increases in the mRNA and protein expression of E-cadherin and significant reductions in the mRNA and protein expression of vimentin (P < 0.01); there were no significant differences in these indices between the JQ1+OVA group and the control group (P > 0.05). Conclusions Mice with OVA-induced asthma have airway remodeling during EMT. BET bromodomain inhibitor JQ1 can reduce airway inflammation, inhibit EMT, and alleviate airway remodeling, which provides a new direction for the treatment of asthma.
ZHU Xiao-Hua,LI Qiu-Gen,WANG Jun et al. Mechanism of action of BET bromodomain inhibitor JQ1 in treating airway remodeling in asthmatic mice[J]. CJCP, 2017, 19(12): 1278-1284.
ZHU Xiao-Hua,LI Qiu-Gen,WANG Jun et al. Mechanism of action of BET bromodomain inhibitor JQ1 in treating airway remodeling in asthmatic mice[J]. CJCP, 2017, 19(12): 1278-1284.
Baldacci S, Maio S, Cerrai S, et al. Allergy and asthma:effects of the exposure to particulate matter and biological allergens[J]. Respir Med, 2015, 109(9):1089-1104.
[2]
Bartis D, Thickett DR. Authors' response:epithelial-mesenchymal transition (EMT) is a common molecular programme in epithelial cells which can be triggered by injury[J]. Thorax, 2014, 69(8):769.
[3]
Belkina AC, Nikolajczyk BS, Denis GV. BET protein function is required for inflammation:Brd2 genetic disruption and BET inhibitor JQ1 impair mouse macrophage inflammatory responses[J]. J Immunol, 2013, 190(7):3670-3678.
[4]
Berair R, Brightling CE. Asthma therapy and its effect on airway remodelling[J]. Drugs, 2014, 74(12):1345-1369.
[5]
Bid HK, Phelps DA, Xaio L, et al. The bromodomain BET inhibitor JQ1 suppresses tumor angiogenesis in models of childhood sarcoma[J]. Mol Cancer Ther, 2016, 15(5):1018-1028.
[6]
Chang H, Liu Y, Xue M, et al. Synergistic action of master transcription factors controls epithelial-to-mesenchymal transition[J]. Nucleic Acids Res, 2016, 44(6):2514-2527.
[7]
Chapman HA. Epithelial-mesenchymal interactions in pulmonary fibrosis[J]. Annu Rev Physiol, 2011, 73:413-435.
[8]
Chung KF. Targeting the interleukin pathway in the treatment of asthma[J]. Lancet, 2015, 386(9998):1086-1096.
[9]
de Boer WI, Sharma HS, Baelemans SM, et al. Altered expression of epithelial junctional proteins in atopic asthma:possible role in inflammation[J]. Can J Physiol Pharmacol, 2008, 86(3):105-112.
[10]
Doerner AM, Zuraw BL. TGF-beta1 induced epithelial to mesenchymal transition (EMT) in human bronchial epithelial cells is enhanced by IL-1beta but not abrogated by corticosteroids[J]. Respir Res, 2009, 10:100.
[11]
Emadali A, Rousseaux S, Bruder-Costa J, et al. Identification of a novel BET bromodomain inhibitor-sensitive, gene regulatory circuit that controls Rituximab response and tumour growth in aggressive lymphoid cancers[J]. EMBO Mol Med, 2013, 5(8):1180-1195.
[12]
Filippakopoulos P, Qi J, Picaud S, et al. Selective inhibition of BET bromodomains[J]. Nature, 2010, 468(7327):1067-1073.
Fischer KD, Hall SC, Agrawal DK. Vitamin D supplementation reduces induction of epithelial-mesenchymal transition in allergen sensitized and challenged mice[J]. PLoS One, 2016, 11(2):e0149180.
[15]
Folli C, Descalzi D, Scordamaglia F, et al. New insights into airway remodelling in asthma and its possible modulation[J]. Curr Opin Allergy Clin Immunol, 2008, 8(5):367-375.
[16]
Hirota N, Martin JG. Mechanisms of airway remodeling[J]. Chest, 2013, 144(3):1026-1032.
[17]
Hussong M, Börno ST, Kerick M, et al. The bromodomain protein BRD4 regulates the KEAP1/NRF2-dependent oxidative stress response[J]. Cell Death Dis, 2014, 5:e1195.
[18]
Ijaz T, Pazdrak K, Kalita M, et al. Systems biology approaches to understanding Epithelial Mesenchymal Transition (EMT) in mucosal remodeling and signaling in asthma[J]. World Allergy Organ J, 2014, 7(1):13.
[19]
Kalita M, Tian B, Gao B, et al. Systems approaches to modeling chronic mucosal inflammation[J]. Biomed Res Int, 2013, 2013:505864.
[20]
Khan YM, Kirkham P, Barnes PJ, et al. Brd4 is essential for IL-1β-induced inflammation in human airway epithelial cells[J]. PLoS One, 2014, 9(4):e95051.
[21]
Khan YM, Kirkham P, Barnes PJ, et al. Brd4 is essential for IL-1β-induced inflammation in human airway epithelial cells[J]. PLoS One, 2014, 9(4):e95051.
[22]
Li M, Luan F, Zhao Y, et al. Epithelial-mesenchymal transition:an emerging target in tissue fibrosis[J]. Exp Biol Med (Maywood), 2016, 241(1):1-13.
[23]
Liu T, Liu Y, Miller M, et al. Autophagy plays a role in FSTL1-induced epithelial mesenchymal transition and airway remodeling in asthma[J]. Am J Physiol Lung Cell Mol Physiol, 2017, 313(1):L27-L40.
[24]
Nawshad A, Lagamba D, Polad A, et al. Transforming growth factor-beta signaling during epithelial-mesenchymal transformation:implications for embryogenesis and tumor metastasis[J]. Cells Tissues Organs, 2005, 179(1-2):11-23.
[25]
Park IH, Kang JH, Shin JM, et al. Trichostatin A inhibits epithelial mesenchymal transition induced by TGF-β1 in airway epithelium[J]. PLoS One, 2016, 11(8):e0162058.
[26]
Shahbazi J, Liu PY, Atmadibrata B, et al. The bromodomain inhibitor JQ1 and the histone deacetylase inhibitor panobinostat synergistically reduce N-Myc expression and induce anticancer effects[J]. Clin Cancer Res, 2016, 22(10):2534-2544.
[27]
Shim JM, Lee JS, Russell KE, et al. BET proteins are a key component of immunoglobulin gene expression[J]. Epigenomics, 2017, 9(4):393-406.
[28]
Tang X, Peng R, Phillips JE, et al. Assessment of Brd4 inhibition in idiopathic pulmonary fibrosis lung fibroblasts and in vivo models of lung fibrosis[J]. Am J Pathol, 2013, 183(2):470-479.
[29]
Wang J, Li FS, Pang NN, et al. Inhibition of asthma in OVA sensitized mice model by a traditional uygur herb nepeta bracteata benth[J]. Evid Based Complement Alternat Med, 2016, 2016:5769897.
[30]
Wang L, Wu X, Wang R, et al. BRD4 inhibition suppresses cell growth, migration and invasion of salivary adenoid cystic carcinoma[J]. Biol Res, 2017, 50(1):19.
[31]
Wang N, Yan D, Liu Y, et al. A HuR/TGF-β1 feedback circuit regulates airway remodeling in airway smooth muscle cells[J]. Respir Res, 2016, 17(1):117.
