Anti-apoptotic effect of the Shh signaling pathway in cigarette smoke extract induced MLE 12 apoptosis
Jinhua Li 1, 2, 3
Dandan Zong 1, 2, 3
Yan Chen 1, 2, 3  
Ping Chen 1, 2, 3  
More details
Hide details
Department of Respiratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
Research Unit of Respiratory Disease, Central South University, Changsha, China
Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, China
Yan Chen   

Department of Respiratory Medicine, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
Ping Chen   

Department of Respiratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
Publish date: 2019-06-06
Tob. Induc. Dis. 2019;17(June):49
Many studies have shown that COPD is associated with apoptosis of bronchial or alveolar epithelial cells. Alveolar type II epithelial cells (AECII) play an important role in the pathogenetic process. Cigarette smoke extract (CSE) can induce apoptosis of AECII. The Sonic hedgehog (Shh) pathway is involved in many adult lung diseases. We aimed to verify the anti-apoptotic effect of Shh in the AECII apoptosis induced by CSE.

Mouse lung epithelial type II cells, MLE 12, were treated by 5% CSE for 24 hours. Apoptosis was measured using flow cytometry and expression of the anti-apoptotic factor BCL-2. The role of the hedgehog pathway in cell apoptosis was assessed by real-time RT-PCT and western blotting to measure the expression of Sonic hedgehog, Patched 1, and Gli1. Recombinant mouse Sonic hedgehog was used to overexpress the Shh pathway.

CSE could induce MLE 12 apoptosis. Sonic hedgehog, Patched 1 and the Gli1 were decreased in the CSE induced MLE 12 apoptosis. Overexpression Shh could partially reverse the CSE induced apoptosis.

Activation of the Shh pathway may relieve the CSE induced MLE 12 apoptosis.

The authors have completed and submitted an ICMJE form for disclosure of potential conflicts of interest and they declare that they have no competing interests, financial or otherwise, related to the current work. All the authors report grants from National Natural Science Foundation of China and grants from Natural Science Foundation of Hunan Province, China, during the conduct of the study.
This work was supported by National Natural Science Foundation of China (81800045) and Natural Science Foundation of Hunan Province, China (2018JJ3747).
Not commissioned; externally peer reviewed.
GBD 2015 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388(10053):1545-1602.
Wang C, Xu J, Yang L, et al. Prevalence and risk factors of chronic obstructive pulmonary disease in China (the China Pulmonary Health [CPH] study): a national cross-sectional study. Lancet. 2018;391(10131):1706-1717. doi:10.1016/s0140-6736(18)30841-9.
Gogebakan B, Bayraktar R, Ulaslı M, Oztuzcu S, Tasdemir D, Bayram H. The role of bronchial epithelial cell apoptosis in the pathogenesis of COPD. Molecular Biology Reports. 2014;41(8):5321-5327. doi:10.1007/s11033-014-3403-3.
Barnes PJ, Shapiro SD, Pauwels RA. Chronic obstructive pulmonary disease: molecular and cellular mechanisms. Eur Respir J. 2003;22(4):672-688. doi:10.1183/09031936.03.00040703.
Comer DM, Kidney JC, Ennis M, Elborn JS. Airway epithelial cell apoptosis and inflammation in COPD, smokers and nonsmokers. The European Respiratory Journal. 2013;41(5):1058-1067. doi:10.1183/09031936.00063112.
Tan S, Jiang D, Hu R, et al. Endoplasmic Reticulum Stress Induces HRD1 to Protect Alveolar Type II Epithelial Cells from Apoptosis Induced by Cigarette Smoke Extract. Cellular Physiology and Biochemistry. 2017;43(4):1337-1345. doi:10.1159/000481845.
Long YJ, Liu XP, Chen SS, Zong DD, Chen Y, Chen P. miR-34a is involved in CSE-induced apoptosis of human pulmonary microvascular endothelial cells by targeting Notch-1 receptor protein. Respir Res. 2018;19(1):21. doi:10.1186/s12931-018-0722-2.
Gea J, Pascual S, Casadevall C, Orozco-Levi M, Barreiro E. Muscle dysfunction in chronic obstructive pulmonary disease: update on causes and biological findings. J Thorac Dis. 2015;7(10):E418-E438.
Kugler MC, Joyner AL, Loomis CA, Munger JS. Sonic hedgehog signaling in the lung. From development to disease. Am J Respir Cell Mol Biol. 2015;52(1):1-13. doi:10.1165/rcmb.2014-0132tr.
Choy SW, Cheng SH. Hedgehog signaling. Vitam Horm. 2012;88:1-23. doi:10.1016/b978-0-12-394622-5.00001-8.
Li X, Wang X, Xie C, et al. Sonic hedgehog and Wnt/beta-catenin pathways mediate curcumin inhibition of breast cancer stem cells. Anticancer Drugs. 2018;29(3):208-215. doi:10.1097/cad.0000000000000584.
Chen KY, Chiu CH, Wang LC. Anti-apoptotic effects of Sonic hedgehog signalling through oxidative stress reduction in astrocytes co-cultured with excretory-secretory products of larval Angiostrongylus cantonensis. Scientific Reports. 2017;7:41574. doi:10.1038/srep41574.
Meng QH, Liu HB, Wang JB. Polydatin ameliorates renal ischemia/reperfusion injury by decreasing apoptosis and oxidative stress through activating sonic hedgehog signaling pathway. Food Chem Toxicol. 2016;96:215-225. doi:10.1016/j.fct.2016.07.032.
Kumari S, Chaurasia SN, Kumar K, Dash D. Anti-apoptotic role of sonic hedgehog on blood platelets. Thromb Res. 2014;134(6):1311-1315. doi:10.1016/j.thromres.2014.09.022.
Dang HX, Li J, Liu C, et al. CGRP attenuates hyperoxia-induced oxidative stress-related injury to alveolar epithelial type II cells via the activation of the Sonic hedgehog pathway. Int J Mol Med. 2017;40(1):209-216. doi:10.3892/ijmm.2017.3002.
Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008;3(6):1101-1108. doi:10.1038/nprot.2008.73.
Morissette MC, Parent J, Milot J. Alveolar epithelial and endothelial cell apoptosis in emphysema: what we know and what we need to know. Int J Chron Obstruct Pulmon Dis. 2009;4:19-31. doi:10.2147/copd.s4432.
Zhou T, Hu Y, Wang Y, et al. Fine particulate matter (PM2.5) aggravates apoptosis of cigarette-inflamed bronchial epithelium in vivo and vitro. Environ Pollut. 2018;248:1-9. doi:10.1016/j.envpol.2018.11.054.
Lee HS, Park DE, Lee JW, et al. IL-23 secreted by bronchial epithelial cells contributes to allergic sensitization in asthma model: role of IL-23 secreted by bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2017;312(1):L13-L21. doi:10.1152/ajplung.00114.2016.
Wang X, Wei S, Zhao Y, et al. Anti-proliferation of breast cancer cells with itraconazole: Hedgehog pathway inhibition induces apoptosis and autophagic cell death. Cancer Lett. 2017;385:128-136. doi:10.1016/j.canlet.2016.10.034.
Zhu J Y, Yang X, Chen Y, et al. Curcumin Suppresses Lung Cancer Stem Cells via Inhibiting Wnt/beta-catenin and Sonic Hedgehog Pathways. Phytother Res. 2017;31(4):680-688. doi:10.1002/ptr.5791.
Bolanos AL, Milla CM, Lira JC, et al. Role of Sonic Hedgehog in idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2012;303(11):L978-L990. doi:10.1152/ajplung.00184.2012.
Krause A, Xu Y, Joh J, et al. Overexpression of sonic Hedgehog in the lung mimics the effect of lung injury and compensatory lung growth on pulmonary Sca-1 and CD34 positive cells. Mol Ther. 2010;18(2):404-412. doi:10.1038/mt.2009.229.