Decreased expression of endothelial cell specific molecule-1 in lung tissue in emphysematous mice and stable COPD patients

Document Type : Original Article


1 Division of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China

2 Research Unit of Respiratory Diseases, Central South University, Changsha 410011, Hunan, China

3 Diagnosis and Treatment Center of Respiratory Diseases, Central South University, Changsha 410011, Hunan, China


Objective(s): Apoptosis of pulmonary alveolar septal cells is a pathogenesis characteristic of chronic obstructive pulmonary disease (COPD). Endothelial cell specific molecule-1 (ESM-1) plays an important role in apoptosis of cells. Here, we aimed to determine whether ESM-1 can involve in cell apoptosis in emphysematous mice and stable COPD patients. The sample size of patients was small, so two separate models were studied.
Materials and Methods: At day 0, 11, and 22, murine were injected IP with 0.3 ml of PBS/Cigarette smoke extract, and euthanized at day 28. Lung tissues from 20 stable COPD patients and 12 Controls were evaluated. Serum was obtained from 25 stable COPD patients and 12 healthy Controls. Pulmonary function, pathology, pulmonary apoptosis index (AI), expression of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF) and ESM-1 in lung tissue, and concentration of ESM-1 in serum were tested.
Results: Protein expression of ESM-1, VEGF and HGF were decreased significantly in emphysematous mice (p <0.05), while AI was increased (p <0.05). Correlation analysis indicated that association between AI and ESM-1 was negative (p <0.01), VEGF and ESM-1 was positive (p <0.01), and HGF and ESM-1 was positive (p <0.01). In stable COPD patients, we proved that ESM-1, VEGF and HGF were decreased significantly, while AI was increased (p <0.05). Correlation between AI and ESM-1 was negative (p <0.01), VEGF and ESM-1 was positive (p <0.01), and HGF and ESM-1 was positive (p <0.01).
Conclusion: ESM-1 expression decreased and AI increased in emphysematous mice and stable COPD patients. Findings suggested that ESM-1 may be involved in anti-apoptotic therapy of COPD.


1. Ozretić P, da Silva Filho MI, Catalano C, Sokolović I, Vukić-Dugac A, Šutić M, et al. Association of NLRP1 coding polymorphism with lung function and serum IL-1β concentration in patients diagnosed with chronic obstructive pulmonary disease (COPD). Genes (Basel) 2019 ;10:783-796.
2. Chen L, Luo L, Kang N, He X, Li T, Chen Y. The protective effect of HBO1 on cigarette smoke extract-induced apoptosis in airway epithelial cells. Int J Chron Obstruct Pulmon Dis 2020;15:15-24.
3. He X, Li T, Kang N, Zeng H, Ren S, Zong D, et al. The protective effect of PRMT6 overexpression on cigarette smoke extract-induced murine emphysema model. Int J Chron Obstruct Pulmon Dis 2017;12:3245-3254.
4. Shi Z, Chen Y, Cao J, Zeng H, Yang Y, Chen P, et al. Intratracheal transplantation of endothelial progenitor cells attenuates smoking-induced COPD in mice. Int J Chron Obstruct Pulmon Dis 2017;12:947-960.  
5. Zhang Y, Cao J, Chen Y, Chen P, Peng H, Cai S, et al. Intraperitoneal injection of cigarette smoke extract induced emphysema, and injury of cardiac and skeletal muscles in BALB/C mice. Exp Lung Res 2013;39:18-31.
6. Lee KH, Lee CH, Jeong J, Jang AH, Yoo CG. Neutrophil Elastase Differentially Regulates Interleukin 8 (IL-8) and Vascular Endothelial Growth Factor (VEGF) Production by Cigarette Smoke Extract. J Biol Chem 2015;290:28438-28445.
7. Calvi C, Podowski M, Lopez-Mercado A, Metzger S, Misono K, Malinina A, et al. Hepatocyte growth factor, a determinant of airspace homeostasis in the murine lung. PLoS Genet 2013;9:e1003228.
8. Tsai JC, Zhang J, Minami T, Voland C, Zhao S, Yi X, et al. Cloning and characterization of the human lung endothelial-cell-specific molecule-1 promoter. J Vasc Res 2002; 39:148-159.
9. Béchard D, Gentina T, Delehedde M, Scherpereel A, Lyon M, Aumercier M, et al. Endocan is a novel chondroitin sulfate/dermatan sulfate proteoglycan that promotes hepatocyte growth factor/scatterfactormitogenic activity. J Biol Chem 2001; 276: 48341-48349.
10. Afsar B, Takir M, Kostek O, Covic A, Kanbay M. Endocan: a new molecule playing a role in the development of hypertension and chronic kidney disease?. J Clin Hypertens (Greenwich) 2014;16:914-916.
11. Shin JW, Huggenberger R, Detmar M. Transcriptional profiling of VEGF-A and VEGF-C target genes in lymphatic endothelium reveals endothelial-specific molecule-1 as a novel mediator of lymphangiogenesis. Blood 2008; 112: 2318-2326.
12. Li C, Geng H, Ji L, Ma X, Yin Q, Xiong H. ESM-1: A Novel tumor biomaker and its research advances. Anticancer Agents Med Chem 2019;19:1687-1694.
13. Pihtili A, Bingol Z, Kiyan E. Serum endocan levels in patients with stable COPD. Int J Chron Obstruct Pulmon Dis 2018;13:3367-3372.
14. Dai L, He J, Chen J, Wang T, Liu L, Shen Y, et al. The association of elevated circulating endocan levels with lung function decline in COPD patients. Int J Chron Obstruct Pulmon Dis 2018;13:3699-3706.
15. Zhang X, Zhuang R, Wu H, Chen J, Wang F, Li G, et al. A novel role of endocan in alleviating LPS-induced acute lung injury. Life Sci 2018;202:89-97.
16. Gaudet A, Parmentier E, Dubucquoi S, Poissy J, Duburcq T, Lassalle P, et al. Low endocan levels are predictive of Acute Respiratory Distress Syndrome in severe sepsis and septic shock. J Crit Care 2018;47:121-126.
17. Sun L, Sun C, Sun J, Yang W. Downregulation of ENDOCAN in myeloid leukemia cells inhibits proliferation and promotes apoptosis by suppressing nuclear factorκB activity. Mol Med Rep 2019;19:3247-3254.
18. Yang J, Sheng S, Yang Q, Li L, Qin S, Yu S, et al. Endocan silencing induces programmed cell death in hepatocarcinoma. Oncol Lett 2017;14:5333-5339.
19. Lu GJ, Shao CJ, Zhang Y, Wei YY, Xie WP, Kong H. Diagnostic and prognostic values of endothelial-cell-specific molecule-1 with malignant pleural effusions in patients with non-small cell lung cancer. Oncotarget 2017;8:49217-49223.
20. Kennelly H, Mahon BP, English K. Human mesenchymal stromal cells exert HGF dependent cytoprotective effects in a human relevant pre-clinical model of COPD. Sci Rep 2016;6:38207-38217.
21. Cho RJ, Kim YS, Kim JY, Oh YM. Human adipose-derived mesenchymal stem cell spheroids improve recovery in a mouse model of elastase-induced emphysema. BMB Rep 2017;50:79-84.
22. Jiménez J, Lesage F, Richter J, Nagatomo T, Salaets T, Zia S, et al. Upregulation of vascular endothelial growth factor in amniotic fluid stem cells enhances their potential to attenuate lung injury in a preterm rabbit model of bronchopulmonary dysplasia. Neonatology 2018;113:275-285.
23. Takahashi Y, Izumi Y, Kohno M, Ikeda E, Nomori H. Airway administration of vascular endothelial growth factor siRNAs induces transient airspace enlargement in mice. Int J Med Sci 2013;10:1702-1714.
24. Wan YF, Huang ZH, Jing K, Li J, Wang Y, Xu CQ, et al. Azithromycin attenuates pulmonary inflammation and emphysema in smoking-induced COPD model in rats. Respir Care 2015;60:128-134.
25. Kawamoto T, Kanazawa H, Tochino Y, Kawaguchi T. Evaluation of the severity of small airways obstruction and alveolar destruction in chronic obstructive pulmonary disease. Respir Med 2018;141:159-164.  
26. Prakash Muyal J, Kumar D, Kotnala S, Muyal V, Kumar Tyagi A. Recombinant human keratinocyte growth factor induces Akt mediated cell survival progression in emphysematous mice. Arch Bronconeumol 2015;51:328-337.
27. Sun Y, An N, Li J, Xia J, Tian Y, Zhao P, et al. miRNA-206 regulates human pulmonary microvascular endothelial cell apoptosis via targeting in chronic obstructive pulmonary disease. J Cell Biochem 2019;120:6223-6236.