Comparison of expression of dipeptidyl peptidase 4 and angiotensin-converting enzyme 2 in lung tissues of four different lung diseases_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

CHEN Hao ,  HU Ke

Department of Respiratory and Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P. R. China;

Corresponding author：

Keywords：

Dipeptidyl peptidase 4; angiotensin-converting enzyme 2; coronavirus disease 2019; chronic obstructive pulmonary disease; smoking

DOI：

10.7507/1671-6205.202301031

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Objective To investigate the expression of dipeptidyl peptidase 4 (DPP4) and angiotensin-converting enzyme 2 (ACE2) in lung tissues of patients with four different diseases including coronavirus disease 2019 (COVID-19), chronic obstructive pulmonary disease (COPD), pulmonary sarcoidosis and pulmonary bullae, and to find out the potential risk factors affecting COVID-19. Methods This study retrospectively analyzed the clinical data of 40 patients admitted to Renmin Hospital of Wuhan University with COVID-19 (COVID-19 group), COPD (COPD group), pulmonary sarcoidosis (pulmonary sarcoidosis group) and pulmonary bullae (pulmonary bullae group) and surgically resected paraffin-embedded pathological lung tissues were obtained from their lung tissue pathological specimens after surgery and paraffin embedding. The GEO database (https://www.ncbi.nlm.nih.gov/geo/) was used for bioinformatics analysis to explore the expression difference of DPP4 and ACE2 mRNA in COVID-19, COPD, pulmonary sarcoidosis and normal lung tissues. Immunohistochemistry method was used to detect the expression of DPP4 and ACE2 protein in lung tissues of each group and the average optical density was measured by image analysis software. Results The results of GEO database analysis showed that compared with pulmonary bullae group, the expression level of DPP4 mRNA had no significant difference in the COPD group and pulmonary sarcoidosis group (both P>0.05), but it was increased in the COVID-19 group (P<0.05); There was no significant difference in the expression level of ACE mRNA in the pulmonary sarcoidosis group (P>0.05), but it was increased in the lung tissue of COVID-19 group and COPD group (both P<0.05). The results of immunohistochemistry showed that DPP4 and ACE2 proteins were lowly expressed in the pulmonary sarcoidosis group and pulmonary bullae group, while their expression level was high in COVID-19 and COPD groups without significant difference (P>0.05). The expression of DPP4 and ACE2 proteins in COVID-19 group was not related to the patient’s gender and age (P>0.05), but was related to smoking and long smoking duration (P<0.05), and there was a positive correlation between DPP4 and ACE2 expression (P<0.05). Conclusions DPP4 and ACE2 proteins are lowly expressed in the pulmonary sarcoidosis group and pulmonary bullae group, while their expression level is high in COVID-19 and COPD groups. There is no significant difference in the expression level of DPP4 and ACE2 protein in the COVID-19 and COPD lung tissues. There may be a positive correlation between DPP4 and ACE2 proteins expression in lung tissue, and smoking may be a potential risk factor for COVID-19.

Citation： CHEN Hao, HU Ke. Comparison of expression of dipeptidyl peptidase 4 and angiotensin-converting enzyme 2 in lung tissues of four different lung diseases. Chinese Journal of Respiratory and Critical Care Medicine, 2023, 22(5): 319-325. doi: 10.7507/1671-6205.202301031 Copy

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2.	Pinto BGG, Oliveira AER, Singh Y, et al. ACE2 expression is increased in the lungs of patients with comorbidities associated with severe COVID-19. J Infect Dis, 2020, 222(4): 556-563.
3.	Smith JC, Sausville EL, Girish V, et al. Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract. Dev cell, 2020, 53(5): 514-529.
4.	Jacobs M, Van Eeckhoutte HP, Wijnant SRA, et al. Increased expression of ACE2, the SARS-CoV-2 entry receptor, in alveolar and bronchial epithelium of smokers and COPD subjects. Eur Respir J, 2020, 56(2): 2002378.
5.	Vankadari N, Wilce JA. Emerging COVID-19 coronavirus: glycan shield and structure prediction of spike glycoprotein and its interaction with human CD26. Emerg Microbes Infect, 2020, 9(1): 601-604.
6.	Li Y, Zhang ZD, Yang L, et al. The MERS-CoV receptor DPP4 as a candidate binding target of the SARS-CoV-2 spike. iScience, 2020, 23(8): 101400.
7.	Du HZ, Wang DW, Chen C. The potential effects of DPP-4 inhibitors on cardiovascular system in COVID-19. J Cell Mol Med, 2020, 24(18): 10274-10278.
8.	Maremanda KP, Sundar IK, Li DM, et al. Age-dependent assessment of genes involved in cellular senescence, telomere, and mitochondrial pathways in human lung tissue of smokers, COPD, and IPF: associations with SARS-CoV-2 COVID-19 ACE2-TMPRSS2-Furin-DPP4 Axis. Front Pharmacol, 2020, 11: 584637.
9.	Seys LJM, Widagdo W, Verhamme FM, et al. DPP4, the Middle East Respiratory Syndrome Coronavirus receptor, is upregulated in lungs of smokers and chronic obstructive pulmonary disease patients. Clin Infect Dis, 2018, 66(1): 45-53.
10.	国家卫生健康委员会办公厅, 国家中医药管理局办公室. 新型冠状病毒肺炎诊疗方案(试行第九版). 中国病毒病杂志, 2022, 12(3): 161-169.
11.	中华医学会呼吸病学分会慢性阻塞性肺疾病学组, 中国医师协会呼吸医师分会慢性阻塞性肺疾病工作委员会. 慢性阻塞性肺疾病诊治指南(2021年修订版). 中华结核和呼吸杂志, 2021, 44(3): 170-205.
12.	Crouser ED, Maier LA, Wilson KC, et al. Diagnosis and Detection of Sarcoidosis. An Official American Thoracic Society Clinical Practice Guideline. Am J Respir Crit Care Med, 2020, 201(8): e26-e51.
13.	Chua RL, Lukassen S, Trump S, et al. COVID-19 severity correlates with airway epithelium-immune cell interactions identified by single-cell analysis. Nat Biotechnol, 2020, 38(8): 970-979.
14.	Hou YJ, Okuda K, Edwards CE, et al. SARS-CoV-2 reverse genetics reveals a variable infection gradient in the respiratory tract. Cell, 2020, 182(2): 429-446.
15.	Bao LL, Deng W, Huang BY, et al. The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice. Nature, 2020, 583(7818): 830-833.
16.	Zhang HJ, Rostami MR, Leopold PL, et al. Expression of the SARS-CoV-2 ACE2 receptor in the human airway epithelium. Am J Respir Crit Care Med, 2020, 202(2): 219-229.
17.	Murdocca M, Citro G, Romeo I, et al. Peptide platform as a powerful tool in the fight against COVID-19. Viruses, 2021, 13(8): 1667.
18.	Kleine-Weber H, Schroeder S, Krüger N, et al. Polymorphisms in dipeptidyl peptidase 4 reduce host cell entry of Middle East respiratory syndrome coronavirus. Emerg Microbe Infect, 2020, 9(1): 155-168.
19.	Gheware A, Ray A, Rana D, et al. ACE2 protein expression in lung tissues of severe COVID-19 infection. Sci Rep, 2022, 12(1): 4058.
20.	South AM, Tomlinson L, Edmonston D, et al. Controversies of renin-angiotensin system inhibition during the COVID-19 pandemic. Nat Rev Nephorl, 2020, 16(6): 305-307.
21.	Nikiforuk AM, Kuchinski KS, Twa DW, et al. The contrasting role of nasopharyngeal angiotensin converting enzyme 2 ( ACE2) transcription in SARS-CoV-2 infection: a cross-sectional study of people tested for COVID-19 in British Columbia, Canada. EBioMedicine, 2021, 66: 103316.
22.	Watson A, Öberg L, Angermann B, et al. Dysregulation of COVID-19 related gene expression in the COPD lung. Respir Res, 2021, 22(1): 164.
23.	Fließer E, Birnhuber A, Marsh LM, et al. Dysbalance of ACE2 levels - a possible cause for severe COVID-19 outcome in COPD. J Pathol Clin Res, 2021, 7(5): 446-458.
24.	Alqahtani JS, Oyelade T, Aldhahir AM, et al. Prevalence, severity and mortality associated with COPD and smoking in patients with COVID-19: a rapid systematic review and meta-analysis. PloS One, 2020, 15(5): e233147.
25.	Seys LJM, Widagdo W, Verhamme FM, et al. DPP4, the Middle East Respiratory Syndrome Coronavirus receptor, is upregulated in lungs of smokers and chronic obstructive pulmonary disease patients. Clin Infect Dis, 2018, 66(1): 45-53.
26.	Liu AB, Zhang X, Li RG, et al. Overexpression of the SARS-CoV-2 receptor ACE2 is induced by cigarette smoke in bronchial and alveolar epithelia. J Pathol, 2021, 253(1): 17-30.
27.	Cai GS, Bossé Y, Xiao FF, et al. Tobacco smoking increases the lung gene expression of ACE2, the receptor of SARS-CoV-2. Am J Respir Crit Care Med, 2020, 201(12): 1557-1559.
28.	Radzikowska U, Ding M, Tan G, et al. Distribution of ACE2, CD147, CD26, and other SARS-CoV-2 associated molecules in tissues and immune cells in health and in asthma, COPD, obesity, hypertension, and COVID-19 risk factors. Allergy, 2020, 75(11): 2829-2845.
29.	Amati F, Vancheri C, Latini A, et al. Expression profiles of the SARS-CoV-2 host invasion genes in nasopharyngeal and oropharyngeal swabs of COVID-19 patients. Heliyon, 2020, 6(10): e05143.
30.	Qi FR, Qian S, Zhang SY, et al. Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses. Biochem Biophys Res Commun, 2020, 526(1): 135-140.
31.	Spitalieri P, Centofanti F, Murdocca M, et al. Two different therapeutic approaches for SARS-CoV-2 in hiPSCs-derived lung organoids. Cells, 2022, 11(7) : 1235.
32.	Cameron K, Rozano L, Falasca M, et al. Does the SARS-CoV-2 spike protein receptor binding domain interact effectively with the DPP4 (CD26) receptor? A molecular docking study. Int J Mol Sci, 2021, 22(13): 7001.

1. Solerte SB, Di Sabatino A, Galli M, et al. Dipeptidyl peptidase-4 (DPP4) inhibition in COVID-19. Acta Diabetol, 2020, 57(7): 779-783.
2. Pinto BGG, Oliveira AER, Singh Y, et al. ACE2 expression is increased in the lungs of patients with comorbidities associated with severe COVID-19. J Infect Dis, 2020, 222(4): 556-563.
3. Smith JC, Sausville EL, Girish V, et al. Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract. Dev cell, 2020, 53(5): 514-529.
4. Jacobs M, Van Eeckhoutte HP, Wijnant SRA, et al. Increased expression of ACE2, the SARS-CoV-2 entry receptor, in alveolar and bronchial epithelium of smokers and COPD subjects. Eur Respir J, 2020, 56(2): 2002378.
5. Vankadari N, Wilce JA. Emerging COVID-19 coronavirus: glycan shield and structure prediction of spike glycoprotein and its interaction with human CD26. Emerg Microbes Infect, 2020, 9(1): 601-604.
6. Li Y, Zhang ZD, Yang L, et al. The MERS-CoV receptor DPP4 as a candidate binding target of the SARS-CoV-2 spike. iScience, 2020, 23(8): 101400.
7. Du HZ, Wang DW, Chen C. The potential effects of DPP-4 inhibitors on cardiovascular system in COVID-19. J Cell Mol Med, 2020, 24(18): 10274-10278.
8. Maremanda KP, Sundar IK, Li DM, et al. Age-dependent assessment of genes involved in cellular senescence, telomere, and mitochondrial pathways in human lung tissue of smokers, COPD, and IPF: associations with SARS-CoV-2 COVID-19 ACE2-TMPRSS2-Furin-DPP4 Axis. Front Pharmacol, 2020, 11: 584637.
9. Seys LJM, Widagdo W, Verhamme FM, et al. DPP4, the Middle East Respiratory Syndrome Coronavirus receptor, is upregulated in lungs of smokers and chronic obstructive pulmonary disease patients. Clin Infect Dis, 2018, 66(1): 45-53.
10. 国家卫生健康委员会办公厅, 国家中医药管理局办公室. 新型冠状病毒肺炎诊疗方案(试行第九版). 中国病毒病杂志, 2022, 12(3): 161-169.
11. 中华医学会呼吸病学分会慢性阻塞性肺疾病学组, 中国医师协会呼吸医师分会慢性阻塞性肺疾病工作委员会. 慢性阻塞性肺疾病诊治指南(2021年修订版). 中华结核和呼吸杂志, 2021, 44(3): 170-205.
12. Crouser ED, Maier LA, Wilson KC, et al. Diagnosis and Detection of Sarcoidosis. An Official American Thoracic Society Clinical Practice Guideline. Am J Respir Crit Care Med, 2020, 201(8): e26-e51.
13. Chua RL, Lukassen S, Trump S, et al. COVID-19 severity correlates with airway epithelium-immune cell interactions identified by single-cell analysis. Nat Biotechnol, 2020, 38(8): 970-979.
14. Hou YJ, Okuda K, Edwards CE, et al. SARS-CoV-2 reverse genetics reveals a variable infection gradient in the respiratory tract. Cell, 2020, 182(2): 429-446.
15. Bao LL, Deng W, Huang BY, et al. The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice. Nature, 2020, 583(7818): 830-833.
16. Zhang HJ, Rostami MR, Leopold PL, et al. Expression of the SARS-CoV-2 ACE2 receptor in the human airway epithelium. Am J Respir Crit Care Med, 2020, 202(2): 219-229.
17. Murdocca M, Citro G, Romeo I, et al. Peptide platform as a powerful tool in the fight against COVID-19. Viruses, 2021, 13(8): 1667.
18. Kleine-Weber H, Schroeder S, Krüger N, et al. Polymorphisms in dipeptidyl peptidase 4 reduce host cell entry of Middle East respiratory syndrome coronavirus. Emerg Microbe Infect, 2020, 9(1): 155-168.
19. Gheware A, Ray A, Rana D, et al. ACE2 protein expression in lung tissues of severe COVID-19 infection. Sci Rep, 2022, 12(1): 4058.
20. South AM, Tomlinson L, Edmonston D, et al. Controversies of renin-angiotensin system inhibition during the COVID-19 pandemic. Nat Rev Nephorl, 2020, 16(6): 305-307.
21. Nikiforuk AM, Kuchinski KS, Twa DW, et al. The contrasting role of nasopharyngeal angiotensin converting enzyme 2 ( ACE2) transcription in SARS-CoV-2 infection: a cross-sectional study of people tested for COVID-19 in British Columbia, Canada. EBioMedicine, 2021, 66: 103316.
22. Watson A, Öberg L, Angermann B, et al. Dysregulation of COVID-19 related gene expression in the COPD lung. Respir Res, 2021, 22(1): 164.
23. Fließer E, Birnhuber A, Marsh LM, et al. Dysbalance of ACE2 levels - a possible cause for severe COVID-19 outcome in COPD. J Pathol Clin Res, 2021, 7(5): 446-458.
24. Alqahtani JS, Oyelade T, Aldhahir AM, et al. Prevalence, severity and mortality associated with COPD and smoking in patients with COVID-19: a rapid systematic review and meta-analysis. PloS One, 2020, 15(5): e233147.
25. Seys LJM, Widagdo W, Verhamme FM, et al. DPP4, the Middle East Respiratory Syndrome Coronavirus receptor, is upregulated in lungs of smokers and chronic obstructive pulmonary disease patients. Clin Infect Dis, 2018, 66(1): 45-53.
26. Liu AB, Zhang X, Li RG, et al. Overexpression of the SARS-CoV-2 receptor ACE2 is induced by cigarette smoke in bronchial and alveolar epithelia. J Pathol, 2021, 253(1): 17-30.
27. Cai GS, Bossé Y, Xiao FF, et al. Tobacco smoking increases the lung gene expression of ACE2, the receptor of SARS-CoV-2. Am J Respir Crit Care Med, 2020, 201(12): 1557-1559.
28. Radzikowska U, Ding M, Tan G, et al. Distribution of ACE2, CD147, CD26, and other SARS-CoV-2 associated molecules in tissues and immune cells in health and in asthma, COPD, obesity, hypertension, and COVID-19 risk factors. Allergy, 2020, 75(11): 2829-2845.
29. Amati F, Vancheri C, Latini A, et al. Expression profiles of the SARS-CoV-2 host invasion genes in nasopharyngeal and oropharyngeal swabs of COVID-19 patients. Heliyon, 2020, 6(10): e05143.
30. Qi FR, Qian S, Zhang SY, et al. Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses. Biochem Biophys Res Commun, 2020, 526(1): 135-140.
31. Spitalieri P, Centofanti F, Murdocca M, et al. Two different therapeutic approaches for SARS-CoV-2 in hiPSCs-derived lung organoids. Cells, 2022, 11(7) : 1235.
32. Cameron K, Rozano L, Falasca M, et al. Does the SARS-CoV-2 spike protein receptor binding domain interact effectively with the DPP4 (CD26) receptor? A molecular docking study. Int J Mol Sci, 2021, 22(13): 7001.

Chinese Journal of Respiratory and Critical Care Medicine

Comparison of expression of dipeptidyl peptidase 4 and angiotensin-converting enzyme 2 in lung tissues of four different lung diseases

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