An Increased Proportion of Apoptosis in CD4+ T Lymphocytes Isolated from the Peripheral Blood in Patients with Stable Chronic Obstructive Pulmonary Disease

  • Ju, Jinyung (Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Wonkwang University Sanbon Hospital, Wonkwang University College of Medicine)
  • Received : 2017.06.28
  • Accepted : 2017.09.13
  • Published : 2018.04.30


Background: The pathophysiology of chronic obstructive pulmonary disease (COPD) includes inflammation, oxidative stress, an imbalance of proteases and antiproteases and apoptosis which has been focused on lately. Abnormal apoptotic events have been demonstrated in both epithelial and endothelial cells, as well as in inflammatory cells including neutrophils and lymphocytes in the lungs of COPD patients. An increased propensity of activated T lymphocytes to undergo apoptosis has been observed in the peripheral blood of COPD patients. Therefore, the apoptosis of T lymphocytes without activating them was investigated in this study. Methods: Twelve control subjects, 21 stable COPD patients and 15 exacerbated COPD patients were recruited in the study. The T lymphocytes were isolated from the peripheral blood using magnetically activated cell sorting. Apoptosis of the T lymphocytes was assessed with flow cytometry using Annexin V and 7-aminoactinomycin D. Apoptosis of T lymphocytes at 24 hours after the cell culture was measured so that the T lymphocyte apoptosis among the control and the COPD patients could be compared. Results: Stable COPD patients had increased rates of $CD4^+$ T lymphocyte apoptosis at 24 hours after the cell culture, more than the $CD4^+$ T lymphocyte apoptosis which appeared in the control group, while the COPD patients with acute exacerbation had an amplified response of $CD4^+$ T lymphocyte apoptosis as well as of $CD8^+$ T lymphocyte apoptosis at 24 hours after the cell culture. Conclusion: Stable COPD patients have more apoptosis of $CD4^+$ T lymphocytes, which can be associated with the pathophysiology of COPD in stable conditions.


  1. Global Strategy for the Diagnosis, Management and Prevention of COPD [Internet]. Gaithersberg: Global Initiative for Chronic Obstructive Lung Disease; 2017 [cited 2017 Dec 1]. Available from:
  2. Barnes PJ, Shapiro SD, Pauwels RA. Chronic obstructive pulmonary disease: molecular and cellular mechanisms. Eur Respir J 2003;22:672-88.
  3. Demedts IK, Brusselle GG, Bracke KR, Vermaelen KY, Pauwels RA. Matrix metalloproteinases in asthma and COPD. Curr Opin Pharmacol 2005;5:257-63.
  4. Rahman I. Oxidative stress in pathogenesis of chronic obstructive pulmonary disease: cellular and molecular mechanisms. Cell Biochem Biophys 2005;43:167-88.
  5. Segura-Valdez L, Pardo A, Gaxiola M, Uhal BD, Becerril C, Selman M. Upregulation of gelatinases A and B, collagenases 1 and 2, and increased parenchymal cell death in COPD. Chest 2000;117:684-94.
  6. Imai K, Mercer BA, Schulman LL, Sonett JR, D'Armiento JM. Correlation of lung surface area to apoptosis and proliferation in human emphysema. Eur Respir J 2005;25:250-8.
  7. Yokohori N, Aoshiba K, Nagai A; Respiratory Failure Research Group in Japan. Increased levels of cell death and proliferation in alveolar wall cells in patients with pulmonary emphysema. Chest 2004;125:626-32.
  8. Calabrese F, Giacometti C, Beghe B, Rea F, Loy M, Zuin R, et al. Marked alveolar apoptosis/proliferation imbalance in endstage emphysema. Respir Res 2005;6:14.
  9. Kasahara Y, Tuder RM, Cool CD, Lynch DA, Flores SC, Voelkel NF. Endothelial cell death and decreased expression of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in emphysema. Am J Respir Crit Care Med 2001;163(3 Pt 1):737-44.
  10. Demedts IK, Demoor T, Bracke KR, Joos GF, Brusselle GG. Role of apoptosis in the pathogenesis of COPD and pulmonary emphysema. Respir Res 2006;7:53.
  11. Saetta M, Baraldo S, Corbino L, Turato G, Braccioni F, Rea F, et al. CD8+ve cells in the lungs of smokers with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999;160:711-7.
  12. Barry M, Bleackley RC. Cytotoxic T lymphocytes: all roads lead to death. Nat Rev Immunol 2002;2:401-9.
  13. Frisch SM, Screaton RA. Anoikis mechanisms. Curr Opin Cell Biol 2001;13:555-62.
  14. Plataki M, Tzortzaki E, Rytila P, Demosthenes M, Koutsopoulos A, Siafakas NM. Apoptotic mechanisms in the pathogenesis of COPD. Int J Chron Obstruct Pulmon Dis 2006;1:161-71.
  15. Hodge S, Hodge G, Holmes M, Reynolds PN. Increased airway epithelial and T-cell apoptosis in COPD remains despite smoking cessation. Eur Respir J 2005;25:447-54.
  16. Hodge SJ, Hodge GL, Reynolds PN, Scicchitano R, Holmes M. Increased production of TGF-beta and apoptosis of T lymphocytes isolated from peripheral blood in COPD. Am J Physiol Lung Cell Mol Physiol 2003;285:L492-9.
  17. Saetta M, Di Stefano A, Turato G, Facchini FM, Corbino L, Mapp CE, et al. CD8+ T-lymphocytes in peripheral airways of smokers with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;157(3 Pt 1):822-6.
  18. Lehmann C, Wilkening A, Leiber D, Markus A, Krug N, Pabst R, et al. Lymphocytes in the bronchoalveolar space reenter the lung tissue by means of the alveolar epithelium, migrate to regional lymph nodes, and subsequently rejoin the systemic immune system. Anat Rec 2001;264:229-36.
  19. Majo J, Ghezzo H, Cosio MG. Lymphocyte population and apoptosis in the lungs of smokers and their relation to emphysema. Eur Respir J 2001;17:946-53.
  20. Liu AN, Mohammed AZ, Rice WR, Fiedeldey DT, Liebermann JS, Whitsett JA, et al. Perforin-independent CD8(+) T-cell-mediated cytotoxicity of alveolar epithelial cells is preferentially mediated by tumor necrosis factor-alpha: relative insensitivity to Fas ligand. Am J Respir Cell Mol Biol 1999;20:849-58.
  21. Vermes I, Haanen C, Reutelingsperger C. Flow cytometry of apoptotic cell death. J Immunol Methods 2000;243:167-90.
  22. Hodge G, Han P. Effect of intermediate-purity factor VIII (FVIII) concentrate on lymphocyte proliferation and apoptosis: transforming growth factor-beta is a significant immunomodulatory component of FVIII. Br J Haematol 2001;115:376-81.
  23. Grutzkau A, Radbruch A. Small but mighty: how the MACStechnology based on nanosized superparamagnetic particles has helped to analyze the immune system within the last 20 years. Cytometry A 2010;77:643-7.
  24. van Engeland M, Ramaekers FC, Schutte B, Reutelingsperger CP. A novel assay to measure loss of plasma membrane asymmetry during apoptosis of adherent cells in culture. Cytometry 1996;24:131-9.<131::AID-CYTO5>3.0.CO;2-M
  25. Gompertz S, O'Brien C, Bayley DL, Hill SL, Stockley RA. Changes in bronchial inflammation during acute exacerbations of chronic bronchitis. Eur Respir J 2001;17:1112-9.
  26. Ledbetter JA, June CH, Grosmaire LS, Rabinovitch PS. Crosslinking of surface antigens causes mobilization of intracellular ionized calcium in T lymphocytes. Proc Natl Acad Sci U S A 1987;84:1384-8.