, Volume 38, Issue 1, pp 187–194 | Cite as

The Development of Early-Onset Ventilator-Associated Pneumonia after Cardiac Surgery with Cardiopulmonary Bypass is Associated with Toll-like Receptor 4 Signal Transduction Pathways

  • Xiang Liu
  • Yanhu Wu
  • Yihu Tang
  • Zhi Geng
  • Yaping Han
  • Dongyue Zhang


We evaluated the hypothesis that early-onset ventilator-associated pneumonia (VAP) after cardiac surgery with cardiopulmonary bypass (CPB) requires Toll-like receptor 4 (TLR4)-dependent signaling pathways. We enrolled 50 patients undergoing mitral and aortic double valve replacement, collecting left atrial blood samples from all patients preoperatively (T1), when opening the atrial septum (T2), closing the atrial septum (T3), and at the end of CPB (T4). TLR4 expression on monocytes and lymphocytes was detected immediately with flow cytometry. Serum levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-10 (IL-10) were measured using enzyme-linked immunosorbent assays (ELISA). Data from flow cytometry, ELISA, and the clinical outcomes in the two groups were evaluated and compared. Seventeen patients were included for analysis, and assigned to group A (without early-onset VAP, n = 10) and group B (with early-onset VAP, n = 7). TLR4 expression on lymphocytes in group B at T1, T3, and T4 were significantly higher than those in group A. Serum levels of IL-10 in group A at T4 were significantly higher than for group B. We found characteristic patterns in TLR4 expression on lymphocytes in left atrial blood of patients undergoing cardiac surgery with CPB. Our findings clarify the role of TLR4 and its association with the development of postoperative pneumonia.


ventilator-associated pneumonia cardiac surgery cardiopulmonary bypass TLR4 


  1. 1.
    Hunter, J.D. 2012. Ventilator associated pneumonia. BMJ 344: e3325.CrossRefPubMedGoogle Scholar
  2. 2.
    Charles, M.P., J.M. Easow, N.M. Joseph, M. Ravishankar, S. Kumar, and S. Umadevi. 2013. Incidence and risk factors of ventilator associated pneumonia in a tertiary care hospital. Australasian Medical Journal 6(4): 178–182.CrossRefPubMedCentralPubMedGoogle Scholar
  3. 3.
    Halpin, L., L. Henry, L. Szelkowski, S. Hunt, J. Vourlekis, and N. Ad. 2013. Ventilator-associated pneumonia among cardiac surgery patients: what can we do for prevention? Journal of Nursing Care Quality 28(4): 345–351.CrossRefPubMedGoogle Scholar
  4. 4.
    Bassetti, M., L. Taramasso, D.R. Giacobbe, and P. Pelosi. 2012. Management of ventilator-associated pneumonia: epidemiology, diagnosis and antimicrobial therapy. Expert Review of Anti-Infective Therapy 10(5): 585–596.CrossRefPubMedGoogle Scholar
  5. 5.
    Lipovy, B., H. Rihová, N. Gregorova, M. Hanslianova, Z. Zaloudikova, Y. Kaloudova, and P. Brychta. 2011. Epidemiology of ventilator-associated tracheobronchitis and vantilator-associated pneumonia in patients with inhalation injury at the Burn Centre in Brno (Czech Republic). Annals of Burns and Fire Disasters 24(3): 120–125.PubMedCentralPubMedGoogle Scholar
  6. 6.
    Chun, C.D., W.C. Liles, C.W. Frevert, R.W. Glenny, and W.A. Altemeier. 2010. Mechanical ventilation modulates toll-like receptor-3-induced lung inflammation via a MyD88-dependent, TLR4-independent pathway: a controlled animal study. BMC Pulmonary Medicine 10: 57.CrossRefPubMedCentralPubMedGoogle Scholar
  7. 7.
    Hu, G., A.B.. Malik, and R.D. Minshall. 2010. Toll-like receptor 4 mediates neutrophil sequestration and lung injury induced by endotoxin and hyperinflation. Critical Care Medicine 38(1): 194–201.Google Scholar
  8. 8.
    Li, J., Y. Han, K. Jin, Y. Wan, S. Wang, B. Liu, Y. Liu, S. Lu, and Z. Huang. 2011. Dynamic changes of cytotoxic T lymphocytes (CTLs), natural killer (NK) cells, and natural killer T (NKT) cells in patients with acute hepatitis B infection. Virology Journal 8: 199.CrossRefPubMedCentralPubMedGoogle Scholar
  9. 9.
    Han, Y., J. Li, Y.-F. Wan, et al. 2009. Application of HBV histocompatibility complex -peptide pentamer in detection of specific cytotoxic T lymphocytes. Chinese Journal of Laboratory Medicine 32: 763–767.Google Scholar
  10. 10.
    Chen, J., Y.H. Zhao, X.L. Liu, X.L. Chen, J. Li, Q.Q. Lian, Y. Xia, and W.N. Shangguan. 2012. Effects of breviscapine on pulmonary inflammatory response and lung injury in children undergoing open heart surgery. Journal of Asian Natural Products Research 14(3): 270–275.CrossRefPubMedGoogle Scholar
  11. 11.
    Suzuki, T. 2010. Additional lung-protective perfusion techniques during cardiopulmonary bypass. Annals of Thoracic and Cardiovascular Surgery 16(3): 150–155.PubMedGoogle Scholar
  12. 12.
    Dong, L.Y., J.H. Zheng, X.X. Qiu, M. Yu, Y.Z. Ye, S. Shi, D.C. Yang, and Y.W. Xie. 2013. Ischemic preconditioning reduces deep hypothermic circulatory arrest cardiopulmonary bypass induced lung injury. European Review for Medical and Pharmacological Sciences 17(13): 1789–1799.PubMedGoogle Scholar
  13. 13.
    Ucgun, I., C.E. Dagli, A. Kiremitci, H. Yildirim, G. Ak, and S. Aslan. 2013. Effects of isolation rooms on the prevalence of hospital acquired pneumonia in a respiratory ICU. European Review for Medical and Pharmacological Sciences 17(Suppl 1): 2–8.PubMedGoogle Scholar
  14. 14.
    Craven, D.E., Y. Lei, R. Ruthazer, A. Sarwar, and J. Hudcova. 2013. Incidence and outcomes of ventilator-associated tracheobronchitis and pneumonia. American Journal of Medicine 126(6): 542–549.CrossRefPubMedGoogle Scholar
  15. 15.
    Bochicchio, G.V., L. Napolitano, M. Joshi, K. Bochicchio, D. Shih, W. Meyer, and T.M. Scalea. 2008. Blood product transfusion and ventilator-associated pneumonia in trauma patients. Surgical Infections 9(4): 415–422.CrossRefPubMedGoogle Scholar
  16. 16.
    Sarani, B., W.J. Dunkman, L. Dean, S. Sonnad, J.I. Rohrbach, and V.H. Gracias. 2008. Transfusion of fresh frozen plasma in critically ill surgical patients is associated with an increased risk of infection. Critical Care Medicine 36(4): 1114–1118.CrossRefPubMedGoogle Scholar
  17. 17.
    Vaure, C., and Y. Liu. 2014. A comparative review of toll-like receptor 4 expression and functionality in different animal species. Frontiers in Immunology 5(316): 1–15.Google Scholar
  18. 18.
    Hu, R., H. Xu, H. Jiang, Y. Zhang, and Y. Sun. 2013. The role of TLR4 in the pathogenesis of indirect acute lung injury. Frontiers in Bioscience (Landmark Ed) 18: 1244–1255.CrossRefGoogle Scholar
  19. 19.
    Kumpf, O., E.J. Giamarellos-Bourboulis, A. Koch, L. Hamann, M. Mouktaroudi, D.Y. Oh, E. Latz, E. Lorenz, D.A. Schwartz, B. Ferwerda, C. Routsi, C. Skalioti, B.J. Kullberg, J.W. van der Meer, P.M. Schlag, M.G. Netea, K. Zacharowski, and R.R. Schumann. 2010. Influence of genetic variations in TLR4 and TIRAP/Mal on the course of sepsis and pneumonia and cytokine release: an observational study in three cohorts. Critical Care 14(3): R103.CrossRefPubMedCentralPubMedGoogle Scholar
  20. 20.
    An, H., C. Qian, and X. Cao. 2010. Regulation of toll-like receptor signaling in the innate immunity. Science China Life Sciences 53(1): 34–43.CrossRefPubMedGoogle Scholar
  21. 21.
    Ha, T., F. Hua, X. Liu, J. Ma, J.R. McMullen, T. Shioi, S. Izumo, J. Kelley, X. Gao, W. Browder, D.L. Williams, R.L. Kao, and C. Li. 2008. Lipopolysaccharide-induced myocardial protection against ischaemia/reperfusion injury is mediated through a PI3K/Akt-dependent mechanism. Cardiovascular Research 78(3): 546–553.CrossRefPubMedGoogle Scholar
  22. 22.
    Liu, X., Y. Chen, Y. Wu, T. Ha, and C. Li. 2010. The cardioprotection induced by lipopolysaccharide involves phosphoinositide 3-kinase/Akt and high mobility group box 1 pathways. Journal of Biomedical Research 24(4): 324–331.CrossRefPubMedCentralPubMedGoogle Scholar
  23. 23.
    Bouabe, H. 2012. Cytokine reporter mice: the special case of IL-10. Scandinavian Journal of Immunology 75(6): 553–567.CrossRefPubMedGoogle Scholar
  24. 24.
    Hoshi, N., D. Schenten, S.A. Nish, Z. Walther, N. Gagliani, R.A. Flavell, B. Reizis, Z. Shen, J.G. Fox, A. Iwasaki, and R. Medzhitov. 2012. MyD88 signalling in colonic mononuclear phagocytes drives colitis in IL-10-deficient mice. Nature Communications 3: 1120.CrossRefPubMedCentralPubMedGoogle Scholar
  25. 25.
    Koike, Y., T. Kanai, K. Saeki, Y. Nakamura, M. Nakano, Y. Mikami, Y. Yamagishi, N. Nakamoto, H. Ebinuma, and T. Hibi. 2012. MyD88-dependent interleukin-10 production from regulatory CD11b+Gr-1(high) cells suppresses development of acute cerulein pancreatitis in mice. Immunology Letters 148(2): 172–177.CrossRefPubMedGoogle Scholar
  26. 26.
    Ma, L., F. Dong, M. Zaid, A. Kumar, and X. Zha. 2012. ABCA1 protein enhances toll-like receptor 4 (TLR4)-stimulated interleukin-10 (IL-10) secretion through protein kinase A (PKA) activation. Journal of Biological Chemistry 287(48): 40502–40512.CrossRefPubMedCentralPubMedGoogle Scholar
  27. 27.
    Chen, C., F. Zhang, Z. Zhang, M. Peng, Y. Wang, and Y. Chen. 2013. TLR4 signaling-induced heme oxygenase upregulation in the acute lung injury: role in hemorrhagic shock and two-hit induced lung inflammation. Molecular Biology Reports 40(2): 1167–1172.CrossRefPubMedGoogle Scholar
  28. 28.
    Rossato, M., G. Curtale, N. Tamassia, M. Castellucci, L. Mori, S. Gasperini, B. Mariotti, M. De Luca, M. Mirolo, M.A. Cassatella, M. Locati, and F. Bazzoni. 2012. IL-10-induced microRNA-187 negatively regulates TNF-α, IL-6, and IL-12p40 production in TLR4-stimulated monocytes. Proceedings of the National Academy of Sciences of the United States of America 109(45): E3101–E3110.CrossRefPubMedCentralPubMedGoogle Scholar
  29. 29.
    Bagchi, A.K., A. Sharma, S. Dhingra, A.R. Lehenbauer Ludke, A.A. Al-Shudiefat, and P.K. Singal. 2013. Interleukin-10 activates toll-like receptor 4 and requires MyD88 for cardiomyocyte survival. Cytokine 61(1): 304–314.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Xiang Liu
    • 1
  • Yanhu Wu
    • 1
  • Yihu Tang
    • 1
  • Zhi Geng
    • 1
  • Yaping Han
    • 2
  • Dongyue Zhang
    • 2
  1. 1.Department of Cardiothoracic SurgeryFirst Affiliated Hospital of Nanjing Medical UniversityNanjingChina
  2. 2.Department of Infectious DiseasesFirst Affiliated Hospital of Nanjing Medical UniversityNanjingChina

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