, Volume 36, Issue 6, pp 1279–1285 | Cite as

Urinary Trypsin Inhibitor Attenuated Inflammatory Response of Patients Undergoing Cardiopulmonary Bypass by Inducing Activated Treg Cells

  • Xing Hao
  • Junyan Han
  • Zhichen Xing
  • Yu Hao
  • Chunjing Jiang
  • Jianping Zhang
  • Jing Yang
  • Xiaotong Hou


The urinary trypsin inhibitor (ulinastatin) is used in the clinic to prevent inflammatory responses in patients undergoing cardiopulmonary bypass (CPB); however, the anti-inflammatory mechanism is unclear. In the current study, we recruited 40 patients undergoing selective cardiac valve replacement surgery; and these patients were randomly divided into two groups (ulinastatin group [UG] and control group [CG]). We collected peripheral blood preoperatively, at the end of CPB, and postoperative days 1 and 3 and analyzed the kinetic changes in regulatory T (Treg) cell subsets. There was no statistically significant difference in the number of CD4+ T cells between the two groups. The number of CD4+CD25+ Treg cells, especially the suppressive activated Treg (aTreg) subset, was higher in the UG than the CG 1 and 3 days postoperatively. Thus, ulinastatin alleviated the inflammatory response during CPB by inducing the expansion of aTreg cells.


cardiopulmonary bypass inflammation responses ulinastatin regulatory T cells 



Cardiopulmonary bypass


Tumor necrosis factor-alpha




Ascending aorta


C-reactive protein


  1. 1.
    Rui, M., Y.Y. Duan, X.H. Zhang, H.L. Wang, and D.P. Wang. 2012. Urinary trypsin inhibitor attenuates seawater-induced acute lung injury by influencing the activities of nuclear factor-kB and its related inflammatory mediators. Respiration 83(4): 335–343.PubMedCrossRefGoogle Scholar
  2. 2.
    Bae, H.B., C.W. Jeong, M. Li, H.S. Kim, and S.H. Kwak. 2012. Effects of urinary trypsin inhibitor on lipopolysaccharide-induced acute lung injury in rabbits. Inflammation 35(1): 176–182.PubMedCrossRefGoogle Scholar
  3. 3.
    Zhang, X., F. Liu, H. Liu, H. Cheng, W. Wang, Q. Wen, and Y. Wang. 2011. Urinary trypsin inhibitor attenuates lipopolysaccharide-induced acute lung injury by blocking the activation of p38 mitogen-activated protein kinase. Inflammation Research 60(6): 569–575.PubMedCrossRefGoogle Scholar
  4. 4.
    Hou, J., M.W. Zhu, X.W. He, J.M. Wei, Y.G. Li, and D.N. Tang. 2010. Effect of hyperbaric oxygen and ulinastatin on plasma endotoxin, soluble CD14, endotoxin-neutralizing capacity and cytokines in acute necrotizing pancreatitis. Canadian Journal of Surgery 53(4): 241–245.Google Scholar
  5. 5.
    Zhang, Y., H. Chen, Y.M. Li, S.S. Zheng, Y.G. Chen, L.J. Li, L. Zhou, H.Y. Xie, and R.K. Praseedom. 2008. Thymosin alpha1- and ulinastatin-based immunomodulatory strategy for sepsis arising from intra-abdominal infection due to carbapenem-resistant bacteria. Journal of Infectious Diseases 198(5): 723–730.PubMedCrossRefGoogle Scholar
  6. 6.
    Matsumi, M., S. Mizobuchi, R. Kaku, I. Ohashi, H. Nakatsuka, and H. Katayama. 2003. Changes of urinary tripsin inhibitor in blood and urine, as well as serum cytokines in living related liver transplantation. Masui 52(3): 251–256.PubMedGoogle Scholar
  7. 7.
    Aosasa, S., S. Ono, H. Mochizuki, H. Tsujimoto, C. Ueno, and A. Matsumoto. 2001. Mechanism of the inhibitory effect of protease inhibitor on tumor necrosis factor alpha production of monocytes. Shock 15(2): 101–105.PubMedCrossRefGoogle Scholar
  8. 8.
    Miyara, M., Y. Yoshioka, A. Kitoh, T. Shima, K. Wing, A. Niwa, C. Parizot, C. Taflin, T. Heike, D. Valeyre, A. Mathian, T. Nakahata, T. Yamaguchi, T. Nomura, M. Ono, Z. Amoura, G. Gorochov, and S. Sakaguchi. 2009. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 30(6): 899–911.PubMedCrossRefGoogle Scholar
  9. 9.
    Zhou, H., Y. Hao, C. Song, J. Han, J. Zhang, G. Gao, N. Han, D. Yang, Y. Li, F. Zhang, H. Zhao, and H. Zeng. 2013. Excessive conversion and impaired thymic output contribute to disturbed regulatory T-cell homeostasis in AIDS patients with low CD4 cell counts. AIDS 27(7): 1059–1106.PubMedCrossRefGoogle Scholar
  10. 10.
    Yu, J.R., S. Yan, X.S. Liu, Y.J. Wu, P.F. Fu, L.H. Wu, and S.S. Zheng. 2005. Attenuation of graft ischemia–reperfusion injury by urinary trypsin inhibitor in mouse intestinal transplantation. World Journal of Gastroenterology 11(11): 1605–1609.PubMedGoogle Scholar
  11. 11.
    Wang, D.J., J.X. Liu, and B.L. Yin. 2005. Protective effects of ulinastatin on the lung injury during cardiopulmonary bypass. Zhong Nan Da Xue Xue Bao. Yi Xue Ban 30(6): 670–672.PubMedGoogle Scholar
  12. 12.
    Zhou, Q., G. Wang, C. Gao, and T. Chen. 2010. Effect of ulinastatin on perioperative inflammatory response to coronary artery bypass grafting with cardiopulmonary bypass. Zhong Nan Da Xue Xue Bao. Yi Xue Ban 35(2): 107–110.PubMedGoogle Scholar
  13. 13.
    Yu, X.Y., and L.L. Fan. 2009. Effects of different doses of ulinastatin on inflammatory response and pulmonary function after cardiopulmonary bypass. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 21(11): 664–667.PubMedGoogle Scholar
  14. 14.
    Jiang, Y.F., W.W. Wang, W.L. Ye, Y.F. Ni, J. Li, X.L. Chen, S.W. Jin, and Q.Q. Lian. 2008. Effects of alprostadil and ulinastatin on inflammatory response and lung injury after cardiopulmonary bypass in pediatric patients with congenital heart diseases. Zhonghua Yi Xue Za Zhi 88(41): 2893–2897.PubMedGoogle Scholar
  15. 15.
    Bingyang, J., L. Jinping, L. Mingzheng, W. Guyan, and F. Zhengyi. 2007. Effects of urinary protease inhibitor on inflammatory response during on-pump coronary revascularisation. Effect of ulinastatin on inflammatory response. The Journal of Cardiovascular Surgery 48(4): 497–503.PubMedGoogle Scholar
  16. 16.
    Brunetti, N.D., R. Padalino, L. De Gennaro, A. Cuculo, L. Ziccardi, P.L. Pellegrino, and M. Di Biase. 2009. Acute phase proteins activation in subjects with coronary atherosclerosis and micro-vessel coronary circulation impairment. Journal of Thrombosis and Thrombolysis 28(1): 50–56.PubMedCrossRefGoogle Scholar
  17. 17.
    Brunetti, N.D., P.L. Pellegrino, M. Correale, L. De Gennaro, A. Cuculo, and M. Di Biase. 2008. Acute phase proteins and systolic dysfunction in subjects with acute myocardial infarction. Journal of Thrombosis and Thrombolysis 26(3): 196–202.PubMedCrossRefGoogle Scholar
  18. 18.
    Brunetti, N.D., M. Correale, P.L. Pellegrino, A. Cuculo, and M.D. Biase. 2007. Acute phase proteins in patients with acute coronary syndrome: correlations with diagnosis, clinical features, and angiographic findings. European Journal of Internal Medicine 18(2): 109–117.PubMedCrossRefGoogle Scholar
  19. 19.
    Ambiru, S., M. Miyazaki, K. Sasada, H. Ito, F. Kimura, K. Nakagawa, H. Shimizu, K. Ando, and N. Nakajima. 2000. Effects of perioperative protease inhibitor on inflammatory cytokines and acute-phase proteins in patients with hepatic resection. Digestive Surgery 17(4): 337–343.PubMedCrossRefGoogle Scholar
  20. 20.
    Habermehl, P., M. Knuf, C. Kampmann, W. Mannhardt, D. Schranz, W. Kuroczynski, C.F. Wippermann, and F. Zepp. 2003. Changes in lymphocyte subsets after cardiac surgery in children. European Journal of Pediatrics 162(1): 15–21.PubMedCrossRefGoogle Scholar
  21. 21.
    Kessel, A., E. Bamberger, M. Masalha, and E. Toubi. 2009. The role of T regulatory cells in human sepsis. Journal of Autoimmunity 32(3–4): 211–215.PubMedCrossRefGoogle Scholar
  22. 22.
    Sojka, D.K., Y.H. Huang, and D.J. Fowell. 2008. Mechanisms of regulatory T-cell suppression—a diverse arsenal for a moving target. Immunology 124(1): 13–22.PubMedCrossRefGoogle Scholar
  23. 23.
    Kondelkova, K., D. Vokurkova, J. Krejsek, L. Borska, Z. Fiala, and A. Ctirad. 2010. Regulatory T cells (TREG) and their roles in immune system with respect to immunopathological disorders. Acta Medica (Hradec Králové) 53(2): 73–77.Google Scholar
  24. 24.
    Wongyanin, P., S. Buranapraditkul, D. Yoo, R. Thanawongnuwech, J.A. Roth, and S. Suradhat. 2012. Role of porcine reproductive and respiratory syndrome virus nucleocapsid protein in induction of interleukin-10 and regulatory T-lymphocytes (Treg). Journal of General Virology 93(Pt 6): 1236–1246.PubMedCrossRefGoogle Scholar
  25. 25.
    Nishise, S., T. Sato, Y. Sasaki, K. Nagino, D. Iwano, T. Yaoita, K. Yoshizawa, Y. Nishise, and H. Takeda. 2012. Production of interleukin-10 by combining a granulocyte and monocyte adsorption carrier with ulinastatin. Therapeutic Apheresis and Dialysis 16(5): 449–455.PubMedCrossRefGoogle Scholar
  26. 26.
    Cao, Y.Z., Y.Y. Tu, X. Chen, B.L. Wang, Y.X. Zhong, and M.H. Liu. 2012. Protective effect of ulinastatin against murine models of sepsis: inhibition of TNF-alpha and IL-6 and augmentation of IL-10 and IL-13. Experimental and Toxicologic Pathology 64(6): 543–547.PubMedCrossRefGoogle Scholar
  27. 27.
    Serafini, P., S. Mgebroff, K. Noonan, and I. Borrello. 2008. Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells. Cancer Research 68(13): 5439–5449.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Xing Hao
    • 1
  • Junyan Han
    • 2
    • 3
  • Zhichen Xing
    • 1
  • Yu Hao
    • 2
    • 3
  • Chunjing Jiang
    • 1
  • Jianping Zhang
    • 2
    • 3
  • Jing Yang
    • 1
  • Xiaotong Hou
    • 1
  1. 1.Department of Extracorporeal Circulation, Center for Cardiac Intensive Care, Beijing Anzhen HospitalCapital Medical UniversityBeijingChina
  2. 2.Beijing Key Laboratory of Emerging Infectious DiseasesBeijingChina
  3. 3.Institute of Infectious Diseases, Beijing Ditan HospitalCapital Medical UniversityBeijingChina

Personalised recommendations