Pengaruh Simvastatin Terhadap Kadar Proliferasi Limfosit Mencit Balb/C yang Diinduce Sepsis dengan LPS

*Made Ryan Kharmayani  -  Bagian Anestesiologi dan Terapi Intensif, Fakultas Kedokteran, Universitas Diponegoro/ RSUP Dr. Kariadi, Indonesia
Haris Lutfi  -  Bagian Anestesiologi dan Terapi Intensif, Fakultas Kedokteran, Universitas Diponegoro/ RSUP Dr. Kariadi, Indonesia
Danu Soesilowati  -  Bagian Anestesiologi dan Terapi Intensif, Fakultas Kedokteran, Universitas Diponegoro/ RSUP Dr. Kariadi, Indonesia
Published: 1 Nov 2013.
Open Access
Citation Format:
Article Info
Section: Penelitian
Language: ID
In Vol 5, No 3 (2013): Jurnal Anestesiologi Indonesia
Statistics: 392 1371
Abstract
Latar Belakang : Statin, inhibitor 3-hidroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase merupakan agen yang paling efektif dalam menurunkan lipid dan mempunyai efek pleiotrofik yaitu anti inflamatori dan immunomodulatori. Statin juga memodifikasi interaksi interseluler dan kemotaksis seluler pada sistem imun serta berpotensi mempengaruhi limfosit T dengan cara menghambat iinteraksi antara adhesi molekul seluler leukocyte function-associated antigen-1 (LFA-1) dan intercellular adhesion molecule-1 (ICAM-1), juga menurunkan interferon gamma (IFN -ɣ) yang berperan dalam ekspresi class II major histocompatibilty complex (MHC II) pada antigen precenting cells (APC) dan merupakan proses penting dalam aktivasi sel T. Penurunan ekspresi MHC II berakibat pada inhibisi aktivasi CD 4 limfosit, sehingga mengakibatkan penurunan diferensiasi T helper-1 (Th1) dan pelepasan sitokin proinflamasi juga menurun.

Tujuan : Membuktikan efek simvastatin dosis bertingkat peroral pada mencit yang diberi LPS intraperitoneal terhadap penurunan kadar proliferasi limfosit.

Metode : Penelitian eksperimental laboratorik dengan desain randomized post test only controlled group pada 20 ekor mencit Balb/c yang disuntik lipopolisakarida 10 mg/KgBB intraperitoneal dan simvastatin dosis 0,03 mg, 0,06 mg dan 0,12 mg peroral. Mencit dibagi menjadi 4 kelompok secara random, yaitu K1 sebagai control,  K2 yang mendapat simvastatin 0,03 mg, K3 yang mendapat simvastatin 0,06 mg dan K4 yang mendapat simvastatin 0,12 mg. Pemeriksaan limfosit diambil dari kultur limpa setelah 72 jam pemberian simvastatin. Uji statistik yang digunakan adalah parametrik ANOVA dan dilanjutkan Posteriori

Hasil : Kadar rerata limfosit kelompok K1 (1,546 ± 0,106), K2 (0,541 ± 0,046), K3 (0,471 ± 0,013) dan K4 (0,553 ± 0,02). Terdapat penurunan kadar limfosit secara signifikan pada kelompok K2, K3 dan K4 dibanding K1 dengan p <0,05. Tidak terdapat perbedaan bermakna antara kadar limfosit kelompok K2 dengan kelompok K3 dan K4 ( p>0,05) tetapi didapatkan perbedaan bermakna antara kelompok K3 dibandingkan kelompok K4 ( p<0,05).

Simpulan : Simvastatin secara signifikan menurunkan kadar proliferasi limfosit pada mencit yang diberi LPS intraperitoneal. Dosis 0,06 mg memiliki efek menekan kadar proliferasi limfosit paling besar.

Keywords: lipopolysaccharide; simvastatin; lymphocyte proliferation

Article Metrics:

  1. Almog Y, Shefer A, Novack V et al. Prior statin therapy is associated with a decreased rate of severe sepsis. Circulation. 2004; 110: 880-5
  2. Almog Y. Statins, inflammation and sepsis. Chest. 2003; 124: 740-3
  3. Dellinger RP, Levy MM, Carlet JM et al. Surviving sepsis campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008; 1-33
  4. Chiche L, Forel JM, Thomas G et al. The role of natural killer cells in sepsis. Journal of biomedicine and biotechnology. 2011:1- 8
  5. Karl IE. Pathogenesis of Sepsis and Multi Organ Dysfunction. J Cell Biochem 1992;267:10931-44
  6. Hermawan AG. Sitokin yang berperan dalam SIRS dan Sepsis. SIRS, Sepsis dan Syok Septik (Imunologi, Diagnosis, Penata- laksanaan). Edisi Pertama. Sebelas Maret University Press. 2008; 19-30
  7. Gao F,Linhartova L,Johnston A, Thickett DR. Statins and sepsis. Br J Anaesth. 2008; 100: 288 – 98
  8. Janeway CA, Travers P, Walport M, Shlom- chik M. Immunobiology : The immune sys- tem in health and disease. Fifth edition. New York; Churchill Livingstone, 2001: 1-34.
  9. Greenwood J, Mason JC. Statins and the Vascular Endothelial Inflammatory Re- sponse. Trends Immunol. 2007; 28: 88–98
  10. Katzung BG. Agents Used in Hyperlipide- mia. In Basic and Clinical Pharmacology. 10th Ed. Mc Graw-Hill. New York.2007. ebook
  11. Greenwood J, Steinman L, Zamvil SS. Statin Therapy and Autoimmune Disease: from Protein Prenylation to Immunomodulation. Nat Rev Immunol 2006; 6: 358–70
  12. Almog Y, Novack V, Eisinger M, Porath A, Novack L, Gilutz H. The Effect of Statin Therapy on Infection-Related Mortality in Patients with Atherosclerotic Diseases. Crit Care Med 2007; 35: 372–8
  13. Merx MWM, Liehn EAM, Graf JM. Statin Treatment after Onset of Sepsis in a Murine Model Improves Survival. Circulation 2005; 112: 117–24
  14. Merx MWM, Liehn EAM, Janssens UM. HMG-CoA Reductase Inhibitor Simvastatin Profoundly Improves Survival in a Murine Model of Sepsis. Circulation 2004; 109: 2560–5
  15. Zelvyte I, Dominaitiene R, Crisby M, Janci- auskiene S. Modulation of Inflammatory Me- diators and PPARgamma and NFkappaB Expression by Pravastatin in Response to Lipoproteins in Human Monocytes in vi- tro. Pharmacol Res. 2002; 45: 147–154.
  16. Yasuda H, Yuen PS, Hu X, Zhou H, Star RA. Simvastatin Improves Sepsis-Induced Mor- tality and Acute Kidney Injury via Renal Vas- cular Effects. Kidney Int 2006; 69: 1535–42
  17. Arnaud C, Burger F, Steffens S. Statins Re- duce Interleukin-6-Induced C-Reactive Pro- tein in Human Hepatocytes: New Evidence for Direct Anti inflammatory Effects of Stat- ins. Arterioscler Thromb Vasc Biol 2005; 25: 1231–6
  18. Merx MW, Weber C. Sepsis and the heart. Circulation. 2007; 116:793-802
  19. Anel R, Kumar A. Human endotoxemia and human sepsis: limits to the model. Critical Care 2005, 9:151-152
  20. Raetz RH, Whitfield C. Lipopolysaccharide Endotoxins. Annu Rev Biochem 2002; 71: 635-700
  21. Neuhaus O, Strasser-Fuchs S, Fazekas F et al. Statins as immunomodulators comparison with interferon-β1b in MS. Neurology. 2002; 59: 990-7
  22. Hillyard DZ, Cameron AJM, McDonald KJ et al. Simvastatin inhibits lymphocyte func- tion in normal subjects and patients with cardiovascular disease. Atherosclerosis. 2004; 175(2): 305 - 13
  23. Mach F. Statins as immunomodulatory agents. Circulation. 2004:109:II-15-II-17
  24. McKay A, Leung BP, McInnes IB et al. A novel anti-inflammatory role of simvastatin in a murine model of allergic asthma. The Journal of Immunology. 2004; 172: 2903 – 8
  25. Nie C, Yang D, Liu G et al. Statins induce immunosuppressive effect on heterotopic limb allografts in rat through inhibiting T cell activation and proliferation. European Jour- nal of Pharmacology. 2009; 602 (1): 168–75
  26. Hillyard DZ, Cameron AJ, MCIntyre AH et al. Inhibition of proliferation and signaling mechanisms in human lymphocytes by flu- vastatin. Clin Exp Pharmacol Physiology. 2002; 29 (28): 673 – 8
  27. Wratchford P, Ponte CD. High-Dose Simvas- tatin and Rhabdomyolysis. Am J Health Syst Pharm. 2003;60(7) 3

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