Lviv clinical bulletin 2013, 1(1): 7-12

https://doi.org/10.25040/lkv2013.01.007

The Role of Proinflammatory Cytokines and Adhesion Molecules in Vascular Disorders and Organ Dysfunction in Acute Pancreatitis Patients

Posted onAuthorAdminЗалишити коментар / Leave a comment

S. Chooklin1, O. Hranat2

1Danylo Halytsky Lviv National Medical University

2Lviv Regional Clinical Hospital

Introduction. The incidence of acute pancreatitis (AP) in the world has increased over the last years, mainly due to alcohol consumption. The increasing of the AP severity is characterized by pancreatic necrosis, local complications and systemic organ dysfunction and is about 20.0% of all cases of AP.

Despite the successes of intensive care, early mortality from AP remains high. The main component in the pathogenesis of acute pancreatitis is the transition from local to the system inflammation that causes the increasing of the disease severity. Changes of microcirculation and endothelial dysfunction are an important step on the way from the mild to severe course of the disease.

Aim. To determine the pathogenetic role of proinflammatory cytokines, adrenal molecules and E-selectin in the occurrence of vascular disorders and organ dysfunction in patients with acute necrotic pancreatitis.

Materials and methods. The study involved 53 AP patients (28 – severe, 25 – mild). We measured interleukin-6, interleukin-18, ICAM-1 and E-selectin in the blood plasma. Flow in the visceral arteries was assessed with the help of the Doppler sonography. Organ dysfunction was evaluated on the SOFA scale. The severity of pancreatitis in patients was determined according to the criteria of J. H. C. Ranson.

Results. Patients with AP during the hospitalization showed an increase of the levels of IL-6 and IL-18 in 12.11 and 2.02 times, respectively. However, a differentiated assessment of the individual forms of AP revealed a significant increase in both proinflammatory cytokines only in the case of acute necrotic pancreatitis, whereas IL-18 was not significantly elevated in patients with edematous pancreatitis. At the same time, the mean values ​​of IL-6 and IL-18 in patients with acute necrotic pancreatitis significantly exceeded the indicators of patients with pulmonary hypertension in 4.25 and 1.84 times, respectively.

It has been established that proinflammatory cytokines mediate the damage of organs by their action on the endothelium of blood vessels and leukocytes by the increasing of the expression of adrenal molecules, which in turn leads to rolling, adhesion, aggregation and transmigration of leukocytes in the involved tissues. Cytokines stimulate endothelial cell membrane and cause the increased synthesis of selectin that bind to leukocytes through the appropriate receptors. This leads to roller leukocytes on the walls of postcapillary venules. The activation of intercellular adhesion molecules (ICAM) and vascular cell adhesion molecules (VCAM) on endothelial cells promotes the adhesion of leukocytes to vascular endothelium and their tissue transmigration. Inflammation cells respond to initial events by releasing enzymes and active forms of oxygen that cause damage of the tissues.

Conclusions. It was determined that the levels of proinflammatory cytokines and adhesion molecules increase in the blood of AP patients. Their level correlates with the organ dysfunction and disturbances in splanchnic blood flow.

References

  1. Pandol SJ, Saluja AK, Imrie CW, Banks PA. Acute pancreatitis: bench to the bedside. Gastroenterology. 2007;132(3):1127-1151. https://doi.org/10.1053/j.gastro.2007.01.055
  2. Recinos A, LeJeune WS, Sun H, Lee CY, Tieu BC, Lu M et al. Angiotensin II induces IL-6 expression and the Jak-STAT3 pathway in aortic adventitia of LDL receptor-deficient mice. Atherosclerosis. 2005;194(1):125-133. https://doi.org/10.1016/j.atherosclerosis.2006.10.013
  3. Morel JCM, Park CC, Woods JM, Koch AE. A novel role for interleukin-18 in adhesion molecule induction through NFкB and phosphatidylinostinol (PI) 3-kinase-dependent signal transduction pathways. J Biol Chem. 2001;276:37069-37075. https://doi.org/10.1074/jbc.M103574200
  4. Leung BP, Culshaw S, Gracie JA, Hunter D, Canetti CA, Campbell C et al. A role for IL-18 in neutrophil activation. J Immunol. 2001;167(5):2879-2886. https://doi.org/10.4049/jimmunol.167.5.2879
  5. Mofidi R, Duff MD, Wigmore SJ, Madhavan KK, Garden OJ, Parks RW. Association between early systemic inflammatory response, severity of multiorgan failure and death in acute pancreatitis. Br J Surg. 2006;93(6):738-744. https://doi.org/10.1002/bjs.5290
  6. Bradley EL. Clinically based classification system for acute pancreatitis. Arch Surg. 1993;128(5):586-590. https://doi.org/10.1001/archsurg.1993.01420170122019
  7. Brasier AR. The nuclear factor-kB-interleukin-6 signalling pathway mediating vascular inflammation. Cardiovascular Research. 2010;86:211-218. https://doi.org/10.1093/cvr/cvq076
  8. Chooklin S. Pathogenic aspects of pulmonary complications in acute pancreatitis patients. Hepatobiliary Pancreat Dis Int. 2009;8:186-192.
  9. Malmstrøm ML, Hansen MB, Andersen AM, Ersbøll AK, Nielsen OH, Jørgensen LN et al. Cytokines and organ failure in acute pancreatitis inflammatory response in acute pancreatitis. Pancreas. 2012;41(2):271-277. https://doi.org/10.1097/MPA.0b013e3182240552
  10. Ellis MP, French JJ, Charnley RM. Acute pancreatitis and the influence of socioeconomic deprivation. Br J Surg. 2009;96(1):74-80. https://doi.org/10.1002/bjs.6414
  11. Gerdes N, Sukhova GK, Libby P, Reynolds RS, Young JL, Schönbeck U. Expression of interleukin (IL)-18 and functional IL-18 receptor on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for atherogenesis. J Exp Med. 2002;195(2):245-257. https://doi.org/10.1084/jem.20011022
  12. Frick TW. The role of calcium in acute pancreatitis. Surgery. 2012;152(1 Suppl):157-163. https://doi.org/10.1016/j.surg.2012.05.013
  13. Iversen PO, Nicolaysen A, Kvernebo K, Benestad HB, Nicolaysen G. Human cytokines modulate arterial vascular tone via endothelial receptors. Pflügers Arch. 1999;439(1-2):93-100. https://doi.org/10.1007/s004240051132
  14. Matsuda T, Hirano T, Nagasawa S, Kishimoto T. Identification of α2-macroglobulin as a carrier protein for IL-6. J Immunol. 1989;142(1):148-152.
  15. Biffl WL, Moore EE, Moore FA, Peterson VM. Interleukin-6 in the injured patients: Marker of injury or mediator of inflammation? Ann Surg. 1996;224:647-664. https://doi.org/10.1097/00000658-199611000-00009
  16. Miranda CJ, Babu BI, Siriwardena AK. Recombinant human activated protein C as a disease modifier in severe acute pancreatitis: Systematic review of current evidence. Pancreatology. 2012;12(2):119-123. https://doi.org/10.1016/j.pan.2012.01.002
  17. Petrov MS, Shanbhag S, Chakraborty M, Phillips AR, Windsor JA. Organ failure and infection of pancreatic necrosis as determinants of mortality in patients with acute pancreatitis. Gastroenterology. 2010;139(3):813-820. https://doi.org/10.1053/j.gastro.2010.06.010
  18. Escobar J, Pereda J, Arduini A, Sandoval J, Moreno ML, Pérez S et al. Oxidative and nitrosative stress in acute pancreatitis. Modulation by pentoxifylline and oxypurinol. Biochem Pharmacol. 2012;83(1):122-130. https://doi.org/10.1016/j.bcp.2011.09.028
  19. Klar E, Messmer K, Warshaw AL, Herfarth C. Pancreatic ischaemia in experimental acute pancreatitis: mechanism, significance and therapy. Br J Surg. 1990;77(11):1205-1210. https://doi.org/10.1002/bjs.1800771104
  20. Tsuji Y, Hamaguchi K, Watanabe Y, Okumura A, Isoda H, Yamamoto N et al. Perfusion CT is superior to angiography in predicting pancreatic necrosis in patients with severe acute pancreatitis. J Gastroenterol. 2010;45(11):1155-1162. https://doi.org/10.1007/s00535-010-0267-8
  21. Ranson JH, Rifkind KM, Roses DF, Fink SD, Eng K, Spencer FC. Prognostic signs and the role of operative management in acute pancreatitis. Surg Gynecol Obstet. 1974;139(1):69-81.
  22. Rabkin SW. The role of interleukin 18 in the pathogenesis of hypertension-induced vascular disease. Nat Clin Pract Cardiovasc Med. 2009;6(3):192-199. https://doi.org/10.1038/ncpcardio1453
  23. Revision of the Atlanta classification of acute pancreatitis. Acute Pancreatitis Classification Working Group. 2008. Available from: http://www.pancreasclub.com/resources/AtlantaClassification.pdf.
  24. Frossard JL, Lenglet S, Montecucco F, Steffens S, Galan K, Pelli G et al. Role of CCL-2, CCR-2 and CCR-4 in cerulein-induced acute pancreatitis and pancreatitis-associated lung injury. J Clin Pathol. 2011;64(5):387-393. https://doi.org/10.1136/jcp.2010.088500
  25. Romano M, Sironi M, Toniatti C, Polentarutti N, Fruscella P, Ghezzi P et al. Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. Immunity. 1997;6(3):315-325. https://doi.org/10.1016/S1074-7613(00)80334-9
  26. Abdulla A, Awla D, Thorlacius H, Regnér S. Role of neutrophils in the activation of trypsinogen in severe acute pancreatitis. J Leukoc Biol. 2011;90(5):975-982. https://doi.org/10.1189/jlb.0411195
  27. Koh YH, Tamizhselvi R, Moochhala S, Bian JS, Bhatia M. Role of protein kinase C in caerulein induced expression of substance P and neurokinin-1-receptors in murine pancreatic acinar cells. J Cell Mol Med. 2011;15(10):2139-2149. https://doi.org/10.1111/j.1582-4934.2010.01205.x
  28. Sah RP, Garg P, Saluja AK. Pathogenic mechanisms of acute pancreatitis. Curr Opin Gastroenterol. 2012;28(5):507-515. https://doi.org/10.1097/MOG.0b013e3283567f52
  29. Werner J, Z’graggen K, Fernández-del Castillo C, Lewandrowski KB, Compton CC, Warshaw AL. Specific therapy for local and systemic complications of acute pancreatitis with monoclonal antibodies against ICAM-1. Ann Surg. 1999;229(6):834-840. https://doi.org/10.1097/00000658-199906000-00010
  30. Hegyi P, Pandol S, Venglovecz V, Rakonczay Z. The acinar-ductal tango in the pathogenesis of acute pancreatitis. Gut. 2011;60(4):544-552. https://doi.org/10.1136/gut.2010.218461
  31. Vincent JL, Moreno R, Takala J, Willatts S, De Mendonça A, Bruining H et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996;22(7):707-710. https://doi.org/10.1007/BF01709751
  32. Yadav D, O’Connell M, Papachristou GI. Natural history following the first attack of acute pancreatitis. Am J Gastroenterol. 2012;107(7):1096-1103. https://doi.org/10.1038/ajg.2012.126
  33. Zhu HH, Jiang LL. Serum inter-cellular adhesion molecule 1 is an early marker of diagnosis and prediction of severe acute pancreatitis. World J Gastroenterol. 2012;18(20):2554-2560. https://doi.org/10.3748/wjg.v18.i20.2554