Analysis of polyunsaturated fatty acids and the omega-6 inflammatory pathway in hepatic ischemia/re-perfusion injury

Kirac,Ebru; Özcan,Filiz; Tuzcu,Hazal; Elpek,Gulsum  O.; Aslan,Mutay

doi:10.3892/mmr.2015.3908

Analysis of polyunsaturated fatty acids and the omega-6 inflammatory pathway in hepatic ischemia/re-perfusion injury

Authors:
- Ebru Kirac
- Filiz Özcan
- Hazal Tuzcu
- Gulsum O. Elpek
- Mutay Aslan
View Affiliations

Affiliations: Department of Medical Biochemistry, Faculty of Medicine, Akdeniz University, Antalya 07070, Turkey, Department of Pathology, Faculty of Medicine, Akdeniz University, Antalya 07070, Turkey
Published online on: June 11, 2015 https://doi.org/10.3892/mmr.2015.3908
Pages: 4149-4156
Copyright: © Kirac et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The aim of the present study was to assess omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) in liver tissue and evaluate changes in the n‑6-associated inflammatory pathway following liver ischemia/re‑perfusion (IR) injury. Male Wistar rats which were allowed free access to standard rat chow were included in the study. Blood vessels supplying the median and left lateral hepatic lobes were occluded with an arterial clamp for 60 min, followed by 60 min of re‑perfusion. Levels of arachidonic acid (AA, C20:4n‑6), dihomo‑gamma‑linolenic acid (DGLA, C20:3n‑6), eicosapentaenoic acid (EPA, C20:5n‑3) and docosahexaenoic acid (DHA, C22:6n‑3) in liver tissue were determined by an optimized multiple reaction monitoring method using ultra fast‑liquid chromatography coupled with tandem mass spectrometry. Phospholipase A2 (PLA2), cyclooxygenase (COX) and prostaglandin E2 (PGE2) were measured in tissue samples to evaluate changes in the n‑6 inflammatory pathway. Total histopathological score of cellular damage were significantly increased following hepatic IR injury. n‑3 and n‑6 PUFA levels were significantly increased in post‑ischemic liver tissue compared to those in non‑ischemic controls. No significant difference was observed in the AA/DHA and AA/EPA ratio in post‑ischemic liver tissues compared with that in the control. Tissue activity of PLA2 and COX as well as PGE2 levels were significantly increased in post‑ischemic liver tissues compared to those in non‑ischemic controls. The results of the present study suggested that increased hydrolysis of fatty acids via PLA2 triggers the activity of COX and leads to increased PGE2 levels. Future studies evaluating agents which block the formation of eicosanoids derived from n‑6 PUFAs may facilitate the development and application of treatment strategies in liver injury following IR.

View Figures

View References

1	Hasselgren PO: Prevention and treatment of ischemia of the liver. Surg Gynecol Obstet. 164:187–196. 1987.PubMed/NCBI
2	Lemasters JJ and Thurman RG: Reperfusion injury after liver preservation for transplantation. Annu Rev Pharmacol Toxicol. 37:327–338. 1997. View Article : Google Scholar : PubMed/NCBI
3	Olthoff KM: Can reperfusion injury of the liver be prevented? Trying to improve on a good thing. Pediatr Transplant. 5:390–393. 2001. View Article : Google Scholar : PubMed/NCBI
4	Dogan S and Aslan M: Hepatic ischemia-reperfusion injury and therapeutic strategies to alleviate cellular damage. Hepatol Res. 41:103–117. 2011. View Article : Google Scholar : PubMed/NCBI
5	Colletti LM, Kunkel SL, Walz A, Burdick MD, Kunkel RG, Wilke CA and Strieter RM: The role of cytokine networks in the local liver injury following hepatic ischemia/reperfusion in the rat. Hepatology. 23:506–514. 1996. View Article : Google Scholar : PubMed/NCBI
6	Jaeschke H, Farhood A and Smith CW: Neutrophils contribute to ischemia/reperfusion injury in rat liver in vivo. FASEB J. 4:3355–3359. 1990.PubMed/NCBI
7	Bates EJ, Ferrante A, Smithers L, Poulos A and Robinson BS: Effect of fatty acid structure on neutrophil adhesion, degranulation and damage to endothelial cells. Atherosclerosis. 116:247–259. 1995. View Article : Google Scholar : PubMed/NCBI
8	De Caterina R, Liao JK and Libby P: Fatty acid modulation of endothelial activation. Am J Clin Nutr. 71(1 Suppl): 213S–223S. 2000.PubMed/NCBI
9	Wall R, Ross RP, Fitzgerald GF and Stanton C: Fatty acids from fish: The anti-inflammatory potential of long-chain omega-3 fatty acids. Nutr Rev. 68:280–289. 2010. View Article : Google Scholar : PubMed/NCBI
10	Serhan CN, Chiang N and Van Dyke TE: Resolving inflammation: Dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol. 8:349–361. 2008. View Article : Google Scholar : PubMed/NCBI
11	Marsman HA, Heger M, Kloek JJ, Nienhuis SL, ten Kate FJ and van Gulik TM: Omega-3 fatty acids reduce hepatic steatosis and consequently attenuate ischemia-reperfusion injury following partial hepatectomy in rats. Dig Liver Dis. 43:984–990. 2011. View Article : Google Scholar : PubMed/NCBI
12	Coelho AM, Machado MC, Takahashi HK, Sampietre SN, Stefano JT, Leite AZ, Curi R and D'Albuquerque LA: Ischemic preconditioning-like effect of polyunsaturated fatty acid-rich diet on hepatic ischemia/reperfusion injury. J Gastrointest Surg. 15:1679–1688. 2011. View Article : Google Scholar : PubMed/NCBI
13	Zúñiga J, Cancino M, Medina F, Varela P, Vargas R, Tapia G, Videla LA and Fernández V: N-3 PUFA supplementation triggers PPAR-α activation and PPAR-α/NF-κB interaction: Anti-inflammatory implications in liver ischemia-reperfusion injury. PLoS One. 6:e285022011. View Article : Google Scholar
14	Zhu XH, Wu YF, Qiu YD, Jiang CP and Ding YT: Liver-protecting effects of omega-3 fish oil lipid emulsion in liver transplantation. World J Gastroenterol. 18:6141–6147. 2012. View Article : Google Scholar : PubMed/NCBI
15	Dogan S, Ozlem Elpek G, Kirimlioglu Konuk E, Demir N and Aslan M: Measurement of intracellular biomolecular oxidation in liver ischemia-reperfusion injury via immuno-spin trapping. Free Radic Biol Med. 53:406–414. 2012. View Article : Google Scholar : PubMed/NCBI
16	Curek GD, Cort A, Yucel G, Demir N, Ozturk S, Elpek GO, Savas B and Aslan M: Effect of astaxanthin on hepatocellular injury following ischemia/reperfusion. Toxicology. 267:147–513. 2010. View Article : Google Scholar
17	Yilmaz S, Ates E, Tokyol C, Pehlivan T, Erkasap S and Koken T: The protective effect of erythropoietin on ischaemia/reperfusion injury of liver. HPB (Oxford). 6:169–173. 2004. View Article : Google Scholar
18	Aslan M, Aslan I, Özcan F, Eryılmaz R, Ensari CO and Bilecik T: A pilot study investigating early postoperative changes of plasma polyunsaturated fatty acids after laparoscopic sleeve gastrectomy. Lipids Health Dis. 13:622014. View Article : Google Scholar : PubMed/NCBI
19	Aslan M, Özcan F, Aslan I and Yücel G: LC-MS/MS analysis of plasma polyunsaturated fatty acids in type 2 diabetic patients after insulin analog initiation therapy. In: Lipids Health Dis. 12. pp. 1692013
20	van Gulik TM, de Graaf W, Dinant S, Busch OR and Gouma DJ: Vascular occlusion techniques during liver resection. Dig Surg. 24:274–281. 2007. View Article : Google Scholar : PubMed/NCBI
21	Ozer J, Ratner M, Shaw M, Bailey W and Schomaker S: The current state of serum biomarkers of hepatotoxicity. Toxicology. 245:194–205. 2008. View Article : Google Scholar : PubMed/NCBI
22	Calder PC: Polyunsaturated fatty acids, inflammation and immunity. Lipids. 36:1007–1024. 2001. View Article : Google Scholar : PubMed/NCBI
23	Setty BN, Dampier CD and Stuart MJ: Arachidonic acid metabolites are involved in mediating red blood cell adherence to endothelium. J Lab Clin Med. 125:608–617. 1995.PubMed/NCBI
24	Besse T, Gustin T, Claeys N, Schroeyers P and Lambotte L: Effect of PGI2 and thromboxane antagonist on liver ischemic injury. Eur Surg Res. 21:213–217. 1989. View Article : Google Scholar : PubMed/NCBI
25	Post S, Goerig M, Otto G, Manner M, Senninger N, Kommerell B and Herfarth C: Prostanoid release in experimental liver transplantation. Transplantation. 49:490–494. 1990. View Article : Google Scholar : PubMed/NCBI
26	Post S, Goerig M, Otto G, Manner M, Foltis C, Hofmann W and Herfarth C: Rapid increase in the activity of enzymes of eicosanoid synthesis in hepatic and extrahepatic tissues after experimental liver transplantation. Transplantation. 51:1058–1065. 1991. View Article : Google Scholar : PubMed/NCBI
27	Koike K, Yamamoto Y, Hori Y and Ono T: Group IIA phospholipase A2 mediates lung injury in intestinal ischemia-reperfusion. Ann Surg. 232:90–97. 2000. View Article : Google Scholar : PubMed/NCBI
28	Ogata K, Jin MB, Taniguchi M, Suzuki T, Shimamura T, Kitagawa N, Magata S, Fukai M, Ishikawa H, Ono T, et al: Attenuation of ischemia and reperfusion injury of canine livers by inhibition of type II phospholipase A2 with LY329722. Transplantation. 71:1040–1046. 2001. View Article : Google Scholar : PubMed/NCBI
29	Murakami M and Kudo I: Phospholipase A2. J Biochem. 131:285–292. 2002. View Article : Google Scholar : PubMed/NCBI
30	Menschikowski M, Hagelgans A and Siegert G: Secretory phospholipase A2 of group IIA: Is it an offensive or a defensive player during atherosclerosis and other inflammatory diseases? Prostaglandins Other Lipid Mediat. 79:1–33. 2006. View Article : Google Scholar : PubMed/NCBI
31	Dan P, Nitzan DW, Dagan A, Ginsburg I and Yedgar S: H₂O₂ renders cells accessible to lysis by exogenous phospholipase A2: A novel mechanism for cell damage in inflammatory processes. FEBS Lett. 383:75–78. 1996. View Article : Google Scholar : PubMed/NCBI
32	Murakami M, Nakatani Y, Atsumi G, Inoue K and Kudo I: Regulatory functions of phospholipase A2. Crit Rev Immunol. 17:225–283. 1997. View Article : Google Scholar : PubMed/NCBI
33	Nanji AA, Miao L, Thomas P, Rahemtulla A, Khwaja S, Zhao S, Peters D, Tahan SR and Dannenberg AJ: Enhanced cyclo-oxygenase-2 gene expression in alcoholic liver disease in the rat. Gastroenterology. 112:943–951. 1997. View Article : Google Scholar : PubMed/NCBI
34	Planagumà A, Clària J, Miquel R, López-Parra M, Titos E, Masferrer JL, Arroyo V and Rodés J: The selective cyclooxy-genase-2 inhibitor SC-236 reduces liver fibrosis by mechanisms involving non-parenchymal cell apoptosis and PPARgamma activation. FASEB J. 19:1120–1122. 2005.
35	Waris G and Siddiqui A: Hepatitis C virus stimulates the expression of cyclooxygenase-2 via oxidative stress: Role of pros-taglandin E2 in RNA replication. J Virol. 79:9725–9734. 2005. View Article : Google Scholar : PubMed/NCBI
36	Kim SH and Lee SM: Expression of hepatic vascular stress genes following ischemia/reperfusion and subsequent endotoxemia. Arch Pharm Res. 27:769–775. 2004. View Article : Google Scholar : PubMed/NCBI
37	Breyer RM, Bagdassarian CK, Myers SA and Breyer MD: Prostanoid receptors: Subtypes and signaling. Annu Rev Pharmacol Toxicol. 41:661–690. 2001. View Article : Google Scholar : PubMed/NCBI
38	Wanner GA, Müller P, Ertel W, Busch CJ, Menger MD and Messmer K: Differential effect of cyclooxygenase metabolites on proinflammatory cytokine release by Kupffer cells after liver ischemia and reperfusion. Am J Surg. 175:146–151. 1998. View Article : Google Scholar : PubMed/NCBI
39	Arai M, Peng XX, Currin RT, Thurman RG and Lemasters JJ: Protection of sinusoidal endothelial cells against storage/reperfusion injury by prostaglandin E2 derived from Kupffer cells. Transplantation. 68:440–445. 1999. View Article : Google Scholar : PubMed/NCBI
40	Masaki N, Ohta Y, Shirataki H, Ogata I, Hayashi S, Yamada S, Hirata K, Nagoshi S, Mochida S, Tomiya T, et al: Hepatocyte membrane stabilization by prostaglandins E1 and E2: Favorable effects on rat liver injury. Gastroenterology. 102:572–576. 1992.PubMed/NCBI