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Does leflunomide attenuate the sepsis-induced acute lung injury?

Pediatric Surgery International volume 24, Article number: 899 (2008) Cite this article

Abstract

The organ that is affected first and most severely in intraabdominal sepsis is the lung. Oxygen radicals and active neutrophils in the lung are important sources for severe pulmonary inflammation leading to acute lung injury (ALI)/acute respiratory distress syndrome. The aim of this study was to investigate the effects of leflunomide, an immunomodulatory agent, on oxidant/antioxidant status with nitric oxide (NO) level and myeloperoxidase (MPO) activity in rats with sepsis-induced ALI. Fifty male Wistar albino rats were divided into five groups: control, sham, sepsis, leflunomide (10 mg/kg, intragastrically for two doses with an 8 h interval prior to the experiment) and sepsis + leflunomide. After the animals were anesthetized with ketamine and xylazine, the abdominal cavity was opened and ligated just below the ileocaecal valve with 3–0 silk. The antimesentric surface of the cecum was perforated and the cecum was gently compressed until fecal matter was extruded to induce sepsis. None of the rats received antibiotics during the experimental procedures. The experiment was ended 24 h after cecal ligation puncture (CLP) with the cervical dislocation under anesthesia. The lung tissues were removed for analysis of biochemical parameters and light microscopic investigation. The lung superoxide dismutase (SOD), catalase and glutathione peroxidase activities were decreased in the sepsis group as compared to the group control, sham, leflunomide and sepsis + leflunomide (P < 0.05), and SOD activity were significantly higher in group sepsis + leflunomide than sham, control, leflunomide and sepsis group (P < 0.05). The lung MPO, malondialdehyde (MDA), protein carbonyl and NO levels were higher in the sepsis group when compared to group control, sham, leflunomide and sepsis + leflunomide (P < 0.05), and MPO, MDA and NO levels were higher in the sepsis + leflunomide group than in the sham, control and leflunomide group (P < 0.05). The light microscopic evaluation showed that pulmonary architecture was preserved, and infiltration of neutrophil and edema decreased in sepsis + leflunomide group. The grade of alveolar damage was significantly decreased in sepsis + leflunomide group in comparison with sepsis group (P < 0.05). Our findings suggested that leflunomide attenuated the lung injury after CLP-induced sepsis by inhibition of neutrophils accumulation and increasing endogenous antioxidant capacity.

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References

  1. Chow CW, Herrera Abreu MT, Suzuki T, Downey GP (2003) Oxidative stress and acute lung injury. Am J Respir Cell Mol Biol 29:427–431. doi:10.1165/rcmb.F278

    PubMed  Article  CAS  Google Scholar 

  2. Lang JD, McArdle PJ, O’Reilly PJ, Matalon S (2002) Oxidant–antioxidant balance in acute lung injury. Chest 122:314–320. doi:10.1378/chest.122.6_suppl.314S

    Article  Google Scholar 

  3. Thompson BT (2003) Glucocorticoids and acute lung injury. Crit Care Med 31:253–257. doi:10.1097/01.CCM.0000057900.19201.55

    Article  CAS  Google Scholar 

  4. Manocha S, Feinstein D, Kumar A, Kumar A (2002) Novel therapies for sepsis: antiendotoxin therapies. Expert Opin Investig Drugs 11:1795–1812. doi:10.1517/13543784.11.12.1795

    PubMed  Article  CAS  Google Scholar 

  5. Leeper-Woodford SK, Carey PD, Byrne K, Jenkins JK, Fisher BJ, Blocher C et al (1991) Tumor necrosis factor. Alpha and beta subtypes appear in circulation during onset of sepsis-induced lung injury. Am Rev Respir Dis 143:1076–1082

    PubMed  CAS  Google Scholar 

  6. Brower RG, Ware LB, Berthiaume Y, Matthay MA (2001) Treatment of ARDS. Chest 120:1347–1367. doi:10.1378/chest.120.4.1347

    PubMed  Article  CAS  Google Scholar 

  7. Silverman E, Spiegel L, Hawkins D, Petty R, Goldsmith D, Schanberg L et al (2005) Long-term open-label preliminary study of the safety and efficacy of leflunomide in patients with polyarticular-course juvenile rheumatoid arthritis. Arthritis Rheum 52:554–562. doi:10.1002/art.20861

    PubMed  Article  CAS  Google Scholar 

  8. Kalgutkar AS, Nguyen HT, Vaz AD, Doan A, Dalvie DK, McLeod DG et al (2003) In vitro metabolism studies on the isoxazole ring scission in the anti-inflammatory agent lefluonomide to its active alpha-cyanoenol metabolite A771726: mechanistic similarities with the cytochrome P450-catalyzed dehydration of aldoximes. Drug Metab Dispos 31:1240–1250. doi:10.1124/dmd.31.10.1240

    PubMed  Article  CAS  Google Scholar 

  9. Zhang L, Qi Z, Wu D, Shan S, Ekberg H (2004) Additive effects of leflunomide and tacrolimus in prevention of islet xenograft rejection. Scand J Immunol 59:255–260. doi:10.1111/j.0300-9475.2004.01401.x

    PubMed  Article  CAS  Google Scholar 

  10. Yao HW, Li J, Chen JQ, Xu SY (2004) Inhibitory effect of leflunomide on hepatic fibrosis induced by CCl4 in rats. Acta Pharmacol Sin 25(7):915–20

    PubMed  CAS  Google Scholar 

  11. Chong AS, Huang W, Liu W, Luo J, Shen J, Xu W et al (1999) In vivo activity of leflunomide: pharmacokinetic analyses and mechanism of immunosuppression. Transplantation 68:100–109. doi:10.1097/00007890-199907150-00020

    PubMed  Article  CAS  Google Scholar 

  12. Wichterman KA, Baue AE, Chaudry IH (1980) Sepsis and septic shock—a review of laboratory models and proposal. J Surg Res 29:189–201. doi:10.1016/0022-4804(80)90037-2

    PubMed  Article  CAS  Google Scholar 

  13. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with folin phenol reaction. J Biol Chem 193:265–271

    PubMed  CAS  Google Scholar 

  14. Sun Y, Oberley LW, Li Y (1988) A simple method for clinical assay of superoxide dismutase. Clin Chem 34:497–500

    PubMed  CAS  Google Scholar 

  15. Aebi H (1984) Catalase in vitro. Methods Enzymol 105:121–126. doi:10.1016/S0076-6879(84)05016-3

    PubMed  Article  CAS  Google Scholar 

  16. Paglia DE, Valentine WN (1967) Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med 70:158–170

    PubMed  CAS  Google Scholar 

  17. Wei H, Frenkel K (1993) Relationship of oxidative events and DNA oxidation in SENCAR mice to in vivo promoting activity of phorbol ester-type tumor promoters. Carcinogenesis 14:1195–1201. doi:10.1093/carcin/14.6.1195

    PubMed  Article  CAS  Google Scholar 

  18. Esterbauer H, Cheeseman KH (1990) Determination of aldehydic lipid peroxidation products: malonaldehyde and 4-hydroxynonenal. Methods Enzymol 186:407–421

    PubMed  Article  CAS  Google Scholar 

  19. Cortas NK, Wakid NW (1990) Determination of inorganic nitrate in serum and urine by a kinetic cadmium-reduction method. Clin Chem 36:1440–1443

    PubMed  CAS  Google Scholar 

  20. Levine RL, Garland D, Oliver CN, Amici A, Climent I, Lenz AG et al (1990) Determination of carbonyl content in oxidatively modified proteins. Methods Enzymol 186:464–478

    PubMed  Article  CAS  Google Scholar 

  21. Sener G, Toklu H, Ercan F, Erkanli G (2005) Protective effect of beta-glucan against oxidative organ injury in a rat model of sepsis. Int Immunopharmacol 5:1387–1396. doi:10.1016/j.intimp.2005.03.007

    PubMed  Article  CAS  Google Scholar 

  22. Babayigit H, Kucuk C, Sozuer E, Yazici C, Kose K, Akgun H (2005) Protective effect of beta-glucan on lung injury after cecal ligation and puncture in rats. Intensive Care Med 31:865–870. doi:10.1007/s00134-005-2629-x

    PubMed  Article  Google Scholar 

  23. Guo RF, Ward PA (2007) Role of oxidants in lung injury during sepsis. Antioxid Redox Signal 9:1991–2002. doi:10.1089/ars.2007.1785

    PubMed  Article  CAS  Google Scholar 

  24. Reutershan J, Ley K (2004) Bench-to-bedside review: acute respiratory distress syndrome—how neutrophils migrate into the lung. Crit Care 8:453–461. doi:10.1186/cc2881

    PubMed  Article  Google Scholar 

  25. Victor VM, Rocha M, Esplugues JV, De la Fuente M (2005) Role of free radicals in sepsis: antioxidant therapy. Curr Pharm Des 11:3141–3158. doi:10.2174/1381612054864894

    PubMed  Article  CAS  Google Scholar 

  26. Ritter C, Andrades M, Frota Júnior ML, Bonatto F, Pinho RA, Polydoro M et al (2003) Oxidative parameters and mortality in sepsis induced by cecal ligation and perforation. Intensive Care Med 29:1782–1789. doi:10.1007/s00134-003-1789-9

    PubMed  Article  Google Scholar 

  27. Demirbilek S, Ersoy MO, Demirbilek S, Karaman A, Akin M, Bayraktar M et al (2004) Effects of polyenylphosphatidylcholine on cytokines, nitrite/nitrate levels, antioxidant activity and lipid peroxidation in rats with sepsis. Intensive Care Med 30:1974–1978. doi:10.1007/s00134-004-2234-4

    PubMed  Article  Google Scholar 

  28. Karaman A, Fadillioglu E, Turkmen E, Tas E, Yilmaz Z (2006) Protective effects of leflunomide against ischemia-reperfusion injury of the rat liver. Pediatr Surg Int 22:428–434. doi:10.1007/s00383-006-1668-x

    PubMed  Article  Google Scholar 

  29. Karaman A, Iraz M, Kirimlioglu H, Karadag N, Tas E, Fadillioglu E (2006) Hepatic damage in biliary-obstructed rats is ameliorated by leflunomide treatment. Pediatr Surg Int 22:701–708. doi:10.1007/s00383-006-1744-2

    PubMed  Article  Google Scholar 

  30. Reddy SV, Wanchu A, Khullar M, Govindrajan S, Bambery P (2005) Leflunomide reduces nitric oxide production in patients with active rheumatoid arthritis. Int Immunopharmacol 5:1085–1090. doi:10.1016/j.intimp.2004.11.013

    PubMed  Article  CAS  Google Scholar 

  31. Manna SK, Aggarwal BB (1999) Immunosuppressive leflunomide metabolite (A77 1726) blocks TNF-dependent nuclear factor-kappa B activation and gene expression. J Immunol 162:2095–2102

    PubMed  CAS  Google Scholar 

  32. Li WD, Ran GX, Teng HL, Lin ZB (2002) Dynamic effects of leflunomide on IL-1, IL-6, and TNF-alpha activity produced from peritoneal macrophages in adjuvant arthritis rats. Acta Pharmacol Sin 23:752–756

    PubMed  CAS  Google Scholar 

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Affiliations

  1. Department of Anesthesiology and Reanimation, Faculty of Medicine, Turgut Ozal Medical Center, Inonu University, 44315, Malatya, Turkey

    Erdogan Ozturk, Semra Demirbilek, Zekine Begec, Murat Surucu & M. Ozcan Ersoy

  2. Department of Physiology, Faculty of Medicine, Hacettepe University, Ankara, Turkey

    Ersin Fadillioglu

  3. Department of Pathology, Faculty of Medicine, Turgut Ozal Medical Center, Inonu University, Malatya, Turkey

    Hale Kırımlıoglu

Authors
  1. Erdogan Ozturk
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  2. Semra Demirbilek
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  4. Murat Surucu
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  5. Ersin Fadillioglu
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  6. Hale Kırımlıoglu
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Correspondence to Erdogan Ozturk.

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Ozturk, E., Demirbilek, S., Begec, Z. et al. Does leflunomide attenuate the sepsis-induced acute lung injury?. Pediatr Surg Int 24, 899 (2008). https://doi.org/10.1007/s00383-008-2184-y

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  • DOI: https://doi.org/10.1007/s00383-008-2184-y

Keywords

  • Leflunomide
  • Acute lung injury
  • Oxidative stress
  • Sepsis