Sildenafil treatment attenuates lung and kidney injury due to overproduction of oxidant activity in a rat model of sepsis: A biochemical and histopathological study

Clinical and Experimental Immunology

Volumn 166, Issue 3, 2011, Pages 374-384

  Cadirci, E ^a   Halici, Z ^a   Odabasoglu, F ^b   Albayrak, A ^a   Karakus, E ^b   Unal, D ^c   Atalay, F ^b   Ferah, I ^a   Unal, B ^c  

^a Departments of Pharmacology   (Turkey)

^b ATATÜRK UNIVERSITY   (Turkey)

^c ATATURK UNIVERSITY   (Turkey)

Author keywords

Lung injury; Oxidative stress; Polymicrobial sepsis; Rat; Sildenafil

Indexed keywords

GLUTATHIONE; LIPID PEROXIDASE; MYELOPEROXIDASE; SILDENAFIL; SUPEROXIDE DISMUTASE; TUMOR NECROSIS FACTOR ALPHA;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIOXIDANT ACTIVITY; ARTICLE; BLOOD SAMPLING; CONTROLLED STUDY; CYTOKINE RESPONSE; ENZYME ACTIVATION; HISTOPATHOLOGY; INFLAMMATION; KIDNEY INJURY; LUNG INJURY; MALE; NONHUMAN; OXIDATIVE STRESS; PRIORITY JOURNAL; RAT; SCORING SYSTEM; SEPSIS; SHAM PROCEDURE;

ANIMALS; CECAL DISEASES; GLUTATHIONE; INFLAMMATION; KIDNEY; LIPID PEROXIDATION; LUNG; LUNG INJURY; OXIDATIVE STRESS; PEROXIDASE; PIPERAZINES; PURINES; RATS; RATS, WISTAR; SEPSIS; SULFONES; SUPEROXIDE DISMUTASE; TUMOR NECROSIS FACTOR-ALPHA;

EID: 80855144594     PISSN: 00099104     EISSN: 13652249     Source Type: Journal    
DOI: 10.1111/j.1365-2249.2011.04483.x     Document Type: Article

References (66)

1. Parrillo JE. Pathogenetic mechanisms of septic shock. N Engl J Med 1993; 328:1471-7.
2. Parrish WR, Gallowitsch-Puerta M, Czura CJ, Tracey KJ. Experimental therapeutic strategies for severe sepsis: mediators and mechanisms. Ann NY Acad Sci 2008; 1144:210-36.
3. Matot I, Sprung CL. Definition of sepsis. Intens Care Med 2001; 27 (Suppl. 1):S3-9.
4. Remick DG. Pathophysiology of sepsis. Am J Pathol 2007; 170:1435-44.
5. Griffiths B, Anderson ID. Sepsis, SIRS and MODS. Surgery 2009; 27:446-9.
6. Terblanche M, Almog Y, Rosenson RS, Smith TS, Hackam DG. Statins: panacea for sepsis? Lancet Infect Dis 2006; 6:242-8.
7. Hietbrink F, Koenderman L, Rijkers G, Leenen L. Trauma: the role of the innate immune system. World J Emerg Surg 2006; 1:15. doi: 10.1186/1749-7922-1-15. Available at:
8. Nduka OO, Parrillo JE. The pathophysiology of septic shock. Crit Care Clin 2009; 25:677-702.
9. Jourd'heuil D, Morise Z, Conner EM, Grisham MB. Oxidants, transcription factors, and intestinal inflammation. J Clin Gastroenterol 1997; 25 (Suppl. 1):S61-72.
10. van der Vliet A, Eiserich JP, Shigenaga MK, Cross CE. Reactive nitrogen species and tyrosine nitration in the respiratory tract: epiphenomena or a pathobiologic mechanism of disease? Am J Respir Crit Care Med 1999; 160:1-9.
11. Chabot F, Mitchell JA, Gutteridge JM, Evans TW. Reactive oxygen species in acute lung injury. Eur Respir J 1998; 11:745-57.
12. Blackwell TS, Blackwell TR, Holden EP, Christman BW, Christman JW. In vivo antioxidant treatment suppresses nuclear factor-kappa B activation and neutrophilic lung inflammation. J Immunol 1996; 157:1630-7.
13. Spapen H, Zhang H, Demanet C, Vleminckx W, Vincent JL, Huyghens L. Does N-acetyl-L-cysteine influence cytokine response during early human septic shock? Chest 1998; 113:1616-24.
14. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med 2003; 348:138-50.
15. Andrades ME, Ritter C, Dal-Pizzol F. The role of free radicals in sepsis development. Front Biosci (Elite Ed) 2009; 1:277-87.
16. Barichello T, Fortunato JJ, Vitali AM etal. Oxidative variables in the rat brain after sepsis induced by cecal ligation and perforation. Crit Care Med 2006; 34:886-9.
17. Peralta JG, Llesuy S, Evelson P, Carreras MC, Flecha BG, Poderoso JJ. Oxidative stress in skeletal muscle during sepsis in rats. Circ Shock 1993; 39:153-9.
18. Schrier RW, Wang W. Acute renal failure and sepsis. N Engl J Med 2004; 351:159-69.
19. Corbin JD, Francis SH, Webb DJ. Phosphodiesterase type 5 as a pharmacologic target in erectile dysfunction. Urology 2002; 60:4-11.
20. Hemnes AR, Zaiman A, Champion HC. PDE5A inhibition attenuates bleomycin-induced pulmonary fibrosis and pulmonary hypertension through inhibition of ROS generation and RhoA/Rho kinase activation. Am J Physiol Lung Cell Mol Physiol 2008; 294:L24-33.
21. Ladha F, Bonnet S, Eaton F, Hashimoto K, Korbutt G, Thebaud B. Sildenafil improves alveolar growth and pulmonary hypertension in hyperoxia-induced lung injury. Am J Respir Crit Care Med 2005; 172:750-6.
22. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med 2004; 351:1425-36.
23. Salloum F, Yin C, Xi L, Kukreja RC. Sildenafil induces delayed preconditioning through inducible nitric oxide synthase-dependent pathway in mouse heart. Circ Res 2003; 92:595-7.
24. Yildirim A, Ersoy Y, Ercan F etal. Phosphodiesterase-5 inhibition by sildenafil citrate in a rat model of bleomycin-induced lung fibrosis. Pulm Pharmacol Ther 2010; 23:215-21.
25. Muzaffar S, Shukla N, Srivastava A, Angelini GD, Jeremy JY. Sildenafil citrate and sildenafil nitrate (NCX 911) are potent inhibitors of superoxide formation and gp91phox expression in porcine pulmonary artery endothelial cells. Br J Pharmacol 2005; 146:109-17.
26. Rodriguez-Iturbe B, Ferrebuz A, Vanegas V etal. Early treatment with cGMP phosphodiesterase inhibitor ameliorates progression of renal damage. Kidney Int 2005; 68:2131-42.
27. Jeong KH, Lee TW, Ihm CG, Lee SH, Moon JY, Lim SJ. Effects of sildenafil on oxidative and inflammatory injuries of the kidney in streptozotocin-induced diabetic rats. Am J Nephrol 2009; 29:274-82.
28. Lin G, Huang YC, Wang G, Lue TF, Lin CS. Prominent expression of phosphodiesterase 5 in striated muscle of the rat urethra and levator ani. J Urol 2010; 184:769-74.
29. Sasser JM, Baylis C. Effects of sildenafil on maternal hemodynamics and fetal growth in normal rat pregnancy. Am J Physiol Regul Integr Comp Physiol 2010; 298:R433-8.
30. Ali BH, Abdelrahman AM, Al-Salam S etal. The effect of sildenafil on cisplatin nephrotoxicity in rats. Basic Clin Pharmacol Toxicol 2011; 109:300-8.
31. Medeiros PJ, Villarim Neto A, Lima FP, Azevedo IM, Leao LR, Medeiros AC. Effect of sildenafil in renal ischemia/reperfusion injury in rats. Acta Cir Bras 2010; 25:490-5.
32. Brink CB, Clapton JD, Eagar BE, Harvey BH. Appearance of antidepressant-like effect by sildenafil in rats after central muscarinic receptor blockade: evidence from behavioural and neuro-receptor studies. J Neural Transm 2008; 115:117-25.
33. Thorsen LB, Eskildsen-Helmond Y, Zibrandtsen H, Stasch JP, Simonsen U, Laursen BE. BAY 41-2272 inhibits the development of chronic hypoxic pulmonary hypertension in rats. Eur J Pharmacol 2010; 647:147-54.
34. Walker DK, Ackland MJ, James GC etal. Pharmacokinetics and metabolism of sildenafil in mouse, rat, rabbit, dog and man. Xenobiotica 1999; 29:297-310.
35. Liebenberg N, Harvey BH, Brand L, Brink CB. Antidepressant-like properties of phosphodiesterase type 5 inhibitors and cholinergic dependency in a genetic rat model of depression. Behav Pharmacol 2010; 21:540-7.
36. Guzman DC, Olguin HJ, Brizuela NO etal. Effect of prostaglandin E1 (PGE1) and sildenafil on serotonin metabolism and some oxidative damage markers in rat prostate gland and brain. Andrologia 2011; 43:266-72.
37. Bae SH, Bae SK, Lee MG. Effect of hepatic CYP inhibitors on the metabolism of sildenafil and formation of its metabolite, N-desmethylsildenafil, in rats in vitro and in vivo. J Pharm Pharmacol 2009; 61:1637-42.
38. Otero-Anton E, Gonzalez-Quintela A, Lopez-Soto A, Lopez-Ben S, Llovo J, Perez LF. Cecal ligation and puncture as a model of sepsis in the rat: influence of the puncture size on mortality, bacteremia, endotoxemia and tumor necrosis factor alpha levels. Eur Surg Res 2001; 33:77-9.
39. Coskun AK, Yigiter M, Oral A etal. The effects of montelukast on antioxidant enzymes and proinflammatory cytokines on the heart, liver, lungs, and kidneys in a rat model of cecal ligation and puncture-induced sepsis. ScientificWorldJournal 2011; 11:1341-56.
40. Uyanik A, Unal D, Uyanik MH etal. The effects of polymicrobial sepsis with diabetes mellitus on kidney tissues in ovariectomized rats. Ren Fail 2010; 32:592-602.
41. Cadirci E, Altunkaynak BZ, Halici Z etal. Alpha-lipoic acid as a potential target for the treatment of lung injury caused by cecal ligation and puncture-induced sepsis model in rats. Shock 2010; 33:479-84.
42. Albayrak A, Uyanik MH, Odabasoglu F etal. The effects of diabetes and/or polymicrobial sepsis on the status of antioxidant enzymes and pro-inflammatory cytokines on heart, liver, and lung of ovariectomized rats. J Surg Res 2011; 169:67-75.
43. Koga H, Hagiwara S, Inomata M etal. The new vitamin E derivative, ETS-GS, protects against cecal ligation and puncture-induced systemic inflammation in rats. Inflammation 2011; doi: 10.1007/s10753-011-9344-2.
44. Gouma DJ, Coelho JC, Schlegel JF, Li YF, Moody FG. The effect of preoperative internal and external biliary drainage on mortality of jaundiced rats. Arch Surg 1987; 122:731-4.
45. Sun Y, Oberley LW, Li Y. A simple method for clinical assay of superoxide dismutase. Clin Chem 1988; 34:497-500.
46. Bradley PP, Priebat DA, Christensen RD, Rothstein G. Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. J Invest Dermatol 1982; 78:206-9.
47. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979; 95:351-8.
48. Sedlak J, Lindsay RH. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman's reagent. Anal Biochem 1968; 25:192-205.
49. Singh B, Shinagawa K, Taube C, Gelfand EW, Pabst R. Strain-specific differences in perivascular inflammation in lungs in two murine models of allergic airway inflammation. Clin Exp Immunol 2005; 141:223-9.
50. Koksal GM, Sayilgan C, Aydin S, Oz H, Uzun H. Correlation of plasma and tissue oxidative stresses in intra-abdominal sepsis. J Surg Res 2004; 122:180-3.
51. Sakaguchi S, Kanda N, Hsu CC, Sakaguchi O. Lipid peroxide formation and membrane damage in endotoxin-poisoned mice. Microbiol Immunol 1981; 25:229-44.
52. Dickson S. Sepsis and multiple organ failure anaesthesia. Intens Care Med 2009; 10:165-8.
53. Starkopf J, Zilmer K, Vihalemm T, Kullisaar T, Zilmer M, Samarutel J. Time course of oxidative stress during open-heart surgery. Scand J Thorac Cardiovasc Surg 1995; 29:181-6.
54. Goode HF, Webster NR. Free radicals and antioxidants in sepsis. Crit Care Med 1993; 21:1770-6.
55. Cuzzocrea S, Mazzon E, Dugo L etal. Protective effects of n-acetylcysteine on lung injury and red blood cell modification induced by carrageenan in the rat. FASEB J 2001; 15:1187-200.
56. Ogilvie AC, Groeneveld AB, Straub JP, Thijs LG. Plasma lipid peroxides and antioxidants in human septic shock. Intens Care Med 1991; 17:40-4.
57. Soriano FG, Liaudet L, Szabo E etal. Resistance to acute septic peritonitis in poly(ADP-ribose) polymerase-1-deficient mice. Shock 2002; 17:286-92.
58. Kharb S, Singh V, Ghalaut PS, Sharma A, Singh GP. Role of oxygen free radicals in shock. J Assoc Physicians India 2000; 48:956-7.
59. Kannan R, Kuhlenkamp JF, Jeandidier E, Trinh H, Ookhtens M, Kaplowitz N. Evidence for carrier-mediated transport of glutathione across the blood-brain barrier in the rat. J Clin Invest 1990; 85:2009-13.
60. Ortolani O, Conti A, De Gaudio AR, Moraldi E, Cantini Q, Novelli G. The effect of glutathione and N-acetylcysteine on lipoperoxidative damage in patients with early septic shock. Am J Respir Crit Care Med 2000; 161:1907-11.
61. Lyons J, Rauh-Pfeiffer A, Ming-Yu Y etal. Cysteine metabolism and whole blood glutathione synthesis in septic pediatric patients. Crit Care Med 2001; 29:870-7.
62. Carbonell LF, Nadal JA, Llanos MC, Hernandez I, Nava E, Diaz J. Depletion of liver glutathione potentiates the oxidative stress and decreases nitric oxide synthesis in a rat endotoxin shock model. Crit Care Med 2000; 28:2002-6.
63. Ritter C, Andrades M, Frota Junior ML etal. Oxidative parameters and mortality in sepsis induced by cecal ligation and perforation. Intens Care Med 2003; 29:1782-9.
64. Damas P, Ledoux D, Nys M etal. Cytokine serum level during severe sepsis in human IL-6 as a marker of severity. Ann Surg 1992; 215:356-62.
65. Zanotti S, Kumar A. Cytokine modulation in sepsis and septic shock. Exp Opin Investig Drugs 2002; 11:1061-75.
66. Ayala A, Lomas JL, Grutkoski PS, Chung CS. Pathological aspects of apoptosis in severe sepsis and shock? Int J Biochem Cell Biol 2003; 35:7-15.