Selim TEMEL, A. Şükrü TANER, Fikri KÜÇÜKEL, Hilal ÖZER, Koray TOPGÜL

PARS inhibitor 3-aminobenzamide attenuates lung injury in experimental endotoxemia

ÖZET: Amaç: Endotoksine bağlı endotoksemi geliştirilen üç gruba ayrılmış 21 erkek Wistar ratta (250-300g) PARS (poli ADP-riboz sentetaz) inhibitörü 3-aminobenzamidin akciğer hasarı üzerine etkisi araştırıldı. Gereç ve Yöntem: Kontrol grubuna intraperitoneal olarak salin (1ml kg-1 n=7); ikinci gruba, intraperitoneal endotoksin (Escherichia coli lipopolysaccharide 055:B5 10 mg kg-1 :n=7); üçüncü gruba ise, endotoksinden 10 dakika önce olmak üzere intraperitoneal 3-aminobenzamid 10mg kg-1 ve 1 ml kg-1 salin uygulandı (n=7). Altı saat sonra fareler yüksek doz anestezik madde verilerek sakrifiye edildi. Protein konsantrasyonunu ve nötrofil sayımını yapmak için akciğer sağ lobuna bronkoalveolar lavaj (BAL) uygulandı. Sol lobun ise ıslak/kuru akciğer oranı hesaplandı. Sol akciğerin intravaskuler nötrofilleri salin ile yıkandı ve spektrofotometrik olarak myeloperoksidaz aktivitesi ölçüldü. İstatistiki değerlendirme için varyans analizi kullanıldı. Bulgular: Kontrol grubu ile karşılaştırıldığında, endotoksin verilen grupta ortalama pulmoner myeloperoksidaz aktivitesinin, ortalama BAL nötrofil konsantrasyonlarının ve protein ve damar dışı akciğer sıvısının sızıntısının işareti olan ortalama ıslak/kuru akciğer oranı anlamlı şekilde artmış olduğu görüldü. Artmış olarak bulunan bu değerler açısından, endotoksin + 3-aminobenzamid grubunda anlamlı bir fark bulunamadı. Sonuç: Bu çalışmanın sonuçları, endotokseminin belirgin bir şekilde akciğer hasarıyla gittiği ve inflamasyonun olduğu alanda PARS’ın etkisi ile nötrofillerin toplanmasında düşüşün ve bununda gelişen hasarla ilişkili olabileceğini göstermiştir.

Deneysel endotoksemide PARS inhibitörü 3-aminobenzamid akciğer hasarını azaltır

Özet ABSTRACT Background: The role of poly(ADP-ribose) synthetase (PARS) inhibitor 3-aminobenzamide on lung injury was investigated in endotoxin-induced sepsis in 21 male Wistar rats (250-300 g) allocated into three groups. Methods: The control group, received intraperitoneal saline (1ml kg-1 : n=7); the second group, intraperitoneal endotoxin (Escherichia coli lipopolysaccharide 055:B5 10 mg kg-1 :n=7); the third group, intraperitoneal 3-aminobenzamide 10mg kg-1 and 1 ml kg-1 saline 10 min before endotoxin (n=7). Six hours later, rats were sacrified with overdose of anaesthetic. Bronchoalveolar lavage (BAL) of the right lung was performed and used for assey of protein concentration and neutrophil count. The wet/dry lung ratio of the left lower lobe was calculated. Intravascular neutrophils of the left lung were cleared out with saline and asseyed spectrophotometrically for myeloperoxidase activity. For statistical evaluation analysis of variance was used. Results: When compared with controls, administration of endotoxin caused a significant increase in mean pulmonary myeloperoxidase activity which was associated with an increase in mean BAL neutrophil concentration and mean lung wet:dry weight ratios as an expression of pulmonary extravascular lung water and microvascular leakage of protein The increase in these values were not significant in the endotoxin+3-AB group. Conclusion: The results of this study show that endotoxin challenge is associated with marked pulmonary injury and part of the anti-inflamatory effect of PARS in this injury may be related to the reduction of neutrophil recruitment into the inflamatory site.

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1- Altuntaş Y, Koksal G Al, Sayilgan C, et al. Tavşanlarda oluşturulan intraabdominal SIRSn modelinde erken dönemde oluşan değişikliklerin araştırılması. Göğüs Kalp Damar Anestezi ve Yoğun Makim Derneği Dergsi 2003; 9:4-10.
2- Bone RC. The parhogenesis of sepsis. Ann Intern Med 1991; 115: 457 -469.
3- Wolfe TA, Dasıa JF. Use of nitric oxide synthase inhibitors as a novel treatment for septic shock. Ann Pharmamcother 1995; 29: 36 - 46.
4- Mercer DW, Smith GS, Cross JM, et al. Effect of Lipopolisaccharide on intestinal injury:Potential role of nitric oxide and lipid peroxidation. J surg Res 1996; 63:185 - 92.
5- Oliver FJ, Mcnissicr-de Murcia J, Nacci C, et HI. Resistance to endotoxic shock as a consequence of defective NF-kappaB activation in poly (ADP-ribose) polymerase-1 deficient mice. EMBO J 1999; 18: 4446-4454
6- Szabo C, Zingarclli B, Salzman AL. Role of poly-ADP ribosyltransferase activation in the vascular contractile and energetic failure elicited by exogenous and endogenous nitric oxide and peroxynitrite. Circ Res 1996; 78: 1051 - 1063.
7- Szabo C. DNA strand breakage and activation of poly-ADP ribosyltransferase: A cytotoxic pathway triggered by peroxynitrite. Free Rad Biol Med 1996; 21: 855 -869. 8- Farivar AS, Woolley SM, Fragıı CH,ct ai. Intratracheal poiy (ADP) ribose synthelase inhibition ameliorates lung ischemia reperfusion injury. Ann Thorac Surg 2004 ;77(6):1938-1943.
9- Bowes J, McDonald MC, Piper J, et al. Inhibitors of poly (ADP-ribose) synthctase protect rat cardiomyocytes against oxidant stress. Canrdiovase Res 1999; 41: 126- 134.
10- Cuzzocrea S, Zingvırelli B, Costantiııo G, Sotlilc A, Teri D, Caputi AP. Protective effect if poly(ADP-ribose) synthetase inhibition on multiple organ failure after zymosan-induced peritonitis in the rat. Crit Can Med 1999; 27(8): 1517-1523.
11- Cuzzocera S, Thiemermann C, Salvemini D, et al. Potential therapeutic effect of antioxidant therapy in shock and inflammation. Car Med Cbem. 2004 ;11(9):1147-1162.
12- 12-Virag L, Szabo C. The therapeutic potential of poly(ADP-ribose) polymcrase inhibitors. Pharmacol Rev 54: 375-429, 2002
13-Szabo A, Salzman A I,, Szabo C. Poly (ADP-Ribose) Synthetase activation mediates pulmonary microvascular and intestinal mucosal dysfunction in endotoxin shock. Life Sciences 1998; 63: 2133-2139.
14- Wizemann T.M, Gardner CR, Laskin JD, et al. Production of nitric oxide and peroxynitrite in the lung during acute endotoxemia. J Leukoc Biol 1994 ;56(6):759-768.
15- Arkovite MS, Wispe JR, Garcia VF, et al. Selective inhibition of the inducible isoform of nitric oxide synthase prevents pulmonary transvascular flux during acute cndotoxcmia J Pediatr Surg. 1996 ;31(8):1009-1015
16- Cuzzocrea S, Zingarclli B, Gilad E, et al: Protective effects of 3-aminobenzamide, an inhibitor of poly(ADP-ribose) synthetase in a carrageenan-induced model of local inflammation. Eur J Pharmacol. 1998 .19;342(l):67-76.
17- Artigas A, Bernard GR, Cadet J, el al. The American-European Consensus Conference on ARDS. Part 2: Ventilator)', pharmacologic, supportive therapy, study design strategies, and issues related to recovery and remodeling. Acute respiratory distress syndrome. Respir Crit Care Med 1998; 157:1332-1347.
18- Szabo, C, L. H. Lim, S. Cuzzocrea, S, et al. Inhibition of poly (ADP-ribose) synthetase attenuates neutrophil recruitment and exerts antiinflammatory effects./ Exp Med 1997; 186: 1041-1049
19- Shimado K, Murakami K, Enkhbaatar P, et al. Effect of poly(ADP ribose) synthetase inhibition on burn and smoke inhalation injury in sheep. Am Physiol Lung Cell Mol Physiol 2003; 285: 240-249.
20- Kiefmann R, Heckel K, Dörger M, et al. Role of poly(ADP-ribose) synthetase in npulmonary leukocyte recruitment. Am] Physiol Lung Cell Mol Phisol; 285: 996-1005.