Dirlik Musa, Karahan Aydin, Canbaz Hakan, Caglikulekci Mehmet, Polat Ayşe, Tamer Lulufer, Aydin Suha
Department of General Surgery, Mersin University Medical School, Mersin, Turkey.
Department of Pathology, Mersin University Medical School, Mersin, Turkey.
Curr Ther Res Clin Exp. 2009 Aug;70(4):299-315. doi: 10.1016/j.curtheres.2009.08.005.
Sulfasalazine, an inhibitor of cyclooxygenase, 5-lipoxygenase, and nuclear factor κB (NF-κB), has been found to alleviate oxidative damage, proinflammatory cytokine production, bile-duct proliferation, neutrophil infiltration, and fibrosis. Therefore, it may have a potential effect in attenuating lipid peroxidation and histologic liver damage in patients with biliary obstruction and biliary obstruction with sepsis.
The aim of this study was to investigate the effect of sulfasalazine on lipid peroxidation and histologic liver damage due to obstructive jaundice (OJ) and to OJ with lipopolysaccharide (LPS)-induced sepsis in an experimental model.
Male Wistar rats, weighing 150 to 220 g, were randomized into 6 groups: OJ; OJ + LPS; OJ + sulfasalazine; OJ + sulfasalazine + LPS (sulfasalazine administered before sepsis); OJ + LPS + sulfasalazine (sulfasalazine administered after sepsis); and sham. Liver malondialdehyde (MDA) and myeloperoxidase (MPO) activities were assessed to monitor lipid peroxidation and neutrophil infiltration in liver tissue. Histologic liver damage was evaluated with hematoxylin-eosin stained slides. Liver tissue NF-κB and caspase-3 expression were studied immunohistopathologically to evaluate lipid peroxidation, liver damage, and hepatocyte apoptosis.
Forty-eight rats were evenly randomized into 6 groups of 8. MDA (P = 0.001), MPO (P = 0.001), NF-κB (P = 0.003), caspase-3 expression (P = 0.002), and liver injury scores (P = 0.002) increased significantly in the OJ group compared with the sham group. Compared with the OJ group, MDA (P = 0.030) and MPO levels (P = 0.001), and liver injury scores (P = 0.033) were decreased significantly in the OJ + sulfasalazine group. In the OJ + sulfasalazine + LPS and OJ + LPS + sulfasalazine groups, MDA (P = 0.008 and P = 0.023, respectively) and MPO (both, P = 0.001) were significantly decreased; however, liver NF-κB, caspase-3 expression, and liver injury scores were not significantly different compared with the OJ + LPS group. There was no significant difference between the OJ + LPS + sulfasalazine and OJ + sulfasalazine + LPS groups in regard to all end points when comparing the effects of sulfasalazine administered before or after sepsis.
Sulfasalazine was associated with decreased neutrophil accumulation and lipid peroxidation in these rats with OJ. Administration of sulfasalazine before or after LPS-induced sepsis was associated with a reduction in lipid peroxidation and neutrophil accumulation; however, it did not attenuate histologic liver damage. There was no difference between the findings when sulfasalazine was administered before or after sepsis in OJ.
柳氮磺胺吡啶是一种环氧化酶、5-脂氧合酶和核因子κB（NF-κB）的抑制剂，已被发现可减轻氧化损伤、促炎细胞因子产生、胆管增生、中性粒细胞浸润和纤维化。因此，它可能对减轻胆道梗阻患者以及伴有脓毒症的胆道梗阻患者的脂质过氧化和肝脏组织学损伤具有潜在作用。
本研究旨在探讨柳氮磺胺吡啶对实验模型中梗阻性黄疸（OJ）以及脂多糖（LPS）诱导脓毒症的OJ所致脂质过氧化和肝脏组织学损伤的影响。
体重150至220 g的雄性Wistar大鼠被随机分为6组：OJ组；OJ + LPS组；OJ +柳氮磺胺吡啶组；OJ +柳氮磺胺吡啶+ LPS组（脓毒症前给予柳氮磺胺吡啶）；OJ + LPS +柳氮磺胺吡啶组（脓毒症后给予柳氮磺胺吡啶）；假手术组。评估肝脏丙二醛（MDA）和髓过氧化物酶（MPO）活性以监测肝组织中的脂质过氧化和中性粒细胞浸润。用苏木精-伊红染色切片评估肝脏组织学损伤。通过免疫组织病理学研究肝组织NF-κB和半胱天冬酶-3表达，以评估脂质过氧化、肝损伤和肝细胞凋亡。
48只大鼠平均随机分为6组，每组8只。与假手术组相比，OJ组的MDA（P = 0.001）、MPO（P = 0.001）、NF-κB（P = 0.003）、半胱天冬酶-3表达（P = 0.002）和肝损伤评分（P = 0.002）显著升高。与OJ组相比，OJ +柳氮磺胺吡啶组的MDA（P = 0.030）、MPO水平（P = 0.001）和肝损伤评分（P = 0.033）显著降低。在OJ +柳氮磺胺吡啶+ LPS组和OJ + LPS +柳氮磺胺吡啶组中，MDA（分别为P = 0.008和P = 0.023）和MPO（均为P = 0.001）显著降低；然而，与OJ + LPS组相比，肝脏NF-κB、半胱天冬酶-3表达和肝损伤评分无显著差异。比较脓毒症前或后给予柳氮磺胺吡啶的效果时，OJ + LPS +柳氮磺胺吡啶组和OJ +柳氮磺胺吡啶+ LPS组在所有终点方面均无显著差异。
柳氮磺胺吡啶与这些OJ大鼠中性粒细胞积聚和脂质过氧化减少有关。在LPS诱导的脓毒症之前或之后给予柳氮磺胺吡啶与脂质过氧化和中性粒细胞积聚减少有关；然而，它并未减轻肝脏组织学损伤。在OJ中脓毒症之前或之后给予柳氮磺胺吡啶时，结果无差异。
