Altavilla Domenica, Famulari Ciro, Passaniti Maria, Campo Giuseppe M, Macrì Antonio, Seminara Paolo, Marini Herbert, Calò Margherita, Santamaria Letterio B, Bono Daniela, Venuti Francesco S, Mioni Chiara, Leone Sheila, Guarini Salvatore, Squadrito Francesco
Section of Pharmacology, Department of Clinical and Experimental Medicine and Pharmacology, University of Messina (Azienda Ospedaliera Universitario G. Martino), Tore Biologica 5th Floor, Via Consolare Valeria, Gazzi, 98100 Messina, Italy.
Free Radic Res. 2003 Apr;37(4):425-35. doi: 10.1080/1071576031000070093.
Increased lipid peroxidation, enhanced nuclear factor kappa-B (NF-kappaB) activation and augmented tumor necrosis factor-alpha (TNF-alpha) production have been implicated in cerulein-induced pancreatitis. We investigated whether lipid peroxidation inhibition might reduce NF-kappaB activation and the inflammatory response in cerulein-induced pancreatitis. Male Sprague-Dawley rats of 230-250g body weight received administration of cerulein (80 microg/kg s.c. for each of four injections at hourly intervals). A control group received four s.c. injections of 0.9% saline at hourly intervals. Animals were randomized to receive either raxofelast, an inhibitor of lipid peroxidation (20 mg/kg i.p. administered with the first cerulein injection) or its vehicle (1 ml/kg of a 10% DMSO/NaCl solution). All these rats were sacrificed 2 h after the last injection of either cerulein or its vehicle. Raxofelast administration (20 mg/kg i.p. with the first cerulein) significantly reduced malondialdehyde (MDA) levels, an index of lipid peroxidation (CER + DMSO = 3.075 +/- 0.54 micromol/g; CER + raxofelast = 0.693 +/- 0.18 micromol/g; p < 0.001), decreased myeloperoxidase (MPO) activity (CER + DMSO = 22.2 +/- 3.54 mU/g; CER + raxofelast = 9.07 +/- 2.05 mU/g, p < 0.01), increased glutathione levels (GSH) (CER + DMSO = 5.21 +/- 1.79 micromol/g; CER + raxofelast = 15.71 +/- 2.14 micronol/g; p < 0.001), and reduced acinar cell damage evaluated by means of histology and serum levels of both amylase (CER + DMSO = 4063 +/- 707.9 U/l; CER + raxofelast = 1198 +/- 214.4 U/l; p < 0.001), and lipase (CER + DMSO = 1654 +/- 330 U/l; CER + raxofelast = 386 +/- 118.2 U/l; p < 0.001), Furthermore, raxofelast reduced pancreatic NF-kappaB activation and the TNF-alpha mRNA levels and tissue content of mature protein in the pancreas. Indeed, lipid peroxidation inhibition might be considered a potential therapeutic approach to prevent the severe damage in acute pancreatitis.
脂质过氧化增加、核因子κB（NF-κB）激活增强以及肿瘤坏死因子-α（TNF-α）产生增多与雨蛙肽诱导的胰腺炎有关。我们研究了抑制脂质过氧化是否可能减少雨蛙肽诱导的胰腺炎中NF-κB的激活和炎症反应。体重230 - 250g的雄性Sprague-Dawley大鼠接受雨蛙肽给药（每小时皮下注射80μg/kg，共注射4次）。对照组每小时皮下注射4次0.9%生理盐水。动物被随机分为接受脂质过氧化抑制剂拉索非酯（首次注射雨蛙肽时腹腔注射20mg/kg）或其溶媒（1ml/kg的10%二甲基亚砜/氯化钠溶液）。在最后一次注射雨蛙肽或其溶媒后2小时处死所有这些大鼠。给予拉索非酯（首次注射雨蛙肽时腹腔注射20mg/kg）显著降低了脂质过氧化指标丙二醛（MDA）水平（雨蛙肽+二甲基亚砜组=3.075±0.54μmol/g；雨蛙肽+拉索非酯组=0.693±0.18μmol/g；p<0.001），降低了髓过氧化物酶（MPO）活性（雨蛙肽+二甲基亚砜组=22.2±3.54mU/g；雨蛙肽+拉索非酯组=9.07±2.05mU/g，p<0.01），增加了谷胱甘肽（GSH）水平（雨蛙肽+二甲基亚砜组=5.21±1.79μmol/g；雨蛙肽+拉索非酯组=15.71±2.14μmol/g；p<0.001），并通过组织学以及淀粉酶（雨蛙肽+二甲基亚砜组=4063±707.9U/L；雨蛙肽+拉索非酯组=1198±214.4U/L；p<0.001）和脂肪酶（雨蛙肽+二甲基亚砜组=1654±330U/L；雨蛙肽+拉索非酯组=386±118.2U/L；p<0.001）的血清水平评估减少了腺泡细胞损伤。此外，拉索非酯降低了胰腺中NF-κB的激活以及胰腺中TNF-α mRNA水平和成熟蛋白的组织含量。事实上，抑制脂质过氧化可能被认为是预防急性胰腺炎严重损伤的一种潜在治疗方法。
