Prostaglandins and thromboxanes are products of arachidonic acid metabolism via the cyclooxygenase (CO) enzyme and are responsible for the pain and swelling common to sites of inflammation. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the production of these substances and are used in the treatment of inflammatory diseases such as arthritis. However, one of the major side-effects of NSAID therapy is gastric ulceration. It is possible that inhibition of prostaglandin production and a related increase in the formation of leukotrienes via the 5-lipoxygenase (5-LO) enzymatic pathway are responsible for attracting inflammatory cells, causing local sites of inflammation and producing ulceration. To determine the effects of 5-LO inhibition on this hypothesis, studies were performed in rats to evaluate the effects of tepoxalin, a dual CO/LO inhibitor on leukotriene B4 levels in gastric mucosa and neutrophil adhesion in mesenteric venules. In rats, chronic oral administration of an NSAID, indomethacin (2 mg/kg daily over 4 days), resulted in 40% mortality, accompanied by intestinal adhesions and perforations when evaluated 24 h after the fourth dose of drug. Additionally, neutrophil adhesion was increased in the mesenteric venules and cell infiltration was evident in the mesenteric interstitium. These gastrointestinal side-effects were inhibited in a separate group of rats administered tepoxalin (20 mg/kg, p.o) 30 min prior to each daily indomethacin treatment. Further studies were performed to determine tepoxalin's effects on early events associated with NSAID-induced gastrointestinal inflammation, including neutrophil adhesion, lipid peroxide generation and LTB4 production. Indomethacin (100 mg/kg, p.o.) produced elevated levels of LTB4 in rat gastric mucosa 90 min after administration. Additionally, neutrophil adhesion in mesenteric venules was increased at this dose and with the administration of another NSAID, naproxen. No generation of lipid peroxides was evident in the gastric mucosa at this timepoint. Tepoxalin (up to 400 mg/kg, p.o.) did not have an effects on gastric mucosal LTB4 generation and lipid peroxide levels. A decrease in neutrophil adhesion was observed at the highest dose. In another study, pretreatment with tepoxalin (ED50=7.5 mg/kg, p.o.) or the selective 5-LO inhibitor zileuton (100 mg/kg, p.o.) prevented the increases in gastric mucosal LTB4 levels and neutrophil adhesion induced by indomethacin (100 mg/kg, p.o.). These data suggest that LO inhibition may play a vital role in the prevention of NSAID-induced gastric inflammation, providing insight into the lack of ulcerogenicity with tepoxalin and new approaches to anti-inflammatory therapy which may prevent gastric side effects.

译文

前列腺素和血栓烷是花生四烯酸通过环氧合酶 (CO) 酶代谢的产物,并负责炎症部位常见的疼痛和肿胀。非甾体抗炎药 (NSAIDs) 抑制这些物质的产生,并用于治疗炎症性疾病,例如关节炎。然而,NSAID治疗的主要副作用之一是胃溃疡。通过5-脂氧合酶 (5-LO) 酶途径抑制前列腺素的产生和白三烯形成的相关增加可能导致吸引炎症细胞,引起局部炎症部位并产生溃疡。为了确定5-LO抑制对该假设的影响,在大鼠中进行了研究,以评估tepoxalin (一种双重CO/LO抑制剂) 对胃粘膜中白三烯B4水平和肠系膜小静脉中性粒细胞粘附的影响。在大鼠中,长期口服NSAID吲哚美辛 (在4天内每天2 mg/kg) 导致40% 死亡率,并在第四剂药物后24小时评估时伴有肠粘连和穿孔。此外,肠系膜小静脉中的中性粒细胞粘附增加,肠系膜间质中的细胞浸润明显。在每天吲哚美辛治疗前30分钟,在单独的大鼠组中抑制了这些胃肠道副作用。进行了进一步的研究以确定tepoxalin对与NSAID诱导的胃肠道炎症相关的早期事件的影响,包括中性粒细胞粘附,脂质过氧化物生成和LTB4生成。给药90分钟后,吲哚美辛 (100 mg/kg,p.o.) 在大鼠胃粘膜中产生升高的LTB4水平。此外,在该剂量下以及使用另一种NSAID萘普生时,肠系膜小静脉中的中性粒细胞粘附增加。此时,胃粘膜中没有明显的脂质过氧化物生成。Tepoxalin (最高400 mg/kg,p.o.) 对胃粘膜LTB4的生成和脂质过氧化物水平没有影响。在最高剂量下观察到中性粒细胞粘附减少。在另一项研究中,用tepoxalin (ED50 = 7.5 mg/kg,p.o.) 或选择性5-LO抑制剂zileuton (100 mg/kg,p.o.) 进行预处理可防止胃粘膜LTB4水平升高和中性粒细胞粘附由吲哚美辛 (100 mg/kg,p、o.)。这些数据表明,LO抑制作用可能在预防NSAID诱导的胃部炎症中起着至关重要的作用,从而深入了解tepoxalin缺乏溃疡性以及可能预防胃副作用的抗炎治疗的新方法。

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