Slomiany B L, Piotrowski J, Slomiany A
Research Center, University of Medicine and Dentistry of New Jersey, Newark 07103-2400, USA.
J Physiol Pharmacol. 1999 Jun;50(2):197-210.
Endothelin-1 (ET-1), nitric oxide, and cytokines are recognized mediators of the inflammatory processes associated with gastric mucosal injury. In this study, we investigated mucosal expression of ET-1, interleukin-4 (IL-4), and the activity of constitutive nitric oxide synthase (cNOS) during indomethacin-induced gastric mucosal injury, and evaluated the effect of antiulcer agents on this process. The experiments were conducted with groups of rats pretreated intragastrically with ranitidine (100 mg/kg), ebrotidine (100 mg/kg), sulglycotide (200 mg/kg) or vehicle, followed 30 min later by an intragastric dose of indomethacin (60 mg/kg). The animals were killed 2 h later and their mucosal tissue subjected to macroscopic damage assessment and the measurements of epithelial cell apoptosis, ET-1, IL-4, and cNOS. In the absence of antiulcer agents, indomethacin caused multiple hemorrhagic lesions and extensive epithelial cell apoptosis, accompanied by a 20.7% reduction in IL-4, a 3.1-fold increase in mucosal expression of ET-1 and a 4.2-fold decline in cNOS. Pretreatment with H2-receptor antagonist, ranitidine produced a 15.7% reduction in the mucosal damage caused by indomethacin, 29.5% decrease in epithelial cell apoptosis and a 19.6% reduction in ET-1, while the expression of IL-4 increased by 10.8% and that of cNOS showed a 2-fold increase. The H2-blocker, ebrotidine, also known for its gastroprotective effects, reduced the indomethacin-induced lesions by 90.2%, epithelial cell apoptosis decreased by 61% and ET-1 showed a 58.2% decline, while IL-4 increased by 30.6% and that of cNOS showed a 3.1-fold increase. Pretreatment with gastroprotective agent, sulglycotide, led to a 51.2% reduction in the extent of mucosal damage caused by indomethacin, a 43.9% decrease in apoptosis, and a 63.5% decrease in ET-1, while the expression of cNOS increased by 3.4-fold and the level of IL-4 showed a 32.2% increase. The results suggest that an increase in vasoconstrictive ET-1 level combined with a decrease in regulatory cytokine, IL-4, and a loss of compensatory action by cNOS may be responsible for gastric mucosal injury caused by indomethacin. Our findings also point to a value of ebrotidine and sulglycotide in countering the untoward gastrointestinal side effects of NSAID therapy.
内皮素 -1（ET -1）、一氧化氮和细胞因子是公认的与胃黏膜损伤相关的炎症过程的介质。在本研究中，我们调查了吲哚美辛诱导的胃黏膜损伤期间ET -1、白细胞介素 -4（IL -4）的黏膜表达以及组成型一氧化氮合酶（cNOS）的活性，并评估了抗溃疡药物对这一过程的影响。实验采用几组大鼠，分别经胃内给予雷尼替丁（100 mg/kg）、依罗替丁（100 mg/kg）、硫糖铝（200 mg/kg）或赋形剂进行预处理，30分钟后再经胃内给予吲哚美辛（60 mg/kg）。2小时后处死动物，对其黏膜组织进行宏观损伤评估，并测量上皮细胞凋亡、ET -1、IL -4和cNOS。在未使用抗溃疡药物的情况下，吲哚美辛导致多处出血性损伤和广泛的上皮细胞凋亡，同时IL -4降低20.7%，ET -1的黏膜表达增加3.1倍，cNOS降低4.2倍。用H2受体拮抗剂雷尼替丁预处理可使吲哚美辛引起的黏膜损伤减少15.7%，上皮细胞凋亡减少29.5%，ET -1降低19.6%，而IL -4的表达增加10.8%，cNOS的表达增加2倍。同样具有胃保护作用的H2阻滞剂依罗替丁可使吲哚美辛诱导的损伤减少90.2%，上皮细胞凋亡减少61%，ET -1降低58.2%，而IL -4增加30.6%，cNOS的表达增加3.1倍。用胃保护剂硫糖铝预处理可使吲哚美辛引起的黏膜损伤程度降低51.2%，凋亡减少43.9%，ET -1降低63.5%，而cNOS的表达增加3.四倍，IL -4水平增加32.2%。结果表明，血管收缩性ET -1水平升高，同时调节性细胞因子IL -4减少以及cNOS的代偿作用丧失，可能是吲哚美辛引起胃黏膜损伤的原因。我们的研究结果还表明依罗替丁和硫糖铝在对抗非甾体抗炎药治疗的不良胃肠道副作用方面具有价值。
