强力霉素通过调节基质金属蛋白酶-2 活性和氧化应激来阻止胃溃疡。
Doxycycline blocks gastric ulcer by regulating matrix metalloproteinase-2 activity and oxidative stress.
机构信息
Department of Physiology, Drug Development Diagnostics and Biotechnology Division, Indian Institute of Chemical Biology, Kolkata-700032, India.
出版信息
World J Gastroenterol. 2011 Jul 28;17(28):3310-21. doi: 10.3748/wjg.v17.i28.3310.
AIM
To examine the effect of doxycycline on the activity of matrix metalloproteinases (MMPs) and oxidative stress in gastric tissues of rats following gastric injury.
METHODS
Gastric ulcers were generated in rats by administration of 70% ethanol, and activity of doxycycline was tested by administration 30 min prior to ethanol. Similarly, the effect of doxycycline was tested in an indomethacin-induced gastric ulcer model. The activities and expression of MMPs were examined by zymography and Western blot analysis.
RESULTS
Gastric injury in rats as judged by elevated ulcer indices following exposure to ulcerogen, either indomethacin or ethanol, was reversed significantly by doxycycline. Indomethacin-induced ulcerated gastric tissues exhibited about 12-fold higher proMMP-9 activity and about 5-fold higher proMMP-3 activity as compared to control tissues. Similarly, ethanol induced about 22-fold and about 6-fold higher proMMP-9 and proMMP-3 activities, respectively, in rat gastric tissues. Both proMMP-9 and MMP-3 activities were markedly decreased by doxycycline in ulcerogen treated rat gastric tissues. In contrast, the reduced MMP-2 activity in ulcerated tissues was increased by doxycycline during ulcer prevention. On the other hand, doxycycline inhibited significantly proMMP-9, -2 and -3 activities in vitro. In addition, doxycycline reduced oxidative load in gastric tissues and scavenged H₂O₂ in vitro. Our results suggest a novel regulatory role of doxycycline on MMP-2 activity in addition to inhibitory action on MMP-9 and MMP-3 during prevention of gastric ulcers.
CONCLUSION
This is the first demonstration of dual action of doxycycline, that is, regulation of MMP activity and reduction of oxidative stress in arresting gastric injury.
目的
观察强力霉素对乙醇致胃损伤大鼠胃组织基质金属蛋白酶（MMPs）活性和氧化应激的影响。
方法
给予 70%乙醇制备大鼠胃溃疡模型，于给予乙醇前 30min 给予强力霉素以检测其活性。同样，在吲哚美辛诱导的胃溃疡模型中检测强力霉素的作用。通过酶谱法和 Western blot 分析检测 MMPs 的活性和表达。
结果
与对照组相比，强力霉素可显著逆转乙醇或吲哚美辛诱导的溃疡指数升高所致的大鼠胃损伤。吲哚美辛诱导的溃疡胃组织中 proMMP-9 活性约升高 12 倍，proMMP-3 活性约升高 5 倍。同样，乙醇诱导的大鼠胃组织中 proMMP-9 和 proMMP-3 活性分别升高约 22 倍和 6 倍。强力霉素可明显降低溃疡原处理大鼠胃组织中的 proMMP-9 和 MMP-3 活性。相反，强力霉素可增加溃疡组织中 MMP-2 活性。另一方面，强力霉素可显著抑制 MMP-9、-2 和 -3 的体外活性。此外，强力霉素可减轻胃组织中的氧化负荷并清除体外的 H₂O₂。我们的研究结果表明，强力霉素在预防胃溃疡中除了抑制 MMP-9 和 MMP-3 外，还具有调节 MMP-2 活性的新作用。
结论
这是首次证明强力霉素具有双重作用，即调节 MMP 活性和减轻氧化应激以阻止胃损伤。
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