ROLE OF REACTIVE OXYGEN IN BILE-SALT STIMULATION OF COLONIC EPITHELIAL PROLIFERATION
ROLE OF REACTIVE OXYGEN IN BILE-SALT STIMULATION OF COLONIC EPITHELIAL PROLIFERATION
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DOI：
10.1172/jci112382
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发表时间：
1986-03-01
影响因子：
15.9
通讯作者：
DERUBERTIS, FR
中科院分区：
文献类型：
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作者：
CRAVEN, PA;PFANSTIEL, J;DERUBERTIS, FR
我们之前的研究表明，胆汁盐刺激结肠上皮细胞增殖与花生四烯酸酯通过脂加氧酶途径释放和氧化之间存在联系。在本研究中，我们通过环加氧酶和脂加氧酶途径研究了活性氧和花生四烯酸酯代谢终产物在胆盐刺激大鼠结肠上皮细胞增殖中的作用。结肠内灌注5 mM脱氧胆酸盐可增加粘膜鸟氨酸脱羧酶活性和[3H]胸腺嘧啶并入DNA。超氧化物歧化酶模拟物CuII（3,5 -二异丙基水杨酸）2 （CuDIPS）和苯尼酮或埃斯库皮素可以抑制脂氧合酶和环氧合酶的活性，从而消除对脱氧胆酸盐的反应。相反，吲哚美辛增强了反应。Phenidone和esculetin抑制脱氧胆碱诱导的前列腺素E2 （PGE2）、白三烯B4 （LTB4）和5、12和15-羟基二十碳四烯酸（HETE）的升高，而CuDIPS没有作用。吲哚美辛仅抑制PGE2。脱氧胆酸盐（0.5- 5mm）使超氧化物歧化酶敏感的化学发光增加2-10倍，并通过结肠粘膜刮擦或隐窝上皮细胞色素c的减少来刺激超氧化物的产生。胆盐引起的化学发光增加被CuDIPS、苯尼酮和艾斯维丁所消除，但吲哚美辛没有。黄嘌呤-黄嘌呤氧化酶在结肠内产生的活性氧使结肠粘膜鸟氨酸脱羧酶活性和[3H]胸苷并入DNA的能力增加了大约两倍。这些作用被超氧化物歧化酶所消除。研究结果支持活性氧在胆汁盐刺激结肠粘膜增殖中的关键作用，而不是脂氧合酶或环氧合酶途径的远端产物。
Our previous studies had suggested a link between bile salt stimulation of colonic epithelial proliferation and the release and oxygenation of arachidonate via the lipoxygenase pathway. In the present study, we examined the role of reactive oxygen versus end products of arachidonate metabolism via the cyclooxygenase and lipoxygenase pathways in bile salt stimulation of rat colonic epithelial proliferation. Intracolonic instillation of 5 mM deoxycholate increased mucosal ornithine decarboxylase activity and [3H]thymidine incorporation into DNA. Responses to deoxycholate were abolished by the superoxide dismutase mimetic CuII (3,5 diisopropylsalicylic acid)2 (CuDIPS), and by phenidone or esculetin, which inhibit both lipoxygenase and cyclooxygenase activities. By contrast, indomethacin potentiated the response. Phenidone and esculetin suppressed deoxycholate-induced increases in prostaglandin E2 (PGE2), leukotriene B4 (LTB4), and 5, 12, and 15-hydroxyeicosatetraenoic acid (HETE), whereas CuDIPS had no effect. Indomethacin suppressed only PGE2. Deoxycholate (0.5-5 mM) increased superoxide dismutase sensitive chemiluminescence 2-10-fold and stimulated superoxide production as measured by cytochrome c reduction in colonic mucosal scrapings or crypt epithelium. Bile salt-induced increases in chemiluminescence were abolished by CuDIPS, phenidone, and esculetin, but not by indomethacin. Intracolonic generation of reactive oxygen by xanthine-xanthine oxidase increased colonic mucosal ornithine decarboxylase activity and [3H]thymidine incorporation into DNA approximately twofold. These effects were abolished by superoxide dismutase. The findings support a key role for reactive oxygen, rather than more distal products of either the lipoxygenase or cyclooxygenase pathways, in the stimulation of colonic mucosal proliferation by bile salts.