Role of local prostaglandin synthesis in the modulation of proliferative activity of rat colonic epithelium.
Role of local prostaglandin synthesis in the modulation of proliferative activity of rat colonic epithelium.
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局部前列腺素合成在调节大鼠结肠上皮增殖活性中的作用。
DOI：
10.1172/jci111093
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发表时间：
1983
期刊：
影响因子：
--
通讯作者：
DeRubertis,FR
中科院分区：
文献类型：
--
作者：
Craven,PA;Saito,R;DeRubertis,FR
在大鼠结肠中研究了局部前列腺素（PG）合成在结肠上皮增殖活性调节中的作用。给实验大鼠施用吲哚美辛（5 mg/kg s.c.每8小时一次，共3次）或阿司匹林（0.5 g/100 g饮食，共3 d）。吲哚美辛或阿司匹林处理的大鼠，[3 H]胸苷（dThd）掺入体内DNA中增加约2倍以上的控制从远端结肠粘膜刮片，约3倍以上的控制从远端结肠分离的上皮细胞的增殖池。[3 H]dThd掺入DNA也检查了离体后立即远端结肠切除术。它是大约两倍高的粘膜结肠段（1小时孵育）从大鼠吲哚美辛或阿司匹林在体内治疗，与相应的值相比，从对照组大鼠的段。免疫反应性（i）前列腺素E（PGE），通过[14 C]花生四烯酸代谢物的高效液相色谱分析结肠段孵育的主要PG产物，在吲哚美辛或阿司匹林处理大鼠的1小时结肠孵育培养基中与对照大鼠相比显著（95%）减少。此外，环（c）AMP含量从吲哚美辛或阿司匹林治疗大鼠段粘膜显着低于对照组大鼠。在体外不存在吲哚美辛的情况下，吲哚美辛处理大鼠的结肠节段的延长孵育（4-24 h）导致[3 H]dThd掺入DNA、iPGE和粘膜cAMP最终恢复至对照值。相反，包括吲哚美辛（0.25 mM）在孵育（6小时）的结肠段吲哚美辛治疗的大鼠导致持续抑制iPGE和粘膜cAMP，以及持续增强的[3 H]dThd纳入粘膜DNA。然而，从对照组大鼠（没有在体内药物暴露）的结肠节段与吲哚美辛或阿司匹林在体外长达24小时的时间内孵育未能改变DNA合成，尽管显着减少媒体iPGE和较低的粘膜cAMP。后者的观察结果表明，额外的体内因素开始在吲哚美辛或阿司匹林治疗的大鼠的DNA合成的增强。外源性PGE 2，D2，I2，或F2 α，其中每一个都增加了内源性粘膜cAMP含量的孵育结肠段从控制，吲哚美辛或阿司匹林治疗的大鼠，所有抑制[3 H]dThd掺入到体外粘膜DNA。双丁酰cAMP，但不是双丁酰cGMP，在体外[3 H]dThd掺入DNA有类似的抑制作用。因此，本观察结果与内源性结肠PG合成对结肠上皮细胞增殖活性的抑制作用一致。这种作用可能是通过cAMP介导的。图片
The role of local prostaglandin (PG) synthesis in the modulation of the proliferative activity of colonic epithelium was examined in rat colon. Experimental rats were given either indomethacin (5 mg/kg s.c. every 8 h for three doses) or aspirin (0.5 g/100 g diet for 3 d). In rats treated with indomethacin or aspirin, the incorporation of [3H]thymidine (dThd) into DNA in vivo was increased approximately twofold over control in mucosal scrapings from distal colon, and approximately threefold over control in the proliferating pool of epithelial cells isolated from distal colon. [3H]dThd incorporation into DNA was also examined ex vivo immediately after distal colonic resection. It was approximately twofold higher in mucosa of colonic segments (1-h incubation) from rats treated with indomethacin or aspirin in vivo, compared with corresponding values of segments from control rats. Immunoreactive (i) prostaglandin E (PGE), the dominant PG product of colon segment incubates by high-performance liquid chromatography analysis of [14C]arachidonate metabolites, was markedly (95%) reduced in the media of 1-h colon incubates from indomethacin- or aspirin-treated rats, compared with control rats. Moreover, the cyclic (c)AMP content of mucosa of segments from indomethacin- or aspirin-treated rats was significantly lower than that of control rats. Prolonged incubation (4-24 h) of colonic segments from indomethacin-treated rats, in the absence of indomethacin in vitro, led to an eventual return of [3H]dThd incorporation into DNA, iPGE, and mucosal cAMP to control values. Conversely, inclusion of indomethacin (0.25 mM) in the incubations (6 h) of colonic segments from indomethacin-treated rats resulted in persistent suppression of iPGE and mucosal cAMP, as well as persistent enhancement of [3H]dThd incorporation into mucosal DNA. However, incubation of colonic segments from control rats (no in vivo drug exposure) with indomethacin or aspirin in vitro for periods up to 24 h failed to alter DNA synthesis, despite marked reduction in media iPGE and lower mucosal cAMP. The latter observations suggested that additional in vivo factors initiated the enhancement of DNA synthesis in indomethacin- or aspirin-treated rats. Exogenous PGE2, D2, I2, or F2 alpha, each of which increased the endogenous mucosal cAMP content of incubated colonic segments from control, indomethacin- or aspirin-treated rats, all suppressed [3H]dThd incorporation into mucosal DNA in vitro. Dibutyryl cAMP, but not dibutyryl cGMP, had an analogous suppressive effect on in vitro [3H]dThd incorporation into DNA. Thus, the present observations are consistent with an inhibitory action of endogenous colonic PG synthesis on the proliferative activity of colonic epithelium. This action may be mediated through cAMP.Images