DeRubertis F R, Craven P A, Saito R
Department of Medicine, Veterans Administration Medical Center, University of Pittsburgh, PA, 15240, USA.
J Clin Invest. 1984 Nov;74(5):1614-24. doi: 10.1172/JCI111577.
Prostaglandin E2 (PGE2) and several other prostaglandins synthesized by colon suppress the proliferative activity of colonic epithelium. However, bile salts stimulate colonic epithelial proliferation despite the actions of bile salts to enhance the release of arachidonate and consequent colonic synthesis of PGE2. The current study was conducted to assess whether bile salt-induced increases in colonic formation of arachidonate metabolites other than PGE2 were linked to the stimulation of the proliferative activity of colonic epithelium. Within 10 min of addition, deoxycholate markedly stimulated the in vitro release of [14C]arachidonate from prelabeled rat colon. When given in vivo by intracolonic instillation deoxycholate (10 mumol) increased colonic accumulation of immunoreactive prostaglandin E (PGE), thromboxane B2 (TXB2), and the lipoxygenase product 12-hydroxyeicosatetraenoic acid (12-HETE) by two to fourfold over control in 30 min. This effect of intracolonic deoxycholate was followed by a ninefold increase in mucosal ornithine decarboxylase activity (4 h), and a subsequent two to threefold increase in [3H]thymidine [( 3H]Thd) incorporation into DNA of either mucosal scrapings or isolated pools of proliferative colonic epithelial cells (24 h). Intracolonic instillation of indomethacin (50 mumol) suppressed to low or undetectable levels both basal colonic accumulation of PGE and TXB2 and the increases in each parameter induced by subsequent instillation of deoxycholate. By contrast, indomethacin enhanced accumulation of 12-HETE in both control colons and those subsequently exposed to deoxycholate. The increases in 12-HETE induced by indomethacin alone were correlated with stimulation of mucosal ornithine decarboxylase activity and [3H]Thd incorporation into mucosal DNA. Indomethacin also enhanced the increases in these parameters induced by deoxycholate. Intracolonic instillation of phenidone (25-100 mumol) suppressed accumulation of PGE, TXB2, and 12-HETE in control colons and the increases in these parameters induced by a subsequent instillation of deoxycholate. Phenidone alone did not alter mucosal ornithine decarboxylase activity or [3H]thymidine incorporation into mucosal DNA. However, phenidone suppressed or abolished increases in these parameters induced by a subsequent instillation of deoxycholate. 4-(2-[IH-imidazol-1-yl]ethoxy) benzoic acid hydrochloride UK 37,248, which selectively reduced colonic TXB2 to undetectable levels without altering PGE or 12-HETE, had no effect on control or deoxycholate-induced increases in mucosal ornithine decarboxylase activity or [3H]Thd incorporation into DNA. Neither indomethacin nor phenidone altered the increases in [(14)C]arachidonate release induced in vitro by deoxycholate. Chenodeoxycholate and cholate also stimulated [(14)C]arachidonate release from colon in vitro within 10 min, and increased colonic 12-HETE (30 min) and mucosal ornithine decarboxylase activity (4 h) upon intracolonic installation. Prior installation of phenidone inhibited the increases in both 12-HETE and ornithine decarboxylase activity induced by these bile salts. The results support a role for bile salt-induced increases in colonic accumulation of lipoxygenase products, as reflected by 12-HETE, in the subsequent stimulation of the proliferative activity of colonic epithelium.
前列腺素E2（PGE2）以及结肠合成的其他几种前列腺素可抑制结肠上皮的增殖活性。然而，尽管胆盐可促进花生四烯酸的释放并随之增加结肠中PGE2的合成，但胆盐仍能刺激结肠上皮细胞增殖。本研究旨在评估胆盐诱导的除PGE2之外的花生四烯酸代谢产物在结肠中的增加是否与结肠上皮增殖活性的刺激有关。加入后10分钟内，脱氧胆酸盐显著刺激了预先标记的大鼠结肠中[14C]花生四烯酸的体外释放。当通过结肠内滴注给予脱氧胆酸盐（10 μmol）时，在30分钟内，结肠中免疫反应性前列腺素E（PGE）、血栓素B2（TXB2）和脂氧合酶产物12-羟基二十碳四烯酸（12-HETE）的积累比对照组增加了2至4倍。结肠内给予脱氧胆酸盐后，黏膜鸟氨酸脱羧酶活性在4小时内增加了9倍，随后在24小时内，[3H]胸腺嘧啶核苷（[3H]Thd）掺入黏膜刮片或分离的增殖性结肠上皮细胞池的DNA中的量增加了2至3倍。结肠内滴注吲哚美辛（50 μmol）可将PGE和TXB2的基础结肠积累以及随后滴注脱氧胆酸盐诱导的各参数增加抑制到低水平或检测不到的水平。相比之下，吲哚美辛增强了对照组结肠以及随后暴露于脱氧胆酸盐的结肠中12-HETE的积累。单独使用吲哚美辛诱导的12-HETE增加与黏膜鸟氨酸脱羧酶活性的刺激以及[3H]Thd掺入黏膜DNA相关。吲哚美辛还增强了脱氧胆酸盐诱导的这些参数的增加。结肠内滴注非那吡啶（25 - 100 μmol）可抑制对照组结肠中PGE、TXB2和12-HETE的积累以及随后滴注脱氧胆酸盐诱导的这些参数的增加。单独使用非那吡啶不会改变黏膜鸟氨酸脱羧酶活性或[3H]胸腺嘧啶核苷掺入黏膜DNA的情况。然而，非那吡啶抑制或消除了随后滴注脱氧胆酸盐诱导的这些参数的增加。盐酸4 -（2 - [1H - 咪唑 - 1 - 基]乙氧基）苯甲酸UK 37,248可选择性地将结肠TXB2降低到检测不到的水平，而不改变PGE或12-HETE，对对照组或脱氧胆酸盐诱导的黏膜鸟氨酸脱羧酶活性增加或[3H]Thd掺入DNA均无影响。吲哚美辛和非那吡啶均未改变脱氧胆酸盐在体外诱导的[（14）C]花生四烯酸释放的增加。鹅脱氧胆酸盐和胆酸盐在10分钟内也刺激了结肠中[（14）C]花生四烯酸的体外释放，并在结肠内滴注后增加了结肠12-HETE（30分钟）和黏膜鸟氨酸脱羧酶活性（4小时）。预先滴注非那吡啶可抑制这些胆盐诱导的12-HETE和鸟氨酸脱羧酶活性的增加。这些结果支持了胆盐诱导的结肠中脂氧合酶产物积累（以12-HETE为代表）在随后刺激结肠上皮增殖活性中所起的作用。
