Effects of inhibition of prostaglandin endoperoxide synthase‐2 in chronic gastro‐intestinal ulcer models in rats
Effects of inhibition of prostaglandin endoperoxide synthase‐2 in chronic gastro‐intestinal ulcer models in rats
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抑制前列腺素内过氧化物合酶-2对大鼠慢性胃肠溃疡模型的影响
DOI：
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发表时间：
1998
影响因子：
7.3
通讯作者：
F. Halter
中科院分区：
文献类型：
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作者：
A. Schmassmann;B. Peskar;C. Stettler;P. Netzer;T. Stroff;B. Flogerzi;F. Halter
1在胃中，洋地黄素保护胃粘膜免受损伤。前列腺素合成中的一个限速步骤由前列腺素内过氧化物合酶（PGHS）介导，PGHS是非甾体抗炎药（NSAID）的靶酶。PGHS有两种亚型：组成型（PGHS-1）和诱导型（PGHS-2）。PGHS-1是生理条件下胃内前列腺素的主要来源。传统NSAID（如吲哚美辛和双氯芬酸）非选择性抑制PGHS-1和PGHS-2，可抑制前列腺素合成，导致胃和肠溃疡，并延迟慢性模型中的胃溃疡愈合。已经证明，选择性PGHS-2抑制剂如L-745，337（5-甲磺酰胺-6-（2，4-二氟硫代苯基）-1-茚满酮）不会引起溃疡，也不会抑制胃肠道前列腺素的合成。然而，关于PGHS-2抑制剂对先前建立的胃损伤愈合的长期影响的信息很少。我们评估了胃溃疡愈合过程中PGHS-1和PGHS-2的细胞定位和表达，并评估了L-745，337对大鼠胃中先前建立的冷冻剂的影响。2在实验性胃溃疡愈合过程中，通过免疫组织化学定位和定量PGHS-1和PGHS-2。PGHS-2免疫反应性在正常胃壁中仅可忽略不计，但在胃溃疡后，在再生腺体下方和之间的单核细胞、巨噬细胞、成纤维细胞和内皮细胞中强烈检测到。在正常胃粘膜中检测到PGHS-1免疫反应性，在溃疡口附近的粘膜发生胃溃疡后消失。然而，从第5天开始，它再次出现在再生腺中。因此，PGHS-1和PGHS-2位于不同的位点，其最大表达遵循不同的时间顺序。3我们评估了L-745，337、吲哚美辛和双氯芬酸对大鼠胃溃疡愈合和组织学愈合参数的影响。L-745，337、吲哚美辛和双氯芬酸剂量依赖性地减少胃溃疡的愈合。L-745，337、吲哚美辛和双氯芬酸在第8天降低了溃疡边缘的上皮细胞增殖和溃疡床中的微血管密度，在第15天增加了溃疡火山口下方的肉芽组织厚度和粘膜肌层两侧边缘之间的差距。吲哚美辛和双氯芬酸（而非L-745，337）可减少胃和回肠末端组织碎片中6-酮-PGF 1 α和PGE 2的合成，并减少凝血全血中血小板血栓烷B2的合成。4 L-745，337（每日两次灌胃给药）抑制慢性胃溃疡愈合的剂量反应曲线显示，ID 50值为1.7 mg（4.3 μmol）kg−1。 在急性角叉菜胶海绵大鼠模型中，抑制炎性渗出物中PGE 2合成的剂量反应曲线显示，吲哚美辛和L-745，337的ID 50值分别为1.1mg（3.1 μmol）kg− 1和1.3 mg（3.3μmol）kg−1。 因此，L-745，337在潜在治疗剂量范围内抑制慢性胃溃疡愈合。5总之，胃溃疡后，PGHS-2在最大修复活性区域的单核细胞、巨噬细胞、成纤维细胞和内皮细胞中显著蓄积。L-745，337对PGHS-2的选择性抑制通过在潜在治疗剂量范围内干扰上皮细胞增殖、血管生成和肉芽组织成熟来延迟胃溃疡愈合。PGHS-2衍生的胡兰素似乎在胃溃疡愈合中具有重要作用。
1 In the stomach, prostaglandins protect the gastric mucosa against injuries. One rate‐limiting step in prostaglandin synthesis is mediated by prostaglandin endoperoxide synthase (PGHS), the target enzyme of non‐steroidal anti‐inflammatory drugs (NSAIDs). Two isoforms of PGHS exist: a constitutive (PGHS‐1) and an inducible (PGHS‐2) enzyme. PGHS‐1 is the major source of gastric prostaglandins under physiological conditions. Inhibition of prostaglandin synthesis by traditional NSAIDs such as indomethacin and diclofenac which non‐selectively inhibit both PGHS‐1 and PGHS‐2, causes gastric and intestinal ulceration and delays gastric ulcer healing in chronic models. It has been shown that selective PGHS‐2 inhibitors such as L‐745,337 (5‐methanesulphonamide‐6‐(2,4‐difluorothio‐phenyl)‐1‐indanone) are not ulcerogenic and do not inhibit gastro‐intestinal prostaglandin synthesis. However, minimal information is available on the long‐term effects of PGHS‐2 inhibitors on the healing of previously established gastric injuries. We assessed the cellular localization and expression of PGHS‐1 and PGHS‐2 during gastric ulcer healing and assessed the effects of L‐745,337 on previously established cryoulcers in the rat gastric stomach. 2 PGHS‐1 and PGHS‐2 were located and quantified by immunohistochemistry during experimental gastric ulcer healing. PGHS‐2 immunoreactivity was only negligible in the normal gastric wall, but after gastric ulcerations, it was strongly detected in monocytes, macrophages, fibroblasts and endothelial cells below and between the regenerative glands. PGHS‐1 immunoreactivity detected in normal gastric mucosa, disappeared after gastric ulceration in the mucosa adjacent to the ulcer crater. However, it reappeared in the regenerative glands from day 5 onwards. Thus, PGHS‐1 and PGHS‐2 were located at different sites and their maximal expression followed a different time‐sequence. 3 We assessed the effects of L‐745,337, indomethacin and diclofenac on gastric ulcer healing and histological healing parameters in rats. L‐745,337, indomethacin and diclofenac dose‐dependently decreased the healing of gastric ulcers. L‐745,337, indomethacin and diclofenac decreased epithelial cell proliferation in the ulcer margin and microvessel density in the ulcer bed on day 8 and increased the thickness of the granulation tissue below the ulcer crater and the gap between both edges of the muscularis mucosae on day 15. Indomethacin and diclofenac, but not L‐745,337, decreased synthesis of 6‐keto‐PGF1α and PGE2 in tissue fragments from the stomach and terminal ileum and decreased platelet thromboxane B2 synthesis in clotting whole blood. 4 Dose‐response curves for the inhibition of chronic gastric ulcer healing by L‐745,337 (administered twice daily intragastrically) showed an ID50 value of 1.7 mg (4.3 μmol) kg−1. Dose‐response curves for the inhibition of PGE2 synthesis in inflammatory exudates in the acute carrageenin sponge rat model, showed ID50 values of 1.1 mg (3.1 μmol) kg−1 and 1.3 (3.3 μmol) mg kg−1 for indomethacin and L‐745,337, respectively. Thus, inhibition of chronic gastric ulcer healing by L‐745,337 occurs within a potentially therapeutic dose‐range. 5 In summary, PGHS‐2 is markedly accumulated after gastric ulceration in monocytes, macrophages, fibroblasts and endothelial cells in regions of maximal repair activity. Selective inhibition of PGHS‐2 by L‐745,337 delayed gastric ulcer healing though interference with epithelial cell proliferation, angiogenesis and maturation of granulation tissue in a potentially therapeutic dose range. PGHS‐2‐derived prostaglandins seem to have an important role in gastric ulcer healing.
配体诱导的前列腺素合成需要 TIS10/PGS-2 前列腺素合酶基因在小鼠成纤维细胞和巨噬细胞中表达。
DOI：
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发表时间：
1994
期刊：
The Journal of biological chemistry
影响因子：
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作者：
Reddy,ST;Herschman,HR
通讯作者：
Herschman,HR
DOI：
10.1073/pnas.88.7.2692
发表时间：
1991-04-01
影响因子：
11.1
作者：
XIE, WL;CHIPMAN, JG;SIMMONS, DL
通讯作者：
SIMMONS, DL
DOI：
10.1016/s0021-9258(18)35698-9
发表时间：
1992-12
期刊：
The Journal of biological chemistry
影响因子：
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作者：
Soo-Hee Lee;E. Soyoola;P. Chanmugam;Suzanne B. Hart;Wenqin Sun;Hua Zhong;Shuenn S. Liou;D. Simmons;D. Hwang
通讯作者：
Soo-Hee Lee;E. Soyoola;P. Chanmugam;Suzanne B. Hart;Wenqin Sun;Hua Zhong;Shuenn S. Liou;D. Simmons;D. Hwang