Chiang G, Patra P, Letourneau R, Jeudy S, Boucher W, Green M, Sant G R, Theoharides T C
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts, USA.
J Urol. 2000 Dec;164(6):2119-25.
Mast cells are ubiquitous cells derived from the bone marrow and are responsible for allergic reactions as they release numerous vasodilatory, nociceptive and pro-inflammatory molecules in response to immunoglobulin E (IgE) and specific antigen. Mast cell secretion is also triggered by a number of peptides, such as bradykinin and substance P, and may also be involved in the development of inflammatory responses. An example is interstitial cystitis, which is a sterile painful bladder disorder that has been associated with a defective glycosaminoglycan bladder mucosal layer and an increased number of activated mast cells. Pentosanpolysulfate is a synthetic, sulfated polysaccharide that has been approved for the treatment of interstitial cystitis on the premise that it may replenish the defective glycosaminoglycan layer. We hypothesize that pentosanpolysulfate may also have an additional or alternate action on bladder mast cells. We report that pentosanpolysulfate has a powerful dose dependent inhibitory effect on mast cell release of histamine induced by the mast cell secretagogue compound 48/80.
Inhibition of mast cell secretion was documented by light and electron microscopy and extended to stimulation by substance P or IgE and antigen.
The inhibition was more potent than that seen with the clinically available mast cell stabilizer disodium cromoglycate (cromolyn). Maximal inhibition by pentosanpolysulfate was apparent within 1 minute, was unaffected by the length of pre-incubation and persisted after the drug was washed off. In contrast, the effect of cromolyn was limited by rapid tachyphylaxis. In addition, while cromolyn has no effect on mucosal or rat basophilic leukemia cells, pentosanpolysulfate inhibited histamine secretion from both. Confocal microscopy using a calcium indicator dye showed that pentosanpolysulfate decreased intracellular calcium ion levels.
Pentosanpolysulfate appears to be a potent inhibitor of allergic and nonimmune mast cell stimulation, which is an alternative explanation of its benefit in interstitial cystitis.
肥大细胞是源自骨髓的普遍存在的细胞，当它们响应免疫球蛋白E（IgE）和特定抗原释放大量血管舒张、伤害性感受和促炎分子时，会引发过敏反应。肥大细胞的分泌也可由多种肽触发，如缓激肽和P物质，并且可能也参与炎症反应的发展。一个例子是间质性膀胱炎，这是一种无菌性疼痛性膀胱疾病，与膀胱黏膜层糖胺聚糖缺陷和活化肥大细胞数量增加有关。戊聚糖多硫酸盐是一种合成的硫酸化多糖，已被批准用于治疗间质性膀胱炎，前提是它可能补充有缺陷的糖胺聚糖层。我们假设戊聚糖多硫酸盐可能对膀胱肥大细胞还有额外的或替代的作用。我们报告戊聚糖多硫酸盐对肥大细胞促分泌剂化合物48/80诱导的肥大细胞组胺释放具有强大的剂量依赖性抑制作用。
通过光学显微镜和电子显微镜记录肥大细胞分泌的抑制情况，并扩展到对P物质或IgE和抗原刺激的抑制。
这种抑制作用比临床上可用的肥大细胞稳定剂色甘酸钠（色甘酸）更强。戊聚糖多硫酸盐的最大抑制作用在1分钟内明显，不受预孵育时间的影响，并且在药物洗脱后仍然持续。相比之下，色甘酸的作用受到快速脱敏的限制。此外，虽然色甘酸对黏膜或大鼠嗜碱性白血病细胞没有作用，但戊聚糖多硫酸盐抑制了两者的组胺分泌。使用钙指示剂染料的共聚焦显微镜显示戊聚糖多硫酸盐降低了细胞内钙离子水平。
戊聚糖多硫酸盐似乎是过敏和非免疫性肥大细胞刺激的有效抑制剂，这是其在间质性膀胱炎中有益作用的另一种解释。
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