GALLBLADDER MUCOSAL FUNCTION AND CHOLELITHIASIS

该项目的长期目标是确定 含钙胆结石（GS），并开发安全，有效的方法 用于预防和治疗。我们认为所有的GS都应该被考虑 作为胆固醇（XOL）和钙结石的光谱。的一端 光谱是所谓“纯”XOL宝石（其包含可见光 在它们的中心区域中的琥珀酸钙）。另一端是黑色的 （胆红素钙）色素结石。中间是“混合”石头 含有可变的XOL和钙盐，由Ca 2+离子反应形成 与胆汁的4种“钙敏感”阴离子中的一种或多种： 碳酸盐、磷酸盐和游离脂肪酸。钙 因此，胆汁中的沉淀是启动的一个明确的必要事件。 所有色素结石的生长。此外，由于所有XOL宝石 在它们的中央病灶区域含有钙，我们和其他人 假设钙沉淀物可以作为成核的巢 的XOL。根据这一观点，钙在人体内起着至关重要的作用。 所有类型的GS的形成，并进一步阐明胆结石 形成需要阐明这些因素导致钙 胆汁中沉淀。在联合会的任期内， 在阐明钙在胆汁中溶解的热力学方面所作的工作。 在动力学方面，我们发现胆汁含有有效的抑制剂， 碳酸钙结晶。两个特别重要的发现是：（1）Ca 2 + 离子在对流的H2O通量中被动地在小管处进入胆汁 参与胆汁盐（BS）分泌;（2）犬肝细胞游离[Ca ~（2+）] 胆囊（GB）胆汁受吉布斯-唐南力的支配， 管腔内不渗透的阴离子胆汁盐。因此，游离Ca 2+总是 存在于胆汁中，可能治疗性降低[Ca 2 +]， GS的预防和治疗必须通过管腔内 螯合作用因此，已经进行了广泛的研究以开发Ca 2 +- 螯合BS，并取得了很大的进展，进一步的研究是 提出了在这个建议中，我们解决了为什么GS的问题，在所有 动物模型，似乎在粘蛋白凝胶中形成，而不是在本体中形成。 胆汁阶段。在这方面，我们提出的重要意见是， 在严重肥胖的患者中， 胃旁路手术，是：（1）[粘蛋白]和游离（Ca 2+）都是 GB胆汁中显著增加，（2）即使（Ca 2 +] 增加，它实际上低于BS诱导的吉布斯预测- 唐南部队。为了解释这一点，我们提出了一个“库仑捕鼠器” 这一假设取决于两个因素：（1）相对厚的粘蛋白凝胶， GB分泌的H+离子使凝胶部分质子化 上皮（通过Na+/H+交换）。

The long-term goal of this project is to define the pathogenesis of calcium-containing gallstones (GS) and to develop safe, effective methods for their prevention and treatment. We believe all GS should be considered as a spectrum of cholesterol (XOL) and calcium concretions. At one end of the spectrum are so-called "pure" XOL stones (which contain visible calcium bilirubinate in their central regions). At the other end are black (calcium bilirubinate) pigment stones. In-between are "mixed" stones containing variable XOL and calcium salts, formed by reaction of Ca2+ ions with one or more of the 4 "calcium-sensitive" anions of bile: bilirubinate, carbonate, phosphate, and free fatty acids. Calcium precipitation in bile is thus a clear requisite event in the initiation and growth of all pigment stones. In addition, since all XOL stones contain calcium in their central nidus regions, we and others have postulated that calcium precipitates may serve as a nidus for nucleation of XOL. According to this view, calcium plays a crucial role in the formation of all types of GS, and further elucidation of gallstone formation requires elucidation of those factors which lead to calcium precipitation in bile. During tenure of the Consortium, great progress has been made in elucidating the thermodynamics of calcium solubility in bile. In the kinetic area, we have found that bile contains potent inhibitors of CaCO3 crystallization. Two particularly important findings were: (1) Ca2+ ions enter bile passively at the canaliculus in the convective H2O flux attending bile salt (BS) secretion, and (2) free [Ca2+] in canine hepatic and gallbladder (GB) bile is governed by Gibbs-Donnan forces induced by intraluminal, impermeant, anionic bile salts. Thus, free Ca2+ will always be present in bile and possible therapeutic reduction of [Ca2+] for prevention and treatment of GS must be accomplished by intraluminal chelation. Extensive studies have therefore been made to develop a Ca2+- chelating BS, and much progress has been made; further studies are proposed. In this proposal we address the question as to why GS, in all animal models, appear to form in the mucin gel, as opposed to the bulk phase of bile. In this regard, important observations which we have made in patients with severe obesity, who are prone to develop GS following gastric-bypass surgery, are that: (1) Both [Mucin] and free (Ca2+] are significantly increased in GB bile, and (2) Even though (Ca2+] is increased, it is actually lower than that predicted by BS-induced Gibbs- Donnan forces. To explain this, we advance a "Coulombic mousetrap" hypothesis which depends on two factors: (1) A relatively thick mucin gel, and (2) Partial protonation of the gel by H+ ions secreted by the GB epithelium (by Na+/H+ exchange).