Evidence for a regulatory role for histamine in gastric enterochromaffin-like cell proliferation induced by hypergastrinemia.
Evidence for a regulatory role for histamine in gastric enterochromaffin-like cell proliferation induced by hypergastrinemia.
复制标题
组胺在高胃泌素血症诱导的胃肠嗜铬样细胞增殖中发挥调节作用的证据。
作者：
I. Modlin;Z. Zhu;L. Tang;M. Kidd;G. Lawton;K. Miu;R. Powers;J. Goldenring;D. Pasikhov;C. Soroka
背景/目标
高胃泌素血症是由胃酸分泌持续抑制引起的，与胃肠嗜铬样（ECL）细胞增生和类癌肿瘤形成有关。我们检查了选择性 H1-组胺拮抗剂特非那定对胃粘膜细胞增殖的影响，以确定组胺是否可能调节 ECL 细胞的生成。
方法
啮齿动物乳房单独接受H2拮抗剂洛西替丁（2克/升饮用水）或与特非那定（0.5克/升或35毫克/升饮用水）联合治疗120天。对照仅接受水或特非那丁。通过放射免疫测定法测定血清胃泌素水平和组织组胺含量，并测定组织嗜铬粒蛋白水平（蛋白质印迹分析）。通过掺入溴脱氧尿苷（BrdU，200 mg/kg/天，3 天）来测量体内细胞增殖。测定胃粘膜厚度，评估ECL细胞数量，并定量增殖ECL细胞的百分比。为了评估对 ECL 细胞的直接作用，我们研究了特非那定对 ECL 细胞分离制剂（大约 90% 纯度）中组胺分泌和 DNA 合成（BrdU 摄取）的影响。
结果
洛西丁增加血清胃泌素水平、粘膜厚度、组织嗜铬粒蛋白水平、组织胺含量、BrdU掺入、ECL细胞数量和增殖ECL细胞（所有参数p < 0.05）。单独使用特非那定，无论剂量如何，都没有显着效果。与单独使用洛西替丁相比，高剂量与洛西替丁联合显着抑制组织嗜铬粒蛋白水平、组织胺含量、ECL细胞数量和增殖ECL细胞的增加（p < 0.05），但没有改变其他参数。低浓度并没有改变洛西替丁引起的变化。在纯分离的 ECL 细胞中，特非那定单独使用或与胃泌素 (10 nM) 联合使用均不会改变组胺分泌。特非那定显着抑制DNA合成(IC50 10(-10) M)。
结论
特非那定在体内特异性抑制洛西替丁诱导的 ECL 细胞增殖，在体外显着抑制 ECL 细胞 DNA 合成。我们假设组胺通过 H1 受体正向调节胃 ECL 细胞增殖。
BACKGROUND/AIMS
Hypergastrinemia, induced by sustained suppression of gastric acid secretion, is associated with gastric enterochromaffin-like (ECL) cell hyperplasia and carcinoid tumor formation. We examined the effect of a selective H1-histamine antagonist, terfenadine, on gastric mucosal cell proliferation to determine whether histamine might modulate ECL cell generation.
METHODS
The rodent mastomys received the H2-antagonist loxtidine (2 g/l drinking water) alone or in combination with terfenadine (0.5 g/l or 35 mg/l drinking water) for 120 days. Controls received water or terfenadine alone. Serum gastrin levels and tissue histamine content were assayed by radioimmunoassays, and tissue chromogranin levels determined (Western blot analysis). In vivo cell proliferation was measured by bromodeoxyuridine (BrdU, 200 mg/kg/day, 3 days) incorporation. Gastric mucosal thickness was determined, ECL cell number was assessed, and the percentage of proliferating ECL cells quantitated. To evaluate the direct action on ECL cells we then studied the effect of terfenadine on histamine secretion and DNA synthesis (BrdU uptake) in an isolated preparation (approximately 90% pure) of ECL cells.
RESULTS
Loxtidine increased serum gastrin levels, mucosal thickness, tissue chromogranin levels, tissue histamine content, BrdU incorporation, ECL cell number, and proliferating ECL cells (all parameters p < 0.05). Terfenadine alone, irrespective of dosage, had no significant effect. The high dose in combination with loxtidine significantly inhibited the increase in tissue chromogranin levels, tissue histamine content, ECL cell number and proliferating ECL cells (p < 0.05), but did not alter other parameters, compared to loxtidine alone. The low does did not alter the loxtidine-induced changes. In pure isolated ECL cells, terfenadine did not alter histamine secretion either alone or in combination with gastrin (10 nM). DNA synthesis was significantly inhibited by terfenadine (IC50 10(-10) M).
CONCLUSIONS
Terfenadine specifically inhibited the effect of loxtidine-induced ECL cell proliferation in vivo and significantly inhibited ECL cell DNA synthesis in vitro. We postulate that histamine, through an H1 receptor, positively modulates gastric ECL cell proliferation.