Modlin I M, Zhu Z, Tang L H, Kidd M, Lawton G P, Miu K, Powers R E, Goldenring J R, Pasikhov D, Soroka C J
Department of Surgery, Yale University School of Medicine, New Haven, CT 06520-8062, USA.
Digestion. 1996;57(5):310-21. doi: 10.1159/000201351.
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.
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.
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).
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.
背景/目的：胃酸分泌持续受抑制所诱导的高胃泌素血症与胃嗜铬样（ECL）细胞增生及类癌形成有关。我们研究了选择性H1组胺拮抗剂特非那定对胃黏膜细胞增殖的影响，以确定组胺是否可能调节ECL细胞生成。
将啮齿动物马斯特鼠单独给予H2拮抗剂洛替丁（2 g/l饮用水）或与特非那定（0.5 g/l或35 mg/l饮用水）联合给予120天。对照组单独给予水或特非那定。通过放射免疫分析法测定血清胃泌素水平和组织组胺含量，并用蛋白质印迹分析法测定组织嗜铬粒蛋白水平。通过溴脱氧尿苷（BrdU，200 mg/kg/天，共3天）掺入法测定体内细胞增殖。测定胃黏膜厚度，评估ECL细胞数量，并对增殖的ECL细胞百分比进行定量。为了评估对ECL细胞的直接作用，我们随后研究了特非那定对分离的（纯度约90%）ECL细胞组胺分泌和DNA合成（BrdU摄取）的影响。
洛替丁可提高血清胃泌素水平、黏膜厚度、组织嗜铬粒蛋白水平、组织组胺含量、BrdU掺入量、ECL细胞数量及增殖的ECL细胞数量（所有参数p < 0.05）。单独使用特非那定，无论剂量如何，均无显著影响。高剂量特非那定与洛替丁联合使用可显著抑制组织嗜铬粒蛋白水平、组织组胺含量、ECL细胞数量及增殖的ECL细胞数量的增加（p < 0.05），但与单独使用洛替丁相比，未改变其他参数。低剂量未改变洛替丁诱导的变化。在纯分离的ECL细胞中，特非那定单独或与胃泌素（10 nM）联合使用均未改变组胺分泌。特非那定可显著抑制DNA合成（IC50为10(-10) M）。
特非那定在体内特异性抑制洛替丁诱导的ECL细胞增殖作用，并在体外显著抑制ECL细胞DNA合成。我们推测组胺通过H1受体对胃ECL细胞增殖起正向调节作用。
