Cytological and pharmacological studies on the pathogenesis of nifedipine-associated gingival hyperplasia

1. 我们选择了12例硝苯地平治疗后伴有牙龈增生的牙周炎患者（应答组）和4例硝苯地平治疗后无牙龈增生的牙周炎患者，分别就诊于东京医科大学牙科医院。采用高效液相色谱法检测硝苯地平给药后6 h血清中硝苯地平的浓度。血清硝苯地平浓度与牙龈增生指数有相关性，但相关性不显著。从反应组和牙周健康组获得人牙龈成纤维细胞（HGF）。我们检测了硝苯地平及其代谢物对反应组和牙周健康受试者HGF蛋白聚糖生成的影响。硝苯地平诱导反应组HGF以剂量依赖性方式产生蛋白多糖。相反，硝苯地平以剂量依赖的方式抑制牙周健康受试者HGF中蛋白多糖的产生。硝苯地平的代谢物也有类似的效果。研究了牙龈假单胞菌和放线菌合成假单胞菌的脂多糖（LPS）对牙周健康牙龈HGF蛋白多糖生成的影响。LPS对蛋白多糖的生成没有影响。研究了多种细胞因子包括IL-4、IL-13、inf - γ和TNFalpha对牙周健康牙龈HGF原聚糖生成的影响。IL-4和IL-13显著增加蛋白多糖的总量，而inf - γ显著降低蛋白多糖的总量。TNFalpha增加了培养基中的蛋白多糖产量，但减少了细胞质中的蛋白多糖产量。IL-4和TNFalpha或IL-13和TNFalpha的组合在培养基中协同上调蛋白多糖的产量，并在细胞质中略有提高。

1. We selected 12 periodontitis patients with gingival hyperplasia in response to nifedipine (responder group) and 4 periodontitis patients with no gingival hyperplasia in response to nifedipine who visited Dental hospital at Tokyo Medical and Dental University. The concentration of nifedipine in serum 6 h after intake of nifedipine was examined using high performance liquid chromatography. The concentration of nifedipine in serum tended to be associated with gingival hyperplasia index, but the association was not significant.2. Human gingival fibroblasts (HGF) were obtained from responder group and periodontally healthy subjects. We examined the effect of nifedipine and its metabolite on proteoglycan production in HGF from responder group and in HGF from periodontally healthy subjects. Nifedipine induced proteoglycan production in a dose-dependent fashion in HGF from responder group. In contrast, nifedipine depressed proteoglycan production in a dose-dependent manner in HGF from periodontally healthy subjects. A metabolite of nifedipine had similar effects.3. The effect of lipopolysaccharides (LPS) derived from P. gingivalis and A. actinomycetemcomitans on proteoglycan production was examined in HGF derived from periodontally healthy gingiva. The LPS had no effect on proteoglycan production.4. The effect of various cytokines including IL-4, IL-13, INF-gamma and TNFalpha on protoglycan production was examined in HGF derived from periodontally healthy gingiva. IL-4 and IL-13 significantly enhanced total amounts of proteoglycans, but INF-gamma decreased them. TNFalpha increased proteoglycan production in the culture medium, but decreased it in the cytosol. Combination of IL-4 and TNFalpha or IL-13 and TNFalpha synergistically upregulated proteoglycan production in the culture medium and slightly enhanced it in the cytosol.