Pisoschi Cătălina Gabriela, Stănciulescu Camelia Elena, Andrei Ana Marina, Berbecaru-Iovan Anca, Munteanu Cristina, Popescu Florica, Banită Ileana Monica
Department of Pharmacy, University of Medicine and Pharmacy of Craiova, Romania;
Rom J Morphol Embryol. 2014;55(2):285-90.
Gingival overgrowth was reported as a side effect after chronic administration of several drugs, which, despite their different pharmacological effect, seem to have the gingival mucosa as a secondary target. The thickness of the gingival epithelium and fibrosis in the lamina propria are unspecific changes that together determine the enlargement of the gingival mucosa, but the molecular mechanisms responsible for the imbalance of collagen synthesis/breakdown are still uncertain. The aim of our study was to assess the role of TGF-β1-CTGF pathway in the activation of cells with a fibrilogenetic phenotype responsible for the gingival fibrosis developed after chronic administration of dihydropyridine calcium channel blockers.
Fragments of gingival tissue collected from patients clinically diagnosed with gingival overgrowth after chronic administration of nifedipine and amlodipine were processed for paraffin embedding. Serial sections were used for routine staining Masson and Gömöri's silver impregnation in order to reveal collagen accumulation and for immunohistochemical reactions to label TGF-β1, CTGF, Ki67 and α-SMA.
Routine histological staining for collagen revealed the presence of gingival fibrosis and a change between type I collagen/type III collagen ratio. Regardless of the drug involved, many slides showed extended TGF-β1 positive areas, mainly in the profound - spinous and basal - layers, but also in some cells from the subjacent connective tissue. CTGF exposed intense positive reaction in the basal and parabasal layers, but also in resident cells from the connective tissue. Ki67 immunolabeling did not reveal an increased fibroblast proliferation in the lamina propria. We noticed the presence of a small number of myofibroblasts in the lamina propria.
These findings suggest that TGF-β1-CTGF axis is activated in dihydropyridine calcium channel blockers-induced gingival overgrowth and exerts a different control on the activation of fibroblasts with a synthetic phenotype. These results also have implications for better understanding mechanisms of fibrosis and the future use of this pathogenic pathway as a therapeutic target in order to limit gingival fibrosis.
据报道，长期服用几种药物后会出现牙龈增生这一副作用，尽管这些药物的药理作用不同，但似乎都将牙龈黏膜作为次要靶点。牙龈上皮的厚度和固有层的纤维化是非特异性变化，共同决定了牙龈黏膜的增大，但导致胶原合成/分解失衡的分子机制仍不确定。我们研究的目的是评估转化生长因子-β1（TGF-β1）-结缔组织生长因子（CTGF）通路在慢性服用二氢吡啶类钙通道阻滞剂后发生的牙龈纤维化中，对具有纤维生成表型的细胞激活所起的作用。
从临床诊断为长期服用硝苯地平和氨氯地平后出现牙龈增生的患者身上采集牙龈组织碎片，进行石蜡包埋处理。连续切片用于常规的Masson染色和Gömöri银浸染，以显示胶原积累，并用于免疫组织化学反应，标记TGF-β1、CTGF、Ki67和α-平滑肌肌动蛋白（α-SMA）。
胶原的常规组织学染色显示存在牙龈纤维化以及I型胶原/III型胶原比例的变化。无论涉及何种药物，许多切片都显示TGF-β1阳性区域扩大，主要在深层-棘层和基底层，但也在相邻结缔组织的一些细胞中。CTGF在基底层和副基底层以及结缔组织的驻留细胞中呈现强烈阳性反应。Ki67免疫标记未显示固有层中成纤维细胞增殖增加。我们注意到固有层中存在少量肌成纤维细胞。
这些发现表明，在二氢吡啶类钙通道阻滞剂诱导的牙龈增生中，TGF-β1-CTGF轴被激活，并对具有合成表型的成纤维细胞的激活发挥不同的调控作用。这些结果对于更好地理解纤维化机制以及未来将这一致病途径用作治疗靶点以限制牙龈纤维化也具有重要意义。
