摘 要：牙髓疾病是口腔中常见的疾病，机械、化学、微生物和热因素等会刺激牙髓触发炎症免疫反应，引起牙髓血管扩张、免疫细胞聚集，最终导致组织损伤。地塞米松作为糖皮质激素，因具有抗炎、成骨及镇痛作用，在牙髓病学中的应用越来越广泛，在根管治疗、活髓保存术等领域具有较好的应用前景。本文总结了地塞米松在牙髓疾病中的作用机制及应用。
关键词:地塞米松;根管治疗;盖髓;活髓保存;口腔医学;
Application of Dexamethasone in Dental Pulp Diseases
LIU Xiaoli LIYi
Department of Pediatric Dentistry, Hospital of Stomatology, Jilin University Jilin Provincial Key
Laboratory of Tooth Development and Bone Remodeling
Abstract：Dental pulp disease is a common disease in oral cavity. Mechanical, chemical, microbial, and thermal factors will stimulate dental pulp, trigger inflammatory immune response, cause dental pulp vascular dilatation and immune cell aggregation, and finally lead to tissue damage. As a glucocorticoid, dexamethasone is more and more widely used in endodontics because of its anti-inflammatory, osteogenic, and analgesic effects. It has a better practical perspective in the fields of root canal therapy, vital pulp preservation, and so on. This paper summarizes the mechanism and application of dexamethasone in dental pulp diseases.
Keyword：dexamethasone; root canal therapy; pulp capping; preservation of living pulp; stomatology;
牙髓疾病是口腔中常见的疾病，机械、化学、微生物等会刺激牙髓触发炎症免疫反应，引起牙髓血管扩张、免疫细胞聚集，最终导致组织损伤[1]。地塞米松作为糖皮质激素(glucocorticoid, GC),因具有强大的抗炎和免疫抑制作用被广泛应用于临床，学者们也因GC抗炎、成骨及镇痛作用突出，将其应用于牙髓病学中的研究。本文总结了地塞米松在牙髓疾病中的作用机制及应用。
1 地塞米松的药理作用及作用机制
1.1 地塞米松的抗炎作用
地塞米松通过抑制促炎转录因子释放、刺激抗炎基因表达和诱导淋巴细胞凋亡等发挥强大的抗炎作用[2]。糖皮质激素受体(glucocorticoid receptor, GR)与GC结合后从胞质中转移到细胞核，与其靶基因启动子中的糖皮质激素反应元件结合，可以反式激活抗炎基因的转录，如膜联蛋白A1(annexin A1,AnxA1)[3]。GR激活AnxA1后抑制胞质磷脂酶A2,阻止类花生酸如前列腺素和白三烯的合成，还抑制环氧合酶2的表达，从而抑制促炎介质的释放，同时通过调节内皮细胞与白细胞表面粘附分子的相互作用，抑制白细胞的迁移[4]。GC还可通过反式抑制促炎转录因子的表达发挥抗炎作用，其中激活蛋白-1(activating protein-1,AP-1)和核因子-κB(nuclear factor-kappa B, NF-κB)是关键的促炎转录因子。GR通过直接干扰c-Jun介导的转录和诱导丝裂原活化蛋白激酶磷酸酶 1来抑制AP-1的促炎途径[2]。GR还通过直接抑制NF-κB或诱导亮氨酸拉链的表达间接抑制NF-κB的转录，从而抑制了肿瘤坏死因子-α、白细胞介素-1β、白细胞介素-6、趋化因子、细胞粘附分子、基质金属蛋白酶等的表达[5,6]。
1.2 地塞米松对骨形成的双向作用
Wnt信号传导通过多种机制调节骨形成和重塑，有助于骨再生，地塞米松通过激活经典的Wnt信号途径，提高成骨细胞生长和分化的能力[7]。实验表明地塞米松通过激活Wnt3a、Runx2、β-catenin和p-GSK-3β的表达，促进成牙骨质细胞的分化[8]。此外，低浓度的地塞米松还可以通过细胞内活性氧诱导自噬来增强成骨细胞的活力[9]。但是，地塞米松对成骨细胞的分化和矿化也有负作用，高浓度的地塞米松会抑制成骨。地塞米松在10-6 mol/L时会破坏线粒体动力学、抑制干细胞的成骨并促进脂肪形成，这与地塞米松诱导细胞周期停滞在G0/G1期，抑制 PI3K/AKT 信号通路，上调活性氧水平及FOXO1表达诱导成骨细胞凋亡有关[10,11,12]。
1.3 地塞米松的镇痛作用
炎症发生时，炎性介质可以直接刺激感觉神经纤维引起疼痛，其中作为促炎介质的前列腺素能引起局部血管扩张，促进炎症细胞的趋化，并使疼痛纤维的受体对其他介质的刺激敏感[13,14]。GC通过抑制磷脂酶从细胞膜磷脂中释放游离花生四烯酸，阻断炎症反应中的环氧合酶和脂氧合酶途径，并降低组织缓激肽和神经肽的分泌，抑制伤害性C纤维传导疼痛信号来发挥镇痛作用[15,16]。
2 地塞米松在根管治疗中的应用
根管治疗是治疗牙髓炎和根尖周炎最有效的方法，但术后疼痛是其常见的并发症。在根管预备过程中器械易超出根尖孔，细菌及其代谢产物、感染的牙本质碎屑可能会进入根尖周组织，引起炎症和术后疼痛，影响根尖周组织的愈合[17]。
由于地塞米松具有抗炎镇痛作用，现以多种方式应用于根管治疗中。Aksoy等[18]在90例下颌磨牙伴有症状不可逆性牙髓炎患者中评估地塞米松对术后镇痛的效果，阻滞麻醉后分别用4 mg/mL地塞米松、曲马多和生理盐水进行颊侧黏膜浸润，再一次性完成根管治疗，结果发现术前黏膜下注射地塞米松可以减轻术后48 h内的疼痛。另有学者在242例不可逆性牙髓炎患者中进行阻滞麻醉后一次性完成根管治疗，治疗结束后分别黏膜下注射4 mg/mL地塞米松、长效倍他米松、无菌生理盐水，术后疼痛结果显示地塞米松在术后24 h内缓解疼痛效果更好[19]。此外，Konagala等[20]在132例不可逆性牙髓炎患者中比较术前口服4 mg地塞米松、20 mg吡罗昔康、30 mg地夫可特预防术后疼痛的疗效中发现，地塞米松在术后 6、12和24 h时疼痛显著降低。Suresh等[21]在有症状的不可逆性牙髓炎和根尖周炎患者中探究口服地塞米松的效果，实验结果表明，术前单次口服4 mg地塞米松可以降低术后24 h内疼痛的发生率。此外，地塞米松磷酸钠还可作为根管冲洗剂减轻急性不可逆性牙髓炎患者一次性根管治疗术后疼痛[22]。虽然目前已有大量研究表明地塞米松以麻醉、口服、根管冲洗等各种方式应用于根管治疗中具有良好的镇痛效果，但是究竟以何种方式应用、最适药物剂量以及应用时间效果更佳等问题还未得到学者们的一致认可。
3 地塞米松提高下牙槽神经阻滞麻醉成功率
下牙槽神经阻滞麻醉(inferior alveolar nerve block anesthesia, IANB)是患有不可逆性牙髓炎下颌牙的首选麻醉技术，但术前炎症的严重程度会影响IANB的成功率，这与炎症介质降低伤害性感受器的激活阈值有关[23]。
近年来，研究者利用地塞米松的抗炎特性在提高IANB成功率方面取得了进展。Aggarwal等[24]在117例患有症状性不可逆性牙髓炎患者中比较4 mg/mL地塞米松、25 mg/mL双氯芬酸钠和生理盐水分别进行牙周膜浸润麻醉30 min后IANB的成功率，结果显示地塞米松的成功率为73%,远高于双氯芬酸钠和生理盐水的37%和32%。Bidar等[25]在78例不可逆性牙髓炎患者中探究IANB前1 h口服4 mg地塞米松、400 mg布洛芬、安慰剂对IANB成功的效果，结果显示地塞米松组、布洛芬组和安慰剂组的总成功率分别为80.8%、73.1%、38.5%,地塞米松组成功率最高。一项Meta分析结果显示，口服药中地塞米松同非甾体抗炎药、对乙酰氨基酚、阿片类等药物相比能更大地提高不可逆性牙髓炎牙齿IANB成功率，而且0.5 mg剂量最有效[26]。由此可见，地塞米松可以提高IANB的成功率，但是其成功率仍然较低，临床推广还存在困难，目前在不同给药途径和剂量之间的比较研究也较少，还需要更多的临床实验研究。
4 地塞米松在活髓保存术中的应用
活髓保存术是牙齿因机械性或外伤性露髓首选技术。而活髓保存术中盖髓剂的类型在很大程度上影响着盖髓成功的预后，它们覆盖在牙髓暴露处，以减轻炎症反应， 并诱导深部未受损的牙髓干细胞迁移分化， 促进修复性牙本质的形成[27]。
随着地塞米松的抗炎成骨作用研究越来越深入，学者们也开始研究将其应用于盖髓剂。一项用狗进行的盖髓实验结果表明，MTA和地塞米松盖髓相对于单独MTA盖髓会上调牙本质涎磷蛋白和细胞外基质磷酸糖蛋白的基因表达，而这两种蛋白均参与着牙本质的形成和矿化[28]。临床试验结果也表明使用地塞米松盖髓可使炎症反应水平降低[29]。但由于高浓度地塞米松会抑制成骨，越来越多学者开始研究更合适的局部给药机制，在如何提高其初始溶解度而不使药物超载的问题上进行探索。Zhang等[30]将地塞米松载入中空羟基磷灰石微球中，采用茜素红染色技术、实时聚合酶链反应、检测碱性磷酸酶活性来探究该载药微球对人牙髓干细胞体外分化的影响，结果显示地塞米松中空羟基磷灰石微球在无成骨培养基的情况下能明显促进人牙髓干细胞的生物矿化，并增强碱性磷酸酶、Runt相关转录因子2、骨钙素、牙本质唾液酸磷蛋白和牙本质基质蛋白1的基因表达。Alagha等[31]采用冷冻干燥法制备了多孔生物海绵，并将地塞米松载入其中，通过动物实验结果表明载有地塞米松的多孔生物海绵盖髓剂比氢氧化钙具有更佳的促牙本质桥形成作用。也有学者将地塞米松载入生物活性玻璃纳米粒子，再通过静电纺丝技术将该复合物掺入生物聚合物纳米纤维基质中，将该载药系统用于盖髓剂研究，结果表明该载药系统具有良好的缓释作用并能促进牙髓细胞成牙本质的作用，并与激活了整合素、BMP/Smad和Akt/mTOR信号通路有关[32]。大量实验研究结果表明地塞米松在盖髓剂中具有良好的抗炎成骨作用，将地塞米松载入载体中可以达到药物缓释的目的，但有些载体还存在地塞米松的初始突发释放和释放周期短的问题，还需要进一步的改进。
5 总结和展望
综上，地塞米松不仅具有强大的抗炎作用，同时还具有良好的成骨和镇痛作用，在牙髓病学领域越来越受到学者的关注。但在根管治疗领域中地塞米松的作用效果还未得到大多数学者的认可，缺乏地塞米松给药方式或计量配伍的系统性研究；在活髓保存术中的应用也仅局限于体外研究，还缺乏深入的机制探索和临床研究。地塞米松在牙髓疾病中的应用由实验转化为临床还有一段较长的路要走，但仍有信心相信地塞米松将有希望成为一种治疗牙髓相关疾病的有效药物。
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