Rogers Jill E, Li Fei, Coatney Derek D, Otremba Jodie, Kriegl Jaclynn M, Protter T Andrew A, Higgins Linda S, Medicherla Satyanarayana, Kirkwood Keith L
Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI 48109-1078, USA.
J Periodontol. 2007 Oct;78(10):1992-8. doi: 10.1902/jop.2007.070101.
Gram-negative bacterial species, such as Actinobacillus actinomycetemcomitans, contain lipopolysaccharide (LPS) that initiates the innate immune system, resulting in inflammatory alveolar bone loss. LPS activates Toll-like receptors on membrane surfaces, stimulating many intracellular signaling cascades, including the p38 mitogen-activated protein kinase (MAPK). Activation of p38 signaling mediates inflammatory cytokine expression, contributing toward osteoclastogenesis and bone loss. The aim of this study was to determine whether the novel, orally active p38 MAPK inhibitor SD282 could arrest progression of LPS-induced alveolar bone destruction in rats.
Three groups of female Sprague-Dawley rats received LPS injections to the palatal molar gingiva three times per week for 4 weeks to establish periodontitis. From weeks 5 through 8, two groups received the drug SD282 (N = 14) or 1% polyethylene glycol drug vehicle (N = 14) via oral gavage in addition to LPS injections. The third group continued to receive only LPS injections (N = 8). Microcomputed tomography was used to measure volumetric alveolar bone loss, expressed as bone volume fraction (BVF). Expression of interleukin (IL)-1 and -6 and tumor necrosis factor-alpha (TNF-alpha) was assessed by immunohistochemistry, and osteoclasts were enumerated by tartrate-resistant acid phosphatase staining.
By 4 weeks, severe alveolar bone resorption was seen in LPS-injected animals. Administration of SD282 significantly blocked additional volumetric bone loss in the LPS-only versus LPS + SD282 groups (0.37 +/- 0.01 BVF versus 0.43 +/- 0.01 BVF; P < 0.01). Significant reductions in IL-1beta (P < 0.01 ), TNF-alpha (P < 0.05), and osteoclast formation (P < 0.01) occurred in the presence of SD282.
An orally active p38 MAPK inhibitor reduced LPS-induced inflammatory cytokine expression, osteoclastogenesis, and alveolar bone loss in rats. Within the limits of the current study, SD282 arrested periodontal disease progression, thus highlighting the therapeutic potential of this novel class of inhibitors.
革兰氏阴性菌，如伴放线放线杆菌，含有脂多糖（LPS），可启动先天免疫系统，导致炎症性牙槽骨丧失。LPS激活膜表面的Toll样受体，刺激许多细胞内信号级联反应，包括p38丝裂原活化蛋白激酶（MAPK）。p38信号的激活介导炎症细胞因子的表达，促进破骨细胞生成和骨质流失。本研究的目的是确定新型口服活性p38 MAPK抑制剂SD282是否能阻止LPS诱导的大鼠牙槽骨破坏的进展。
三组雌性Sprague-Dawley大鼠每周三次向腭部磨牙牙龈注射LPS，持续4周以建立牙周炎。从第5周到第8周，除LPS注射外，两组通过口服灌胃接受药物SD282（N = 14）或1%聚乙二醇药物载体（N = 14）。第三组继续仅接受LPS注射（N = 8）。使用微型计算机断层扫描测量体积性牙槽骨丧失，以骨体积分数（BVF）表示。通过免疫组织化学评估白细胞介素（IL）-1和-6以及肿瘤坏死因子-α（TNF-α）的表达，并通过抗酒石酸酸性磷酸酶染色对破骨细胞进行计数。
到4周时，在注射LPS的动物中观察到严重的牙槽骨吸收。与仅注射LPS组相比，SD282给药显著阻止了LPS + SD282组额外的体积性骨丧失（0.37±0.01 BVF对0.43±0.01 BVF；P < 0.01）。在存在SD282的情况下，IL-1β（P < 0.01）、TNF-α（P < 0.05）和破骨细胞形成（P < 0.01）显著减少。
一种口服活性p38 MAPK抑制剂可降低LPS诱导的大鼠炎症细胞因子表达、破骨细胞生成和牙槽骨丧失。在本研究的范围内，SD282阻止了牙周疾病进展,从而突出了这类新型抑制剂的治疗潜力。
