He Yuting, Zhang Ling, Zhu Zhuoli, Xiao Anqi, Yu Haiyang, Gan Xueqi
Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China.
PLoS One. 2017 Mar 8;12(3):e0173270. doi: 10.1371/journal.pone.0173270. eCollection 2017.
Glucocorticoids (GCs) are frequently used for the suppression of inflammation in chronic inflammatory diseases. Excessive GCs usage is greatly associated with several side effects, including gingival ulceration, the downward migration of the epithelium, attachment loss and disruption of transeptal fibers. The mechanisms underlying GCs-induced impairments in gingival tissue remains poorly understood. Mitochondrial dysfunction is associated with various oral diseases, such as chronic periodontitis, age-related alveolar bone loss and hydrogen peroxide-induced cell injury in gingival. Here, we reported an unexplored role of cyclophilin D (CypD), the major component of mitochondrial permeability transition pore (mPTP), in dexamethasone (Dex)-induced oxidative stress accumulation and cell dysfunctions in gingival tissue. We demonstrated that the expression level of CypD significantly increased under Dex treatment. Blockade of CypD by pharmaceutical inhibitor cyclosporine A (CsA) significantly protected against Dex-induced oxidative stress accumulation in gingival tissue. And the protective effects of blocking CypD in Dex-induced gingival fibroblasts dysfunction were evidenced by rescued mitochondrial function and suppressed production of reactive oxygen species (ROS). In addition, blockade of CypD by pharmaceutical inhibitor CsA or gene knockdown also restored Dex-induced cell toxicity in HGF-1 cells, as shown by suppressed mitochondrial ROS production, increased CcO activity and decreased apoptosis. We also suggested a role of oxidative stress-mediated p38 signal transduction in this event, and antioxidant N-acety-l-cysteine (NAC) could obviously blunted Dex-induced oxidative stress. These findings provide new insights into the role of CypD-dependent mitochondrial pathway in the Dex-induced gingival injury, indicating that CypD may be potential therapeutic strategy for preventing Dex-induced oxidative stress and cell injury in gingival tissue.
糖皮质激素（GCs）常用于抑制慢性炎症性疾病中的炎症反应。过度使用GCs与多种副作用密切相关，包括牙龈溃疡、上皮细胞向下迁移、附着丧失和跨龈纤维破坏。GCs诱导牙龈组织损伤的潜在机制仍知之甚少。线粒体功能障碍与多种口腔疾病相关，如慢性牙周炎、与年龄相关的牙槽骨丧失以及过氧化氢诱导的牙龈细胞损伤。在此，我们报道了环孢素D（CypD），线粒体通透性转换孔（mPTP）的主要成分，在地塞米松（Dex）诱导的牙龈组织氧化应激积累和细胞功能障碍中的一个未被探索的作用。我们证明，在Dex处理下，CypD的表达水平显著增加。药物抑制剂环孢素A（CsA）对CypD的阻断显著保护牙龈组织免受Dex诱导的氧化应激积累。通过挽救线粒体功能和抑制活性氧（ROS）的产生，证实了阻断CypD对Dex诱导的牙龈成纤维细胞功能障碍的保护作用。此外，药物抑制剂CsA或基因敲低对CypD的阻断也恢复了Dex诱导的HGF-1细胞毒性，表现为线粒体ROS产生受抑制、细胞色素c氧化酶（CcO）活性增加和细胞凋亡减少。我们还提出了氧化应激介导的p38信号转导在这一过程中的作用，抗氧化剂N-乙酰半胱氨酸（NAC）可以明显减轻Dex诱导的氧化应激。这些发现为CypD依赖性线粒体途径在Dex诱导的牙龈损伤中的作用提供了新的见解，表明CypD可能是预防Dex诱导的牙龈组织氧化应激和细胞损伤的潜在治疗策略。
