基于“肝主泪”和Cytokines/P38MAPK/P53炎症相关通路的养阴润目丸治疗干眼的研究

Xerophthalmia is a syndrome characterized by ocular lesions and refers to quality and quantity of tears or tears film stability decreased due to the dynamics abnormality,,often associated with eye discomfort. Modern life style changes make the disease incidence increased year by year. Under the condition of xerophthalmia,lacrimal gland and ocular surface tissues are at the state of chronic inflammation,inflammatory cytokines can directly induce apoptosis by Cytokines/P38MAPK signal pathway. Through the preliminary study,we confirmed that through the intervention on the P38MAPK pathway can inhibit the inflammatory signal transduction to the apoptosis, and the P53 protein phosphorylation, acetylation and ubiquitination play a significant role in the process of cell apoptosis but the regulation mode of its protein has not been elucidated.We speculate that Yangyinrunmu pills may play a role through the inhibit of P53 protein in the of treatment xerophthalmia.This study was designed to further investigate the intervention effect of P38MAPK/P53 signal pathway in the pathologic process of xerophthalmia and the specific contact between the. This will provide a new understanding of the connection between the state of chronic inflammatory and xerophthalmia and based on the "liver advocate tears" theory on the treatment of xerophthalmia.

干眼是指由于泪液的质或量，或动力学异常而导致的泪膜稳定性下降，出现以眼部不适和眼表组织损害为特征的多种疾病的总称。现代生活模式的改变使该病发病率逐年升高。干眼状态下，泪腺及眼表组织处于慢性炎症状态，炎性因子可通过Cytokines/P38MAPK细胞信号转导通路诱导细胞凋亡。通过前期研究，我们证实了通过干预以P38MAPK为核心的信号通路可抑制炎性信号向细胞凋亡进行转导，而其下游P53蛋白的磷酸化、乙酰化和泛素化对细胞凋亡的影响极为重要，但具体调控方式目前尚不完全清楚。我们推测：基于“肝主泪”理论化裁而出的养阴润目丸治疗干眼可能通过干预P53蛋白后修饰而发挥作用。本研究拟进一步探讨P38MAPK/P53信号通路与干眼的联系及养阴润目丸的干预作用，这将为进一步认识干眼与炎症之间的关系提供科学依据，为基于“肝主泪”理论治疗干眼提供新的认识。

干眼是指由于泪液的质或量，或动力学异常而导致的泪膜稳定性下降，出现以眼部不适和眼表组织损害为特征的多种疾病的总称。现代生活模式的改变使该病发病率逐年升高。干眼状态下，泪腺及眼表组织处于慢性炎症状态，炎性因子可通过Cytokines/P38MAPK细胞信号转导通路诱导细胞凋亡。体内我们通过构建兔、大鼠干眼模型，开展干眼的发病机制及养阴润目丸的调控作用研究。结果表明：养阴润目丸一方面可以能够通过纠正Bax/Bcl-2失衡，改善干眼泪腺细胞凋亡，进而减轻泪腺细胞损伤，恢复泪腺细胞的代谢功能；另外一方面，养阴润目丸可以下调结膜上皮细胞中IL-1、TNF-α、NF-κB、Caspase-3、Caspase-6的表达活性从而阻断相关细胞凋亡级联反应相关。体外我们建立了一种细胞纯度较高、相对简便、快速，模型稳定的兔干眼细胞模型，为兔泪腺上皮细胞功能及干眼的基础研究提供了更稳定的体外实验模型。药物干预结果表明，养阴润目丸可以下调TNF-α、P38MAPK和P53的蛋白表达，从而减少炎性因子分泌，抑制其凋亡率，改善其存活率。临床研究中我们分析了60例养阴润目丸联合羧甲基纤维素钠滴眼剂与单独运用羧甲基纤维素钠滴眼剂治疗干眼的疗效。结果表明，养阴润目丸联合羧甲基纤维素钠滴眼剂治疗干眼临床效果确切，其协同作用达到的疗效优于单独使用羧甲基纤维素纳眼液，提示眼表疾病采用内外兼治，安全有效，值得深入研究。本研究工作为进一步认识干眼与炎症之间的关系提供科学依据，为基于“肝主泪”理论治疗干眼提供新的认识。