内源性抗炎脂质N-棕榈酰乙醇胺对干眼眼表炎症的调控机制研究

Dry eye is a chronic inflammatory ocular surface disease，and has become the most common ophthalmic disease except of refractive error. The mechanism of inflammation resolution has become a hot research area these years. Inflammation resolution is an active process controlled by the endogenous anti-inflammatory and proinflammatory resolving mediators. The dysfunction of endogenous anti-inflammatory and proinflammatory resolving mediators will make the inflammation fail to subside and gradually toward chronic. N-palmitoylethanolamine (PEA), as the body's important endogenous anti-inflammatory and proinflammatory resolving lipid, plays a key role in many human inflammatory diseases. To date, the role of PEA in ocular surface inflammation of dry eye remains unknown. Previously, we found that the expression of PEA was decreased in ocular surface of dry eye, and NAAA inhibition could improve ocular surface damage and decrease conjunctival CD4+ T cell infiltration in dry eye. This evidence indicated that PEA may play an important role in the process toward chronic for ocular surface inflammation in dry eye. The purpose of this study was to investigate the role of PEA in ocular surface inflammation of dry eye. The main research contents are as follows: 1) The expression and activity of PEA system in the ocular surface of dry eye; 2) Whether the changes of PEA system in ocular surface is caused by hypertonic osmotic environment; 3) The role of PEA and its synthase and hydrolase in ocular surface epithelial damage and inflammation (including secretion of inflammatory cytokines, expression of prostaglandins, activation of antigen-presenting cells, and proliferation of CD4+ T cells) in dry eye; and 4) The effect of PEA system on activation of inflammatory signaling pathways by which to regulate the ocular surface inflammation in dry eye. This study is hopeful to find more effective biological targets for dry eye treatment.

干眼是一种慢性炎症性眼表疾病,已成为除屈光不正之外最常见的眼科疾病。炎症消退是一个由内源性抗炎、促炎消退介质控制的主动的程序化过程，内源性促炎消退介质的功能不全是炎症走向慢性化的关键原因。N-棕榈酰乙醇胺（PEA），是一种重要的内源性抗炎、促炎消退脂质，在人类诸多炎症性疾病中扮演着关键角色。我们前期研究发现，干眼眼表PEA含量下降，PEA水解酶NAAA抑制剂可显著改善干眼小鼠眼表损害与炎症，因此，我们推测，PEA的抗炎功能不足可能是干眼眼表炎症迁延不愈的重要原因。本项目拟应用干燥环境诱导小鼠干眼模型与高渗透压培养角膜上皮细胞模型，系统研究PEA在干眼眼表表达的改变，干眼眼表PEA的改变是否由高渗透压环境引起，PEA及其合成酶与水解酶在干眼眼表炎症反应中的作用，以及PEA起抗炎、促炎消退作用所调控的信号通路。本研究有望为干眼治疗找到更安全、更有效的生物靶点，具有重要的研究意义。

干眼是一种慢性炎症性眼表疾病, 已成为除屈光不正之外最常见的眼科疾病。预防炎症的发生对于干眼的治疗至关重要。N-棕榈酰乙醇胺（PEA），是一种重要的内源性抗炎、促炎消退脂质，在人类诸多炎症性疾病中扮演着关键角色。在本研究中，我们应用干燥环境诱导小鼠干眼模型与高渗透压培养角膜上皮细胞模型，系统研究PEA在干眼眼表表达的改变，干眼眼表PEA的改变是否由高渗透压环境引起，PEA及其合成酶与水解酶在干眼眼表炎症反应中的作用，以及PEA起抗炎、促炎消退作用所调控的信号通路。结果发现, 干眼眼表PEA含量下降, PEA水解酶NAAA抑制剂可显著改善干眼小鼠眼表损害与炎症。PEA能够增加结膜杯状细胞数量、增加泪液分泌量从而降低干眼小鼠角膜敏感性、减少角膜屏障损伤，改善引发的干眼症状。进一步研究发现, 棕榈酰乙醇酰胺（PEA）通过可激活过氧化物酶体增殖物激活受体α（PPARα）直接与TGFβ活化激酶1（TAK1）结合，从而防止其过度磷酸化和活化下游p38和JNK1/2信号传导。本研究有望为干眼治疗找到更安全、更有效的生物靶点，具有重要的研究意义。