过氧化物酶体增殖物激活受体-α对干眼中眼表炎症的作用

Dry eye is one of the most common ocular surface diseases that results in symptoms of discomfort with potential damages to the ocular surface。However, the underlying mechanisms of dry eye are not fully understood. Ocular surface inflammation, epithelial squamous metaplasia and apoptosis are three key components in the pathogenesis dry eye, which promotes each other and forms a vicious cycle. Anti-inflammation therapy is critical for the treatment of moderate or severe dry eye. However, commercially available anti-inflammatory agents show various limitations that lead to restrited effectiveness. Peroxisome proliferator-activated receptors-α (PPAR-α) is one of the crucial pathways that modulate lipid metabolism. Recent evidences suggest that the activation of PPAR-α shows apparente anti-inflammatory activity by inhibiting other transcriptional factors such as NF-κB and consequently downregulation of a series of inflammatory factors. The major contents of the thesis include: whether PPAR-α has the ability to directly regulate the expression of inflammatory cytokines in ocular surface epithelium; what are the different patterns of PPAR-α expression between normal and dry eye condition; and whether dry eye could be prevented or alleviated or even reversed by the activation of PPAR-α through the suppression of ocular surface inflammation. This project attempts to elucidate brand-new molecular signaling mechanisms associated with dry eye, and conceive the perspectives in dry eye treatment with PPAR-α agonists. On the whole, the successful implementation of this project would probably promote scientific research in this area and bring great economic and social value.

干眼是最常见的眼表疾病之一，可引起眼部不适并造成严重眼表损害，但其发病机制并不十分明确。各类干眼的基本病理表现包括眼表炎症、鳞状上皮化生和细胞凋亡。三者相互促进，形成恶性循环。控制眼表炎症是治疗中重度干眼的关键，但临床常用抗炎药物存在各种局限性，影响了疗效。过氧化物酶体增殖物激活受体-α（PPAR-α）是调控脂类代谢的经典通路之一。近年发现活化的PPAR-α可通过影响NF-κB等转录因子调控一系列炎症因子的表达水平，具有很强的抗炎作用。本研究内容包括明确PPAR-α能否直接调控眼表上皮细胞的炎症因子表达水平，明确PPAR-α在正常及干眼状态的表达特点，探讨PPAR-α的激活能否通过抑制眼表炎症达到预防或逆转干眼的作用。本研究试图从全新角度阐释干眼相关的分子信号机制，推测PPAR-α激活剂用于治疗干眼的前景。因此，本项目的成功实施具有重大的科学意义和经济社会价值。

1.项目背景：.干眼是最常见的眼表疾病之一，可引起眼部不适并造成严重眼表损害，但其发病机制并不十分明确。控制眼表炎症是治疗中重度干眼的关键，但临床常用抗炎药物存在各种局限性，影响了疗效。过氧化物酶体增殖物激活受体-α（PPAR-α）是调控脂类代谢的经典通路之一。近年发现活化的PPAR-α可通过影响NF-κB等转录因子调控一系列炎症因子的表达水平，具有很强的抗炎作用。.2.主要研究内容：.本研究内容包括明确PPAR-α能否直接调控眼表上皮细胞的炎症因子表达水平，明确PPAR-α在正常及干眼状态的表达特点，探讨PPAR-α的激活能否通过抑制眼表炎症达到预防或逆转干眼的作用。.3.重要结果及关键数据：.(1)PPAR-α激动剂Fenofibrate显著抑制干眼形成，表现为泪膜破裂时间的维持，角膜上皮损伤及基质炎症浸润程度的下降。.(2)Fenofibrate能显著减轻眼表鳞状上皮化生程度，K10及Ki67表达下降。.(3)Fenofibrate均具有显著抗炎作用，可抑制活体F4/80阳性巨噬细胞和体外培养RAW264.7细胞活力。.(4)Fenofibrate的各种作用均可被PPAR-α抑制剂MK886所阻断。.(5)PPAR-α基因敲除的小鼠具有自发角膜新生血管和上皮缺损。而Fenofibrate对此种小鼠的干眼形成没有抑制作用。.4.科学意义：.本研究从全新角度阐释了干眼发生发展相关的分子信号机制，初步揭示了PPAR-α激活剂用于治疗干眼的潜力。因此，本项目的成功实施具有重要的科学意义和经济社会价值。