基于TNF-α/PPAR-β/δ通路探讨凉血解毒方对银屑病合并脂代谢紊乱的调控机制

In recent years, psoriasis patients accompanied with dyslipidemia is significantly increasing, and has become a potential risk factor affecting patients quality of life, but the relevant mechanism is unclear, which is a hot topics in research field. Tumor necrosis factor-α (TNF-α) is a link between innate immunity and lipid metabolism disorders, as well as peroxisome proliferator-activated receptor (PPAR-β/δ) ,which is closely related with psoriasis and dyslipidemia. "Dampness, stasis and toxicity accumulation" is the common pathogenesis of psoriasis and dyslipidemia.LiangXueJieDu Fang(LXJDF) is a Chinese herbal compound for the treatment of psoriasis blood-heat syndrome in Dermatology Department of Beijing Chinese Medicine Hospital, its curative effect has been verified in clinical research and basic experiments，especially it could regulate glycolipid metabolism.Based on TNF-α/PPAR-β/δ pathway, we observe influence of Liangxuejiedu Fang on imiquimod induced ApoE-/- mice psoriasis-like lesions (PASI score, pathological changes), lipid levels, TNF-α and other inflammatory cytokines and PPAR-β/δ pathway. Moreover, we try to validate drug targets and signaling pathways through Lipid Metabonomics and Bioinformatics, to discuss the mechanism of Chinese herbal compound treatment on psoriasis and dyslipidemia comorbidity, and provide theoretical foundation and scientific evidence for clinical treatment.

近年来，银屑病患者合并脂代谢紊乱呈显著增高趋势，并成为影响患者生存质量的潜在危险因素，相关机制尚不明确，是目前研究的热点问题。肿瘤坏死因子-α（TNF-α）及其激活的过氧化物酶体增生物激活受体（PPAR-β/δ）是联系先天免疫和脂质代谢紊乱之间的桥梁，与银屑病和脂代谢紊乱密切相关。“湿瘀毒互结”是银屑病和脂代谢紊乱的共同病机。凉血解毒方是北京中医医院皮肤科治疗银屑病血热证的有效方剂，临床观察和基础实验均证实其具有较好的疗效，并能够调节患者的糖脂类代谢。基于TNF-α/PPAR-β/δ通路，观察凉血解毒方对咪喹莫特诱导ApoE-/-小鼠银屑病样皮损（PASI评分、病理学改变）和血脂水平以及TNF-α等炎症因子和PPAR-β/δ通路的影响，并通过脂质代谢组学和生物信息学验证药物作用的靶点和信号通路，探讨中药复方治疗银屑病合并脂代谢紊乱的作用机制，为临床治疗奠定理论基础和科学依据。

银屑病合并脂代谢紊乱等心脏代谢疾病已引起专业领域学者的重视，但研究多集中于流行病学资料和临床观察，基础实验研究较少。本研究通过构建咪喹莫特诱导ApoE-/-小鼠复合动物模型，尝试从免疫炎症与脂质代谢相关联的靶点和通路探讨凉血解毒方对银屑病合并脂代谢紊乱的干预作用及相关机制，为临床用药提供理论基础和科学依据。研究结果表明：咪喹莫特诱导的ApoE-/-小鼠模型符合银屑病合并脂代谢紊乱的病理特征，可作为研究合并症的病理机制和治疗药物的理想动物模型。凉血解毒方可显著改善咪喹莫特诱导的ApoE-/-小鼠银屑病样皮损：鳞屑减少、红斑和浸润减轻，表皮厚度变薄，抑制表皮基底层细胞核有丝分裂、角化不全、真皮炎性浸润，减少表皮层的脂质堆积，并调节血脂水平。凉血解毒方能够显著抑制咪喹莫特诱导的ApoE-/-小鼠银屑病样皮损中炎症因子的基因表达，降低血清中炎症因子；降低皮肤中PPAR-β/δ基因和蛋白表达，升高PPAR-α和PPAR-γ表达；调控PI3K/Akt/mTOR通路，使其磷酸化，发挥一定的抑制炎症作用。通过脂质组学分析，咪喹莫特诱导的ApoE-/-小鼠复合动物模型具有甘油磷酸代谢功能紊乱，与临床银屑病患者脂质代谢紊乱相一致；同时PPAR-β/δ是甘油磷酸代谢的主要上游调控因子。凉血解毒方能够降低复合模型小鼠血清中PC、LPC和TG，上调SM，呈现出对脂代谢中甘油磷酸代谢的调节作用，其途径是通过干预PPAR-β/δ调控的转移酶实现的。因此，凉血解毒方通过PPAR-β/δ及相应通路发挥药物对银屑病样皮损和脂代谢紊乱的调节作用。