Iversen L, Kragballe K, Ziboh V A
Department of Dermatology, Marselisborg Hospital, University of Aarhus, Denmark.
Skin Pharmacol. 1997;10(4):169-77. doi: 10.1159/000211501.
The 5-lipoxygenase (5-LO) product of arachidonic acid, leukotriene (LT-)B4, is considered to play a significant role in the pathogenesis of psoriasis. In vitro LTB4 is a potent chemoattractant for leukocytes, and it increases DNA synthesis in human cultured keratinocytes. Intradermal injection of LTB4 into human skin in vivo results in a wheal and flare reaction, and topical application produces intraepidermal microabscesses and induces hyperproliferation. Furthermore, LTB4 has been determined in biologically active amounts in psoriatic skin lesions. Despite the importance of LTB4 in psoriasis, the capacity of the human epidermis to synthesize LTB4 has remained controversial. Recently, a very limited 5-LO activity was reported in human epidermis. Thus, it was shown that human epidermis can contribute significantly to LT formation by transcellular LT synthesis. By this mechanism, LTA4 released from activated leukocytes is further transformed into LTB4 in the keratinocytes by the LTA4 hydrolase. Transcellular metabolism may be of importance in psoriasis where neutrophils migrate into the epidermis, because in human neutrophils the LTA4 hydrolase has been shown as the rate-limiting step in LTB4 formation. The LTA4 hydrolase was localized in the epidermis by activity determination, by inhibition of enzyme activity with known LTA4 hydrolase inhibitors, by Western blotting and by immunohistochemical staining. Moreover the enzyme was purified and further characterized from human cultured keratinocytes and human epidermis. Because of these recent results it is concluded that LTB4 is of significance in the pathogenesis of psoriasis, and it is suggested that future work should focus on developing potent LTA4 hydrolase inhibitors for treatment of psoriasis.
花生四烯酸的5-脂氧合酶（5-LO）产物白三烯（LT-）B4被认为在银屑病的发病机制中起重要作用。在体外，LTB4是一种有效的白细胞趋化因子，它能增加人培养角质形成细胞中的DNA合成。在体内将LTB4皮内注射到人体皮肤会导致风团和潮红反应，局部应用会产生表皮内微脓肿并诱导过度增殖。此外，在银屑病皮肤病变中已检测到具有生物活性量的LTB4。尽管LTB4在银屑病中很重要，但人类表皮合成LTB4的能力仍存在争议。最近，据报道人类表皮中的5-LO活性非常有限。因此，已表明人类表皮可通过跨细胞LT合成对LT的形成有显著贡献。通过这种机制，活化白细胞释放的LTA4在角质形成细胞中被LTA4水解酶进一步转化为LTB4。跨细胞代谢在中性粒细胞迁移到表皮的银屑病中可能很重要，因为在人类中性粒细胞中，LTA4水解酶已被证明是LTB4形成中的限速步骤。通过活性测定、用已知的LTA4水解酶抑制剂抑制酶活性、蛋白质印迹法和免疫组织化学染色，将LTA4水解酶定位在表皮中。此外，还从人培养的角质形成细胞和人表皮中纯化并进一步鉴定了该酶。基于这些最新结果，可以得出结论，LTB4在银屑病的发病机制中具有重要意义，并建议未来的工作应集中在开发有效的LTA4水解酶抑制剂用于治疗银屑病。
