Suppression of autoimmune retinal disease by lovastatin does not require Th2 cytokine induction.
Suppression of autoimmune retinal disease by lovastatin does not require Th2 cytokine induction.
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洛伐他汀抑制自身免疫性视网膜疾病不需要 Th2 细胞因子诱导。
DOI：
10.4049/jimmunol.174.4.2327
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发表时间：
2005-02-15
期刊：
影响因子：
--
通讯作者：
Greenwood J
中科院分区：
文献类型：
--
作者：
Harry R;Gegg M;Hankey D;Zambarakji H;Pryce G;Baker D;Calder V;Adamson P;Greenwood J
眼内炎症性疾病是严重视力障碍和失明的常见原因。在自身免疫性视网膜疾病的急性小鼠模型中，我们证明用 HMG-CoA 还原酶抑制剂洛伐他汀治疗可抑制临床眼部病理、视网膜血管渗漏和白细胞浸润视网膜。合用甲瓦龙酸内酯（HMG-CoA 还原酶的下游产物）可逆转疗效，但角鲨烯则不会逆转疗效，角鲨烯位于胆固醇生物合成途径中类异戊二烯焦磷酸代谢物的远端。洛伐他汀治疗超过 7 天，导致血浆洛伐他汀羟基酸浓度为 0.098 ± 0.03μM，不会导致脾细胞产生 Th2 细胞因子，但会导致抗原诱导的 T 细胞增殖小幅减少，并减少 IFN-γ 和 IL-10 的产生。因此，与预期结果相反，我们证明有可能将他汀类药物的治疗效果与其对 Th1/Th2 平衡的活性分开。他汀类药物抑制类异戊二烯焦磷酸合成，这是异戊二烯化和 Rho GTP 酶翻译后激活所需的前体，Rho GTP 酶是内皮细胞 ICAM-1 介导的途径中的关键分子，可促进淋巴细胞迁移。与体内白细胞浸润的抑制作用一致，洛伐他汀在体外对单层视网膜内皮细胞的治疗会抑制淋巴细胞的迁移，这可能在一定程度上解释了药物疗效。与洛伐他汀不同，阿托伐他汀治疗尽管在实验性自身免疫性脑脊髓炎方面显示出显着的临床益处，但未能减轻视网膜炎症性疾病。这些数据强调了他汀类药物在不同炎症条件下的潜在差异活性及其治疗人类后葡萄膜炎的可能用途。
Intraocular inflammatory diseases are a common cause of severe visual impairment and blindness. In an acute mouse model of autoimmune retinal disease, we demonstrate that treatment with the HMG-CoA reductase inhibitor, lovastatin, suppresses clinical ocular pathology, retinal vascular leakage and leukocytic infiltration into the retina. Efficacy was reversed by co-administration of mevalonolactone, the downstream product of HMG-CoA reductase, but not by squalene which is distal to isoprenoid pyrophosphate metabolites within the cholesterol biosynthetic pathway. Lovastatin treatment over 7 days, which resulted in plasma lovastatin hydroxyacid concentrations of 0.098 ± 0.03μM, did not result in splenocyte production of Th2 cytokines but did cause a small reduction in antigen-induced T cell proliferation and a decrease in the production of IFN-γ and IL-10. Thus, contrary to expected outcome we demonstrate that it is possible to dissociate the therapeutic effect of statins from their activity on the Th1/Th2 balance. Statins inhibit isoprenoid pyrophosphate synthesis, precursors required for the prenylation and posttranslational activation of Rho GTPase, a key molecule in the endothelial ICAM-1 mediated pathway that facilitates lymphocyte migration. Consistent with inhibition of leukocyte infiltration in vivo, lovastatin treatment of retinal endothelial cell monolayers in vitro leads to inhibition of lymphocyte transmigration which may, in part, account for drug efficacy. Unlike lovastatin, atorvastatin treatment failed to attenuate retinal inflammatory disease despite showing significant clinical benefit in experimental autoimmune encephalomyelitis. These data highlight the potential differential activity of statins in different inflammatory conditions and their possible therapeutic use for the treatment of human posterior uveitis.
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DOI：
10.1096/fj.02-1014fje
发表时间：
2003-05
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
--
作者：
Greenwood J;Walters CE;Pryce G;Kanuga N;Beraud E;Baker D;Adamson P
通讯作者：
Adamson P
影响因子：
9.9
作者：
Neuhaus, O;Strasser-Fuchs, S;Archelos, JJ
通讯作者：
Archelos, JJ
通过通过阿托伐他汀靶向Th1细胞，治疗实验性脑脊髓炎中的复发性麻痹。
影响因子：
15.3
作者：
Aktas, O;Waiczies, S;Smorodchenko, A;Dörr, J;Seeger, B;Prozorovski, T;Sallach, S;Endres, M;Brocke, S;Nitsch, R;Zipp, F
通讯作者：
Zipp, F
影响因子：
14.5
作者：
Floris, S;Blezer, ELA;de Vries, HE
通讯作者：
de Vries, HE
DOI：
10.1161/01.atv.18.11.1671
发表时间：
1998-11-01
影响因子：
8.7
作者：
Bellosta, S;Via, D;Bernini, F
通讯作者：
Bernini, F