林口長庚醫學中心 眼科部 視網膜與葡萄膜炎主任 黃奕修
研究發現, doxycycline可降低內毒素所誘發的葡萄膜炎, 而且是經由前列腺素E2-EP4訊息傳遞
本研究成果是動物實驗的結果, 並非以人作為研究對象所得的結果. 可是, 臨床上以doxycyline用作炎症抑制的治療法, 在人類疾病的治療上, 卻是已行之多年
只是, 用於眼葡萄膜炎的治療, 倒是很少見
本研究的重點, 在以易觀察的眼炎症模型為操作動物, 完成了doxycycline 抑制發炎的機制
Doxycycline Attenuates Endotoxin-Induced Uveitis by Prostaglandin E2-EP4 Signaling
PURPOSE. We explored the anti-inflammatory effects of doxycycline in experimental uveitis
and the underlying mechanisms.
METHODS. Rats with endotoxin-induced uveitis (EIU) received doxycycline (1.5 mg/kg) or the
control vehicle via intraperitoneal injection. Clinical scores were graded under a slit lamp. Rat
peritoneal macrophages were used in vitro to further explore the anti-inflammatory
mechanisms of doxycycline. The levels of nitric oxide (NO), TNF-a, IL-1b, prostaglandin E2
(PGE2), cyclooxygenase (COX)-2, I kappa B-a (IjB-a), inducible nitric oxide synthase (iNOS),
Akt, caspase-3, and nuclear factor-kappa B (NF-jB) were analyzed.
RESULTS. Treatment with doxycycline dramatically reduced the clinical scores of EIU (P <
0.001), with significant decreases in inflammatory cell infiltration, protein concentrations,
and the production of NO, TNF-a, and IL-1b in the aqueous humor (AqH). In vitro,
doxycycline significantly inhibited the production of NO, IL-1b, and TNF-a in peritoneal
macrophages by modulating the PI3K/Akt/IjB-a/NF-jB pathway. Importantly, we found that
doxycycline significantly enhanced COX2 expression and PGE2 production both in vivo and
in vitro. More importantly, blockade of the EP4 receptor of PGE2 significantly reversed the
doxycycline-mediated inhibition of macrophages and the PI3K/Akt pathway in vitro.
Furthermore, simultaneous injection of an EP4 antagonist and doxycycline significantly
blocked the doxycycline-mediated attenuation of EIU.
CONCLUSIONS. Doxycycline can ameliorate EIU, and PGE2-EP4 signaling is essential for the anti-
inflammatory effects of doxycycline in vitro and in vivo.
Keywords: uveitis, doxycycline, tetracyclines, inflammation, macrophage