Inflammation ＆ Fever

将角叉菜胶注射到大鼠的后爪会引起局部炎症以及包括发烧在内的全身症状。然而，这种炎症诱导发烧的机制尚不清楚。为了阐明这一机制，我们用这个实验模型分析了引发发热的前列腺素E_2(PGE_2)、环氧合酶-2(COX-2)和微粒体前列腺素E合成酶(MPGES)，这两种酶都是PGE_2生物合成所必需的。给予环氧合酶-2抑制剂抑制角叉菜胶致的发热，并伴有脑脊液中前列腺素E_2的升高和脑内皮细胞中环氧合酶-2的表达。在注射后1.5、3、6、12、24 h的5个时间点测定，水肿、发热、前列腺素E_2和环氧合酶-2的积分反应遵循相似的时间过程，直到6h，所有这些指标都达到高峰。治疗后发热和前列腺素E_2迅速恢复到基线水平，而COX-2积分强度和水肿量仅部分减少。与这些不同的是，mPGES的整合强度上升的速度比上述元素慢，在12小时达到峰值，24小时的水平几乎相同。这些结果表明，COX-2和mPGES在脑内皮细胞中的表达导致PGE_2的产生，从而导致外周炎症引起的发热，并提示在发热恢复期，即使存在COX-2和mPGES，也存在抑制PGE_2形成的未知机制。综上所述，脑内皮细胞COX-2和mPGES的表达通过产生前列腺素E_2在炎症性发热中起重要作用。

Injection of carrageenan into the hind paw of rats evokes localized inflammation as well as systemic symptoms including fever. However, the mechanism of this inflammation-induced fever is not known. To clarify this mechanism, we analyzed prostagrandin E_2 (PGE_2), which triggers fever, cyclooxygenase-2 (COX-2) and microsomal prostagrandin E synthase (mPGES), both of which are required for PGE_2 biosynthesis, with this experimental model. Fever evoked by carageenan was suppressed by administration of an enzyme inhibitor for COX-2 and was accompanied with a rise in PGE_2 in the cerebrospinal fluid (CSF), and expression of COX-2 in the brain endothelial cells. When measured at 5 time points, i.e., 1.5, 3, 6, 12, f 24 he after carageen an injection, edema, fever, PGE_2 and COX-2-integrated-iritensiry followed a similar time course until 6 hours, at which time all of these measures were at their peaks. After that, fever and PGE_2 returned to the baselines promptly whereas the COX-2-integrated-intensity and edema volume decreased only partially. Unlike these, mPGES integrated-intensity rose more slowly than the above elements to its peak at 12 hr and the level was almost the same at 24 hr. These results imply that expression of COX-2 and mPGES in brain endothelial cells lead to the production of PGE_2 resulting in fever caused by peripheral inflammation and also suggests that, in the recovery phase of fever, there is a recruitment of unidentified mechanism that suppresses PGE_2 formation even in the presence of COX-2 and mPGES. In conclusion, COX-2 and mPGES expression in brain endotherial cells play an essential role in the inflammation-induced fever by producing PGE_2.