Laboratory of Pharmacology, Department of Physic and Chemistry, Faculty of Pharmaceutical Sciences, University of São Paulo, Av. do Café, s/n, Campus Universitário, 14049-903, Ribeirão Preto, São Paulo, Brazil.
Med Microbiol Immunol. 2012 May;201(2):219-29. doi: 10.1007/s00430-011-0225-y. Epub 2011 Dec 28.
The purpose of the present study was to better understand the events involved in the febrile response induced by cecal ligation and puncture (CLP), a complex infectious process. To this end, we conducted in vivo experiments in rats examining (1) fever development, (2) bacterial number in the infection focus and in blood, (3) peripheral and hypothalamic synthesis of cytokines, (4) hypothalamic and cerebrospinal fluid (CSF) synthesis of prostaglandin E(2) (PGE(2)), (5) the effect of anti-IL-6 antibody on fever, and (6) the effect of celecoxib on fever and hypothalamic synthesis of PGE(2) after CLP induction. We found that CLP promotes fever and animal death depending on the number of punctures. The peak of CLP-induced fever overlapped with the maximal increase in the number of bacteria in the infectious focus and blood, which occurred at 6 and 12 h. The peak of the febrile response also coincided with increased amounts of interleukin (IL)-1β, IL-6 and IL-10 in the peritoneal exudate and serum; IL-6 in the hypothalamus and PGE(2) in the CSF and predominantly in the hypothalamus. Moreover, intracerebroventricularly injected anti-IL-6 antibody reduced the febrile response while celecoxib reduced the fever and PGE(2) amount in the hypothalamus induced by CLP. Tumor necrosis factor (TNF)-α peaked at 3 h at all sites studied. Conversely, IL-10 concentration decreased in the hypothalamus. These findings show that the peak of CLP-induced fever is accompanied by an increase of bacteria in peritoneal fluid (local infection) and blood; local synthesis of pyrogenic (IL-1β, IL-6) and antipyretic (IL-10) cytokines and central production of IL-6 and PGE(2), suggesting that these last are the central mediators of this response.
本研究旨在深入了解盲肠结扎穿孔（CLP）诱导发热反应所涉及的事件，CLP 是一种复杂的感染过程。为此，我们在大鼠体内实验中进行了以下研究：（1）发热发展；（2）感染灶和血液中的细菌数量；（3）外周和下丘脑细胞因子的合成；（4）下丘脑和脑脊液（CSF）合成前列腺素 E2（PGE2）；（5）抗白细胞介素 6 抗体对发热的影响；（6）塞来昔布对 CLP 诱导后发热和下丘脑 PGE2 合成的影响。结果发现，CLP 可促进发热和动物死亡，且这一过程与穿孔数量有关。CLP 诱导的发热高峰与感染灶和血液中细菌数量的最大增加相吻合，分别发生在 6 小时和 12 小时。发热反应的高峰也与腹腔渗出液和血清中白细胞介素（IL）-1β、IL-6 和 IL-10 的增加以及下丘脑 IL-6 和 CSF 中（主要是下丘脑）PGE2 的增加相吻合。此外，脑室注射抗白细胞介素 6 抗体可减少发热反应，而塞来昔布可减少 CLP 诱导的发热和下丘脑 PGE2 含量。肿瘤坏死因子（TNF）-α在所有研究部位均在 3 小时达到高峰。相反，下丘脑的 IL-10 浓度下降。这些发现表明，CLP 诱导的发热高峰伴随着腹腔液（局部感染）和血液中细菌数量的增加；发热性（IL-1β、IL-6）和退热性（IL-10）细胞因子的局部合成以及 IL-6 和 PGE2 的中枢产生，提示这些物质是该反应的中枢介质。
