Skarnes R C, Brown S K, Hull S S, McCracken J A
J Exp Med. 1981 Oct 1;154(4):1212-24. doi: 10.1084/jem.154.4.1212.
Biphasic fevers were induced in sheep with intravascular infusions or injections of 4-10 mug (80-200 ng/kg) of endotoxin, whereas monophasic fevers were obtained with doses of 1-2/mug (20-40 ng/kg). A marked increase in arterial blood pressure invariably accompanied the onset of fever; the latency of responses to the higher and lower doses of endotoxins averaged 26 min and 42 min, respectively. Prostaglandin (PG) assays of plasma from the carotid artery and jugular vein during fever episodes revealed a surge of PGE and PGF coincident with the pressor response and the first phase of fever, but PG were not detected in plasma samples taken throughout the second phase of fever. PG measurements of arterial and venous plasma collected at a distal site (hind limb) showed a similar surge of PGE and PGF in association with the early fever response, indicating that intravascular PG synthesis and release represents a generalized systemic response to circulating endotoxin. Carotid arterial infusions of PGE(2) produced immediate monophasic fevers and pressor responses, whereas PGD(2) infusions produced an immediate pressor effect but no fever. Infusions of PGF(2alpha) or prostacyclin, however, evoked neither fever nor pressor effects. Intracarotid infusions of leukocyte pyrogen (LP) caused monophasic fevers with latent periods of 15-20 min but pressor responses were not seen and neither PGE nor PGF were detected in plasma samples from the carotid artery or jugular vein before or during fever. Indomethacin, a potent inhibitor of arachidonic acid metabolism, blocked fever responses to endotoxin and to LP. These findings implicate PGE as the mediator of the early phase of endotoxin fever and imply a role for another pyrogenic metabolite ofarachidonic acid in the mediation of the second phase of fever, i.e., the phase associated with circulating LP. It is possible that both pyrogenic metabolites are generated within the vascular compartment, reaching thermoregulatory centers of the brain by transfer across the blood-brain interface.
通过血管内输注或注射4 - 10微克（80 - 200纳克/千克）内毒素可使绵羊产生双相热，而剂量为1 - 2微克（20 - 40纳克/千克）时则产生单相热。发热开始时动脉血压总是显著升高；对较高和较低剂量内毒素反应的潜伏期分别平均为26分钟和42分钟。在发热期间对来自颈动脉和颈静脉的血浆进行前列腺素（PG）测定，结果显示PGE和PGF在升压反应和发热第一阶段时激增，但在发热第二阶段采集的血浆样本中未检测到PG。对在远端部位（后肢）采集的动脉和静脉血浆进行PG测量，结果显示PGE和PGF在早期发热反应时也有类似的激增，这表明血管内PG的合成和释放代表了对循环内毒素的全身性反应。颈动脉内输注PGE₂会立即产生单相热和升压反应，而输注PGD₂会立即产生升压作用但不引起发热。然而，输注PGF₂α或前列环素既不引起发热也不产生升压作用。颈动脉内输注白细胞致热原（LP）会产生单相热，潜伏期为15 - 20分钟，但未观察到升压反应，并且在发热前或发热期间从颈动脉或颈静脉采集的血浆样本中未检测到PGE或PGF。吲哚美辛是一种有效的花生四烯酸代谢抑制剂，它可阻断对内毒素和LP的发热反应。这些发现表明PGE是内毒素发热早期阶段的介质，并暗示花生四烯酸的另一种致热代谢产物在发热第二阶段（即与循环LP相关的阶段）的介导中起作用。有可能这两种致热代谢产物都在血管腔内产生，通过穿过血脑界面转移到达脑的体温调节中枢。
