No abstract

Because the onset of fever induced by intravenously (i.v.) injected bacterial endotoxic lipopolysaccharides (LPS) precedes the appearance in the bloodstream of pyrogenic cytokines, the presumptive peripheral triggers of the febrile response, we have postulated previously that, in their stead, PGE2 could be the peripheral fever trigger because it appears in blood coincidentally with the initial body core temperature (Tc) rise. To test this hypothesis, we injected Salmonella enteritidis LPS (2 microg/kg body wt i.v.) into conscious guinea pigs and measured their plasma levels of LPS, PGE2, TNF-alpha, IL-1beta, and IL-6 before and 15, 30, 60, 90, and 120 min after LPS administration; Tc was monitored continuously. The animals were untreated or Kupffer cell (KC) depleted; the essential involvement of KCs in LPS fever was shown previously. LPS very promptly (<10 min) induced a rise of Tc that was temporally correlated with the elevation of plasma PGE2. KC depletion prevented the Tc and plasma PGE2 rises and slowed the clearance of LPS from the blood. TNF-alpha was not detectable in plasma until 30 min and in IL-1beta and IL-6 until 60 min after LPS injection. KC depletion did not alter the times of appearance or magnitudes of rises of these cytokines, except TNF-alpha, the maximal level of which was increased approximately twofold in the KC-depleted animals. In a follow-up experiment, PGE2 antiserum administered i.v. 10 min before LPS significantly attenuated the febrile response to LPS. Together, these results support the view that, in guinea pigs, PGE2 rather than pyrogenic cytokines is generated by KCs in immediate response to i.v. LPS and triggers the febrile response.

Feleder, Carlos, Vit Perlik, and Clark M. Blatteis. Preoptic ␣1-and ␣2-noradrenergic agonists induce, respectively, PGE2-independent and PGE2-dependent hyperthermic responses in guinea pigs. Am J Physiol Regul Integr Comp Physiol 286: R1156 -R1166, 2004. First published February 12, 2004 10.1152/ajpregu.00486.2003We have shown previously that norepinephrine (NE) microdialyzed into the preoptic area (POA) of conscious guinea pigs stimulates local PGE2 release. To identify the cyclooxygenase (COX) isozyme that catalyzes the production of this PGE2 and the adrenoceptor (AR) subtype that mediates this effect, we microdialyzed for 6 h NE, cirazoline (␣1-AR agonist), and clonidine (␣2-AR agonist) into the POA of conscious guinea pigs pretreated intrapreoptically (intra-POA) with SC-560 (COX-1 inhibitor) or nimesulide or MK-0663 (COX-2 inhibitors) and measured the animals' core temperature (Tc) and intra-POA PGE2 responses. Cirazoline induced Tc rises promptly after the onset of its dialysis without altering PGE2 levels. NE and clonidine caused early falls followed by late rises of Tc; intra-POA PGE2 levels were closely correlated with this thermal course. COX-1 inhibition attenuated the clonidine-induced Tc and PGE2 falls but not the NE-elicited hyperthermia, but COX-2 inhibition suppressed both the clonidine-and NE-induced Tc and PGE2 rises. Coinfused cirazoline and clonidine reproduced the late Tc rise of clonidine but not its early fall and also not the early rise produced by cirazoline; on the other hand, the PGE2 responses were similar to those to NE. Prazosin (␣1-AR antagonist) and yohimbine (␣2-AR antagonist) blocked the effects of their respective agonists. These results indicate that ␣1-and ␣ 2-AR agonists microdialyzed into the POA of conscious guinea pigs evoke distinct Tc responses: ␣1-AR activation produces quick, PGE2-independent T c rises, and ␣2-AR stimulation causes an early Tc fall and a late, COX-2/PGE2-dependent Tc rise. thermoregulation; cyclooxygenase inhibitors; prostaglandin E 2; noradrenergic agonists and antagonists; care temperature; norepinephrine THERE IS MUCH EVIDENCE that norepinephrine (NE) and prostaglandin (PG) E 2 interact in many tissues, including nervous tissue (33). For example, an intimate association between NE and PGE 2 is well documented in the peripheral nervous system (21); to wit, the stimulation of sympathetic neurons induces the postsynaptic release of PGE 2 , which then limits the further presynaptic release of NE, thereby modulating the activity of noradrenergic neurons. It is also well documented that NE induces PGE 2 synthesis in brain tissue (23, 60) where its feedback inhibition of the presynaptic release of NE has been similarly documented (3,13,54).In conscious guinea pigs, NE microinjected into the preoptic-anterior hypothalamic area [POA, the locus of the thermal controller (7)] evokes body (core) temperature (T c ) rises (75,47). Electrical stimulation of the ascending noradrenergic system in the brain stem yields the same result (67), whereas chemical sympat...

Norepinephrine (NE) microdialyzed in the preoptic area (POA) raises core temperature (Tc) via 1) α1-adrenoceptors (AR), quickly and independently of POA PGE2, and 2) α2-AR, after a delay and PGE2 dependently. Since systemic lipopolysaccharide (LPS) activates the central noradrenergic system, we investigated whether preoptic NE mediates LPS fever. We injected LPS (2 μg/kg iv) in guinea pigs prepared with intra-POA microdialysis probes and determined POA cerebrospinal (CSF) NE levels. We similarly microdialyzed prazosin (α1 blocker, 1 μg/μl), yohimbine (α2 blocker, 1 μg/μl), SC-560 [cyclooxygenase (COX)-1 blocker, 5 μg/μl], acetaminophen (presumptive COX-1v blocker, 5 μg/μl), or MK-0663 (COX-2 blocker, 0.5 μg/μl) in other animals before intravenous LPS and measured CSF PGE2. All of the agents were perfused at 2 μg/min for 6 h. Tc was monitored constantly. POA NE peaked within 30 min after LPS and then returned to baseline over the next 90 min. Tc increased within 12 min to a first peak at ∼60 min and to a second at ∼150 min and then declined over the following 2.5 h. POA PGE2 followed a concurrent course. Prazosin pretreatment eliminated the first Tc rise but not the second; PGE2 rose normally. Yohimbine pretreatment did not affect the first Tc rise, which continued unchanged for 6 h; the second rise, however, was absent, and PGE2 levels did not increase. SC-560 and acetaminophen did not alter the LPS-induced PGE2 and Tc rises; MK-0663 prevented both the late PGE2 and Tc rises. These results confirm that POA NE is pivotal in the development of LPS fever.

The intravenous injection of LPS rapidly evokes fever. We have hypothesized that its onset is mediated by prostaglandin (PG)E2 quickly released by Kupffer cells (Kc). LPS, however, does not stimulate PGE2 production by Kc as rapidly as it induces fever; but complement (C) activated by LPS could be the exciting agent. To test this hypothesis, we injected LPS (2 or 8 g/kg) or cobra venom factor (CVF, an immediate activator of the C cascade that depletes its substrate, ultimately causing hypocomplementemia; 25 U/animal) into the portal vein of anesthetized guinea pigs and measured the appearance of PGE2, TNF-␣, IL-1␤, and IL-6 in the inferior vena cava (IVC) over the following 60 min. LPS (at both doses) and CVF induced similar rises in PGE2 within the first 5 min after treatment; the rises in PGE2 due to CVF returned to control in 15 min, whereas PGE2 rises due to LPS increased further, then stabilized. LPS given 3 h after CVF to the same animals also elevated PGE2, but after a 30-to 45-min delay. CVF per se did not alter basal PGE2 and cytokine levels and their responses to LPS. These in vivo effects were substantiated by the in vitro responses of primary Kc from guinea pigs to C (0.116 U/ml) and LPS (200 ng/ml). These results indicate that LPS-activated C rather than LPS itself triggers the early release of PGE2 by Kc. liver; fever; portal vein cannulation; cobra venom factor; pyrogenic cytokines FEVER DEVELOPS QUICKLY AFTER the intravenous bolus administration of a pyrogenic dose of LPS to conscious guinea pigs, rats, and other species, but the afferent mechanism that induces this response is controversial. It is generally thought that it is mediated by pyrogenic cytokines produced secondarily in response to the LPS challenge, rather than by its direct action. Tumor necrosis factor-␣ (TNF-␣), IL-1␤, and IL-6 are the major cytokines implicated in this response (9). There is, however, a temporal disconnect between the first appearance of these cytokines and the onset of the febrile response to intravenous LPS; that is, fever appears within 10 -15 min (13, 51) whereas TNF-␣, the first cytokine to appear, is not detectable until 30 min after LPS treatment (18,23,24,39). This temporal discrepancy is less evident after the intraperitoneal administration of low to moderate doses of LPS, when the latency of fever onset is ϳ60 min but becomes evident also when higher doses are administered, when the onset latency approaches that after intravenous LPS (7).We have shown previously that the onsets of the febrile responses to intravenous and intraperitoneal LPS are correlated with the appearance of LPS in the liver's Kupffer cells (Kc) (31), the body's principal clearinghouse of LPS (16,34,45) and source of pyrogenic cytokines (10). As cytokines are not constitutively expressed by Kc and their de novo production occurs after some delay (32), we and others have proposed, to account for the promptness of the febrile response to intravenous LPS, that the peripheral pyrogenic signal could be transmitted to the preoptic-anterior...