Enhancement of the febrile responses of rats to endogenous pyrogen occurs within the OVLT region

Abstract

The febrile responses of male Sprague-Dawley rats to a semi-purified endogenous pyrogen (EP) derived from human monocytes are markedly enhanced 3 days after the animals are intravenously injected with a variety of immunoadjuvants. The present study was designed to investigate the site within the body at which these substances act to produce this febrile-enhancing phenomenon. Stainless steel microinjection cannula guide tubes were implanted within the region of the organum vasculosum lamina terminalis (OVLT) of the rats and control febrile dose-response curves to EP were established. Minute quantities of the immunoadjuvants zymosan, lipopolysaccharide endotoxin, and the synthetic adjuvant peptide, muramyl dipeptide, were microinjected into the OVLT region and 3 days later, the febrile responses of the animals were retested. In each case the febrile response elicited by a standard dose of EP was more than doubled, the slope of the fever dose-response curve was tripled, and the dose threshold was lowered by a factor of four to five. These responses are identical with those produced when much larger amounts of these immunoadjuvants are injected intravenously, and, thus, we conclude that the site of action of these substances in enhancing fever in response to EP resides in or near the OVLT region. It is proposed that EP stimulates a type of reticuloendothelial cell residing within the OVLT to release prostaglandin E, which in turn crosses the blood-brain barrier to effect the changes in the thermoregulatory neurons of the preoptic anterior hypothalamic area that result in fever.

Involvement of brain cytokines in zymosan-induced febrile response

“…Moreover, expression of TLR2 and TLR6 was reported in endothelial cells of the CNS, and zym was associated with an increase in the permeability of the vessels by damage of the intercellular junctions (44). In addition, as mentioned earlier, zym injected into the OVLT potentiated EP-induced fever (70). Altogether, these studies indicated that zym could also have a direct effect on the CNS, particularly in areas related to fever.…”

“…We further investigated whether zym could activate important regions related to the febrile response; namely, the OVLT [as suggested in Ref. (70)] and median preoptic nucleus (MnPO), a major preoptic site involved in thermoregulation (45,64,75).…”

Essential role for endothelin ETB receptors in fever induced by LPS (E. coli) in rats

“…Therefore, the hypothalamic region seems to be endowed with all the functional requirements needed for local formation and action of endothelins. However, one cannot discard the possibility that endothelins formed in the periphery may reach the hypothalamus via the organum vasculosum laminae terminalis (OVLT, as indeed do several cytokines; Stitt & Shimada, 1989), or that cytokines acting on endothelial cells of this structure stimulate endothelin formation. Whatever the source of endothelins mobilized by LPS to cause fever, it is noteworthy that bosentan and BQ‐788 only inhibited this response significantly from 2.5 h onwards, a finding consistent with the slow onset of temperature changes induced by i.c.v.…”

Impact of muscle injury and accompanying inflammatory response on thermoregulation during exercise in the heat

“…It is conceivable that an initial muscle injury might also "sensitize" the body so that a second set of muscular injuries would accentuate adverse thermoregulatory responses. It has been demonstrated that immunoadjuvant exposure 3 days before introduction of endogenous pyrogen will enhance the febrile response to pyrogen exposure (22,23). Because tissue injury can produce an acute inflammatory response and secretion of cytokines (2,3,6,16), it is possible that muscle or other tissue injury (i.e., gut, endothelial) produced by prior exercise could serve as the priming mechanism to sensitize the brain receptor sites to subsequent cytokine exposure and alter the thermoregulatory responses to exercise-heat stress.…”