ANDREJ ROMANOVSKY

..We speculate that postheating thermoregulatory disorders are associated with threshold dissociation, thus representing the poikilothermic (wide dead-band) type of T(b) control...

..Several new targets for antipyretic therapy, including mPGES-1, have been identified...

..A radical solution is to transform all definitions based on comparing T(b) with the SP into definitions based on balancing active and passive processes of T(b) control...

..Studies to test this new hypothesis seem warranted, and our prediction is that the "smoking gun" will be found...

..We speculate that these mechanisms are triggered by peripherally originated, blood-borne prostaglandin E2...

..Hence, pulmonary and hepatic macrophages that recognize LPS via the TLR4 and rapidly produce PGE(2) are likely triggers of the fever response...

..The term balance point is proposed to designate the regulated level of T(b) and to attract attention to the multiple feedback, feedforward, and open-loop components that contribute to thermal balance...

..Hence, the changed febrile responsiveness of OVLT-lesioned animals is given an alternative interpretation, unrelated to febrigenic signaling to the brain...

..Strategies for creating hyperthermia-free TRPV1 antagonists are outlined. The potential physiological and pathological significance of TRPV1-mediated thermoregulatory effects is discussed...

..6) A hepatoceliac vagal, presumably efferent, mechanism ('an anti-inflammatory pathway') counteracts the development of lipopolysaccharide-induced hypothermia and shock...

..We speculate that this mechanism is triggered by blood-borne prostaglandins of the E series...

..The design of the present study did not allow for evaluating the rapid, hematogenous transport. The results obtained suggest that the abdominal vagus does not control the slow. lymphogenous escape of LPS from the peritoneal cavity...

..0-29.0 degrees C). Skin thermometry or thermography is a definition-based, simple, and inexpensive technique to determine whether experimental or housing conditions are neutral, subneutral, or supraneutral for a given animal...

..This is the first well-controlled study to report SI-associated cold-seeking behavior in rats. Cold-seeking behavior is likely to be an important defense response in severe SI...

..The expression of splenic COX-1 was unaffected by LPS. We conclude that COX-1, but not COX-2, mediates LPS hypothermia, and that both COX isoforms are required for LPS hypotension...

..The normal febrile responses of fatty Zucker rats to pyrogenic stimuli at thermoneutrality indicate that fatty mutation does not interrupt febrigenic signaling from the periphery to the brain...

..Whether PGE2 produced at the level of the blood-brain barrier also contributes to the development of the first phase remains to be clarified...

..We conclude that tonic activation of TRPV1 channels in the abdominal viscera by yet unidentified nonthermal factors inhibits skin vasoconstriction and thermogenesis, thus having a suppressive effect on T(b)...

..Neither sPLA(2)-V nor cPGES was induced by LPS. The high magnitude of upregulation of mPGES and sPLA(2)-IIA (1,257-fold and 133-fold, respectively) makes these enzymes attractive targets for anti-inflammatory therapy...

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..By increasing the blood-brain gradient of PGE(2), this mechanism likely facilitates penetration of PGE(2) into the brain and prevents its elimination from the brain...

..The present investigation identifies experimental conditions to study LPS-induced mono-, bi-, and polyphasic fevers and late hypothermia in mice and provides detailed characteristics of these responses...

..It also suggests that no product of the COX-1 gene, including the splice variant COX-1b (COX-3), is essential for these responses...

..All T(b) responses to dLPS were identical to those of cLPS. We conclude that all known T(b) responses to LPS preparations are triggered by LPS per se and not by non-TLR4-signaling contaminants of such preparations...

..BN 52021 (but not its vehicle) was similarly effective in attenuating LPS (10 microg kg-1, i.v.) fever. It is concluded that PAF is a highly potent endogenous pyrogenic substance and a mediator of LPS fever...

..However, all phases of the febrile response of splanchnicotomized rats to intravenous LPS (10 microg/kg) were similar to those of sham-operated controls. Hence, the splanchnic nerve is likely uninvolved in LPS fever...

..It is concluded that NO is uninvolved in febrigenic signaling to the brain...

..We conclude that, in the absence of albumin, AGP and possibly other carriers participate in immune-to-brain signaling by binding and transporting amphipathic inflammatory mediators...

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..The action of CAP on this mechanism is likely TRPV-1-independent. It is speculated that this mechanism may be the production of prostaglandin E(2) by macrophages in LPS-processing organs...

..The first phase is triggered via the TLR4 on hematopoietic cells. The second and third phases involve TLR4 signaling in both hematopoietic and nonhematopoietic cells...

..None of the three known phases of the febrile response of rats to LPS requires the CCK-A receptor...

..g., fasting) can exaggerate both hypothermia and behavioral depression. Since these manifestations aid energy conservation, exaggeration of these manifestations under conditions of negative energy balance is likely to be beneficial...

..In conclusion, the present study reveals a novel, critical role of brain CB1 receptors in LPS hypothermia. Brain CB1 receptors may constitute a new therapeutic target in systemic inflammation and sepsis...

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..We conclude that acute nicotine administration and nicotine withdrawal affect survival in systemic inflammation and that these effects strongly depend on whether inflammation is aseptic or septic...

..We conclude that the febrile response to circulating PGE2 is mediated by the brain, but that it does not require vagal afferent signaling...

..The high magnitude of up-regulation of mPGES and sPLA2-IIA (1,260 and 130 fold, respectively) and that of down-regulation of 15-PGES (30 fold) during LPS fever makes these enzymes attractive targets for anti-inflammatory therapy...

..Newly discovered signaling pathways for eicosanoids, such as the endovanilloid system, may participate in thermoregulation, but further studies are required before definitive conclusions can be made...

..The relationship between the putative CCK-ergic febrile mechanism and the established central PGE mediation needs further study...

..Taking into consideration the abundance of ephrins and Eph receptors in tissues and the robustness of their signaling effects, the proposed involvement is likely to be substantial and may constitute a novel therapeutic target...

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..This mechanism, if confirmed, will constitute a new target for therapeutic interventions in systemic inflammation. ..

..We will identify some of the mechanisms involved. We may also gain insight into the therapeutic use of selective COX inhibitors in systemic inflammation. ..

..We will identify some of the mechanisms involved. We may also gain insight into the therapeutic use of selective COX inhibitors in systemic inflammation. ..

..We will identify some of the mechanisms involved. We may also gain insight into the therapeutic use of selective COX inhibitors in systemic inflammation. ..