title: Lipopolysaccharide-induced hypothermia and hypotension are associated with inflammatory signaling that is triggered outside the brain.
abstract: Little is known about the neuroimmune mechanisms responsible for the switch from fever to hypothermia observed in severe forms of systemic inflammation. We evaluated whether bacterial lipopolysaccharide (LPS) acting directly on the brain could promote a fever-hypothermia switch as well as the hypotension that is often associated with hypothermia in models of systemic inflammation. At an ambient temperature of 22°C, freely moving rats received intracerebroventricular (i.c.v.) injections of LPS at doses ranging from 0.5 to 25μg. Despite the use of such high doses, the prevailing thermal response was fever. To investigate if a hypothermic response could be hidden within the prevailing febrile response, rats were pretreated with a cyclooxygenase-2 inhibitor (SC-236, 3.5mg/kg i.v.) known to block fever, but this strategy also failed to reveal any consistent hypothermic response following i.c.v. LPS. At the doses tested, i.c.v. LPS was similarly ineffective at inducing hypotension. Additional doses of LPS did not need to be tested because the 25-μg dose was already sufficient to induce both hypothermia and hypotension when administered peripherally (intra-arterially). An empirical 3D model of the interplay among body temperature, arterial pressure and heart rate following intra-arterial LPS reinforced the strong association of hypothermia with hypotension and, at the same time, exposed a bell-shaped relationship between heart rate and body temperature. In summary, the present study demonstrates that hypothermia and hypotension are triggered exclusively by LPS acting outside the brain and provides an integrated model of the thermal and cardiovascular responses to peripheral LPS.
authors.affiliation: Albany College of Pharmacy and Health Sciences, Albany, NY, USA.
authors.forename: Hiba
authors.initials: H
authors.lastname: Al-Saffar
authors.forename: Kevin
authors.initials: K
authors.lastname: Lewis
authors.forename: Elaine
authors.initials: E
authors.lastname: Liu
authors.forename: Alexandra
authors.initials: A
authors.lastname: Schober
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Corrigan
authors.forename: Keita
authors.initials: K
authors.lastname: Shibata
authors.forename: Alexandre A
authors.initials: AA
authors.lastname: Steiner
mesh_terms: D000818:Animals; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D005334:Fever / Q000139:chemically induced; D007022:Hypotension / Q000139:chemically induced*; D007035:Hypothermia / Q000139:chemically induced*; D007249:Inflammation / Q000139:chemically induced*; D007276:Injections, Intraventricular; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D008070:Lipopolysaccharides; D011720:Pyrazoles; D013449:Sulfonamides; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides