title: Cyclooxygenase-1 or -2--which one mediates lipopolysaccharide-induced hypothermia?
abstract: Systemic inflammation is associated with either fever or hypothermia. Fever, a response to mild systemic inflammation, is mediated by cyclooxygenase (COX)-2 and not by COX-1. However, it is still disputed whether COX-2, COX-1, neither, or both mediate(s) responses to severe systemic inflammation, and, in particular, the hypothermic response. We compared the effects of SC-236 (COX-2 inhibitor) and SC-560 (COX-1 inhibitor) on the deep body temperature (T(b)) of rats injected with a lower (10 microg/kg i.v.) or higher (1,000 microg/kg i.v.) dose of LPS at different ambient temperatures (T(a)s). At a neutral T(a) (30 degrees C), the rats responded to LPS with a polyphasic fever (lower dose) or a brief hypothermia followed by fever (higher dose). SC-236 (2.5 mg/kg i.v.) blocked the fever induced by either LPS dose, whereas SC-560 (5 mg/kg i.v.) altered neither the febrile response to the lower LPS dose nor the fever component of the response to the higher dose. However, SC-560 blocked the initial hypothermia caused by the higher LPS dose. At a subneutral T(a) (22 degrees C), the rats responded to LPS with early (70-90 min, nadir) dose-dependent hypothermia. The hypothermic response to either dose was enhanced by SC-236 but blocked by SC-560. The hypothermic response to the higher LPS dose was associated with a fall in arterial blood pressure. This hypotensive response was attenuated by either SC-236 or SC-560. At the onset of LPS-induced hypothermia and hypotension, the functional activity of the COX-1 pathway (COX-1-mediated PGE(2) synthesis ex vivo) increased in the spleen but not liver, lung, kidney, or brain. 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.
authors.affiliation: Systemic Inflammation Laboratory, Trauma Research, St. Joseph's Hospital and Medical Center, 350 W. Thomas Road, Phoenix, AZ 85013, USA.
authors.forename: Alexandre A
authors.initials: AA
authors.lastname: Steiner
authors.forename: John C
authors.initials: JC
authors.lastname: Hunter
authors.forename: Sean M
authors.initials: SM
authors.lastname: Phipps
authors.forename: Tatiane B
authors.initials: TB
authors.lastname: Nucci
authors.forename: Daniela L
authors.initials: DL
authors.lastname: Oliveira
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Roberts
authors.forename: Adrienne C
authors.initials: AC
authors.lastname: Scheck
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Simmons
authors.forename: Andrej A
authors.initials: AA
authors.lastname: Romanovsky
mesh_terms: D000825:Animal Structures / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D001833:Body Temperature Regulation / Q000187:drug effects / Q000502:physiology; D051545:Cyclooxygenase 1 / Q000502:physiology*; D051546:Cyclooxygenase 2 / Q000502:physiology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D007035:Hypothermia / Q000139:chemically induced* / Q000378:metabolism* / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013696:Temperature; D000096926:Benzenesulfonamides
chemical_list: D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D016861:Cyclooxygenase Inhibitors; D015232:Dinoprostone; D008070:Lipopolysaccharides; D011720:Pyrazoles; D013449:Sulfonamides; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C115461:SC 560; C489691:Ptgs2 protein, rat