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This Article Full Text Full Text (PDF) All Versions of this Article: 297/2/R485    most recent 91026.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Steiner, A. A. Articles by Romanovsky, A. A. PubMed PubMed Citation Articles by Steiner, A. A. Articles by Romanovsky, A. A.

ARTICLES

Cyclooxygenase-1 or -2—which one mediates lipopolysaccharide-induced hypothermia?

¹Systemic Inflammation Laboratory, Trauma Research, St. Joseph's Hospital and Medical Center, Phoenix, Arizona; ²Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Albany, New York; ³Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah; and ⁴Neurology and Neurosurgery Research, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona

Submitted 16 December 2008 ; accepted in final form 5 June 2009

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 µg/kg iv) or higher (1,000 µg/kg iv) dose of LPS at different ambient temperatures (T_as). At a neutral T_a (30°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 iv) blocked the fever induced by either LPS dose, whereas SC-560 (5 mg/kg iv) 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°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 PGE₂ 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.

body temperature; thermoregulation; fever; inflammation