title: Platelet-activating factor is a potent pyrogen and cryogen, but it does not mediate lipopolysaccharide fever or hypothermia.
abstract: We examined whether platelet-activating factor (PAF) and its receptor mediate lipopolysaccharide (LPS)-induced fever and hypothermia in rats. Two highly potent, structurally distinct antagonists of the PAF receptor, CV6209 and WEB2086, were used. At a neutral ambient temperature (Ta) of 30ºC, administration of LPS at a low (10 μg/kg, i.v.) or high (1,000 μg/kg, i.v.) dose resulted in fever. The response to the high dose was turned into hypothermia at a subneutral Ta of 22ºC. Neither LPS-induced fever nor hypothermia was affected by pretreatment with CV6209 (5 mg/kg, i.v.) or WEB2086 (5 mg/kg, i.v.). However, both PAF antagonists were efficacious in blocking the thermoregulatory response caused by PAF (334 pmol/kg/min, 1 h, i.v.), regardless of whether the response was a fever (at 30ºC) or hypothermia (at 22ºC). Additional experiments showed that the thermoregulatory responses to LPS and PAF are also distinct in terms of their mediation by prostaglandins. Neither PAF fever nor PAF hypothermia was affected by pretreatment with the cyclooxygenase-2 inhibitor SC236 (5 mg/kg, i.p.), which is known to abrogate LPS fever. The responses to PAF were also unaffected by pretreatment with the cyclooxygenase-1 inhibitor SC560 (5 mg/kg, i.p.), which is known to attenuate LPS hypothermia. In conclusion, PAF infusion at a picomolar dose causes fever at thermoneutrality but hypothermia in a subthermoneutral environment, both responses being dependent on the PAF receptor and independent of prostaglandins. However, the PAF receptor does not mediate LPS-induced fever or hypothermia, thus challenging the dogma that PAF is an upstream mediator of responses to LPS.
authors.affiliation: Feverlab; Trauma Research; St. Joseph's Hospital and Medical Center; Phoenix, AZ USA; Department of Immunology; Institute of Biomedical Sciences; University of São Paulo; São Paulo, SP Brazil.
authors.forename: Alexandre A
authors.initials: AA
authors.lastname: Steiner
authors.affiliation: Feverlab; Trauma Research; St. Joseph's Hospital and Medical Center ; Phoenix, AZ USA.
authors.forename: Andrej A
authors.initials: AA
authors.lastname: Romanovsky
keywords: Body temperature; LPS; PAF; cyclooxygenase; endotoxemia; febrile response; prostaglandins; sepsis; systemic inflammation; thermoregulation