Studies on the mechanism of fever after intravenous administration of endotoxin.

Abstract

The sequential events in fever production after intravenous administration of lipopolysaccharide (LPS) remain unsettled and controversial. Vessels of the organum vasculosum laminae terminalis (OVLT) lack the tight junctions of the blood-brain barrier and allow substances of high molecular weight to enter the interstitium but not the neuropil. The present studies investigate the hypothesis that the OVLT is needed for fever production after intravenous administration of LPS in the rat. Electrolytic lesions were produced in the OVLT of rats. After recovery, left carotid and right atrial catheters were inserted, and 24 hours later calorimetry was performed. Blood was drawn for baseline assay for cytokines and LPS after which LPS was given intravenously, with studies continued for 5 hours, and additional blood samples were drawn at 90 and 300 minutes. The maximal increment in rectal temperature for the sham lesion LPS group (1.25 +/- 0.44 degrees C) was significantly greater than for the sham-saline (-0.05 +/- 0.46 degrees C) and the lesion-LPS groups (0.35 +/- 0.45 degrees C) for minutes 120 to 300. Ninety minutes after LPS administration, serum levels of interleukin (IL)-6, tumor necrosis factor-alpha, and LPS were significantly elevated (p < 0.0001) above baseline for the sham-LPS and lesion-LPS groups. IL-1beta serum levels remained below detection levels. Large lesions of the OVLT prevent and/or attenuate fever due to LPS even though tumor necrosis factor-alpha and IL-6 are greatly increased in serum. IL-1beta does not seem to be an endogenous humoral mediator in this model.