Fever onset is linked to the appearance of lipopolysaccharide in the liver

Abstract

To assess the relative contributions of different phagocytes to the febrile response of guinea pigs to intravenous (i.v.) and intraperitoneal (i.p.) bacterial endotoxic lipopolysaccharide (LPS), we injected fluorescein isothiocyanate (FITC)-labeled LPS at doses of 37.5, 75, 150, 300 and 900 μg/kg, and measured its distribution and corresponding core temperature (T_c) changes before and at 15, 30, 60, 90, and 120 min after injection. At all times, i.v. FITC-LPS appeared as granular fluorescent patches in circulating leukocytes and hepatic macrophages; its density was proportional to dose. At all doses, the density of i.v. FITC-LPS labeling decreased from its peak 15 min after injection at a rate commensurate with its dose. Intraperitoneal FITC-LPS was also present dose- and time-dependently in peritoneal macrophages, but it appeared later and accumulated more slowly except at the highest dose. Compared with i.v. FITC-LPS, its maximal appearance was always lower in density. No labeling was found at any time in brain and kidney following any dose of i.v. or i.p. FITC-LPS injection. The initiation of T_c rises was best correlated with the presence of FITC-LPS in liver, irrespective of its route of injection. Pretreatment with gadolinium chloride 3 days before LPS injection attenuated the febrile response and reduced FITC-LPS labels in liver. These results suggest that the Kupffer cells may be central to the initiation of the febrile response of guinea pigs to i.v. and i.p. LPS.