Oxidative stress and pyrogenic fever pathogenesis

The causative/regulatory connections between changes in tissue redox state and fever induction were investigated herein. Wherefore, LPS, the primary element of bacterial cell wall, in addition to inducing pro-inflammatory cytokines, activated macrophages and other leukocytes to secrete hydroxyl radical (OH), nitric oxide metabolites (NOx−), superoxide (O2) and other reactive oxygen/nitrogen species. Furthermore, inflammation response-associated hypoxia stimulated glutamate release, which caused excitotoxicity of cells by increasing extracellular Ca2+. Cytokines and glutamate in turn also triggered the release of large amounts of NOx−, OH, O2, and other radicals. Those reactive nitrogen species in turn caused cellular injury via the peroxidation of membrane lipids and oxidative damage of proteins and DNA. Glutamate, NOx−, OH and antioxidants participated in the pathogenesis and regulation of LPS- or cytokines-induced fever. In particular, to highlight the role of glutamate, prostaglandin E2, NOx− and OH generated in the hypothalamus during pyrogenic fever was attempted hereby. To find the link among the signaling with the glutamate, NOx− and OH/prostaglandin E2 in the hypothalamus during pyrogenic fever will be challenging and could now clinically suppress pyrogenic fever.

Research highlights
► LPS released pro-inflammatory cytokines, OH, NOx–, and PGE2 in the hypothalamus.
► An oxidative stress-related PGE2 pathway in the hypothalamus mediated LPS-fever.
► NMDA receptor antagonists, free radicals scavengers, and COX-2 inhibitors may caused antipyresis.