title: Localized vs. systemic inflammation in guinea pigs: a role for prostaglandins at distinct points of the fever induction pathways?
abstract: In guinea pigs, dose-dependent febrile responses were induced by injection of a high (100 microg/kg) or a low (10 microg/kg) dose of bacterial lipopolysaccharide (LPS) into artificial subcutaneously implanted Teflon chambers. Both LPS doses further induced a pronounced formation of prostaglandin E(2) (PGE(2)) at the site of localized subcutaneous inflammation. Administration of diclofenac, a nonselective cyclooxygenase (COX) inhibitor, at different doses (5, 50, 500, or 5,000 microg/kg) attenuated or abrogated LPS-induced fever and inhibited LPS-induced local PGE(2) formation (5 or 500 microg/kg diclofenac). Even the lowest dose of diclofenac (5 microg/kg) attenuated fever in response to 10 microg/kg LPS, but only when administered directly into the subcutaneous chamber, and not into the site contralateral to the chamber. This observation indicated that a localized formation of PGE(2) at the site of inflammation mediated a portion of the febrile response, which was induced by injection of 10 microg/kg LPS into the subcutaneous chamber. Further support for this hypothesis derived from the observation that we failed to detect elevated amounts of COX-2 mRNA in the brain of guinea pigs injected subcutaneously with 10 microg/kg LPS, whereas subcutaneous injections of 100 microg/kg LPS, as well as systemic injections of LPS (intra-arterial or intraperitoneal routes), readily caused expression of the COX-2 gene in the guinea pig brain, as demonstrated by in situ hybridization. Therefore, fever in response to subcutaneous injection of 10 microg/kg LPS may, in part, have been evoked by a neural, rather than a humoral, pathway from the local site of inflammation to the brain.
authors.affiliation: Institut für Veterinär-Physiologie, Justus-Liebig-Universität Giessen, Frankfurter Strasse 100, 35392 Giessen, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Rummel
authors.forename: Stephan W
authors.initials: SW
authors.lastname: Barth
authors.forename: Thilo
authors.initials: T
authors.lastname: Voss
authors.forename: Stefan
authors.initials: S
authors.lastname: Korte
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Gerstberger
authors.forename: Thomas
authors.initials: T
authors.lastname: Hübschle
authors.forename: Joachim
authors.initials: J
authors.lastname: Roth
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D004008:Diclofenac / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005334:Fever / Q000209:etiology* / Q000503:physiopathology; D006168:Guinea Pigs; D007249:Inflammation / Q000150:complications* / Q000378:metabolism*; D007269:Injections, Intra-Arterial; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008297:Male; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D011453:Prostaglandins / Q000378:metabolism*; D019736:Prostheses and Implants; D012333:RNA, Messenger / Q000378:metabolism; D040521:Subcutaneous Tissue; D007507:Therapeutic Irrigation
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004338:Drug Combinations; D008070:Lipopolysaccharides; D011453:Prostaglandins; D012333:RNA, Messenger; D004008:Diclofenac; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases