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The source, as well as the site of action of PGE2, as an endogenous pyrogen, is widely accepted as being central, but PGE2 in the circulation, possibly from leukocytes, may also contribute to the development of fever. However, bacterial infections are important causes of high fever in patients receiving myelosuppressive chemotherapy, and such fevers persist despite the use of COX inhibitors. In the study reported here, the febrile response to bacterial LPS was measured in rats made leukopenic by cyclophosphamide. A striking increase in LPS fever occurred in these granulocytopenic rats when compared with febrile responses in normal animals. Unlike LPS fever in normal rats, fever in granulocytopenic rats was neither accompanied by an increase in blood PGE2 nor inhibited by ibuprofen. Both leukopenic and normal rats showed LPS-induced COX-2-immunoreactivity in cells associated with brain blood vessels. Furthermore, LPS induced an increase of PGE2 in cerebrospinal fluid. Induction of COX-2-expression and PGE2 production was inhibited by ibuprofen in normal but not in leukopenic rats. Although the results presented are, in part, confirmatory, they add new information to this field and open a number of important questions as yet unresolved. Overall, the present results indicate that, in contrast to immunocompetent rats, leukocytes and\/or other mechanisms other than PGE2 are implicated in the mechanisms restricting and reducing the enhanced febrile response to endotoxin in immunosuppressed hosts.<\/jats:p>","DOI":"10.1189\/jlb.0106064","type":"journal-article","created":{"date-parts":[[2006,9,22]],"date-time":"2006-09-22T20:38:26Z","timestamp":1158957506000},"page":"1375-1387","source":"Crossref","is-referenced-by-count":15,"title":["Endotoxin fever in granulocytopenic rats: evidence that brain cyclooxygenase-2 is more important than circulating prostaglandin E2"],"prefix":"10.1093","volume":"80","author":[{"given":"Eva","family":"Tavares","sequence":"first","affiliation":[{"name":"Research Unit, Laboratory for Clinical and Experimental Pharmacology, University Hospital of Valme , Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco J","family":"Mi\u00f1ano","sequence":"additional","affiliation":[{"name":"Research Unit, Laboratory for Clinical and Experimental Pharmacology, University Hospital of Valme , Seville, Spain"},{"name":"Department of Pharmacology, Paediatrics and Radiology, Faculty of Medicine, University of Seville , Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosario","family":"Maldonado","sequence":"additional","affiliation":[{"name":"Research Unit, Laboratory for Clinical and Experimental Pharmacology, University Hospital of Valme , Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J","family":"Dascombe","sequence":"additional","affiliation":[{"name":"Faculty of Life Sciences, University of Manchester , Manchester, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2006,9,22]]},"reference":[{"key":"2023033007484119100_jlb1375-cit-B1","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1056\/NEJM200201243460402","article-title":"Persistent fever in patients with neutropenia","volume":"346","author":"Corey","year":"2002","journal-title":"N. 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