Febrile response induced by cecal ligation and puncture (CLP) in rats: involvement of prostaglandin E2 and cytokines.
The purpose of the present study was to better understand the events involved in the febrile response induced by cecal ligation and puncture (CLP), a complex infectious process. To this end, we conducted in vivo experiments in rats examining (1) fever development, (2) bacterial number in the infection focus and in blood, (3) peripheral and hypothalamic synthesis of cytokines, (4) hypothalamic and cerebrospinal fluid (CSF) synthesis of prostaglandin E(2) (PGE(2)), (5) the effect of anti-IL-6 antibody on fever, and (6) the effect of celecoxib on fever and hypothalamic synthesis of PGE(2) after CLP induction. We found that CLP promotes fever and animal death depending on the number of punctures. The peak of CLP-induced fever overlapped with the maximal increase in the number of bacteria in the infectious focus and blood, which occurred at 6 and 12 h. The peak of the febrile response also coincided with increased amounts of interleukin (IL)-1β, IL-6 and IL-10 in the peritoneal exudate and serum; IL-6 in the hypothalamus and PGE(2) in the CSF and predominantly in the hypothalamus. Moreover, intracerebroventricularly injected anti-IL-6 antibody reduced the febrile response while celecoxib reduced the fever and PGE(2) amount in the hypothalamus induced by CLP. Tumor necrosis factor (TNF)-α peaked at 3 h at all sites studied. Conversely, IL-10 concentration decreased in the hypothalamus. These findings show that the peak of CLP-induced fever is accompanied by an increase of bacteria in peritoneal fluid (local infection) and blood; local synthesis of pyrogenic (IL-1β, IL-6) and antipyretic (IL-10) cytokines and central production of IL-6 and PGE(2), suggesting that these last are the central mediators of this response.
Laboratory of Pharmacology, Department of Physic and Chemistry, Faculty of Pharmaceutical Sciences, University of São Paulo, Av. do Café, s/n, Campus Universitário, 14049-903, Ribeirão Preto, São Paulo, Brazil. zzfigueiredo@usp.br
Maria José
MJ
Figueiredo
Denis Melo
DM
Soares
Denis de Melo
Dde M
Soares
Juliano Manvailer
JM
Martins
Renes de Resende
Rde R
Machado
Carlos Arterio
CA
Sorgi
Lucia Helena
LH
Faccioli
Miriam Cristina Contin de
MC
Melo
Miriam Cristina Contin
MC
de Melo
David do Carmo
Ddo C
Malvar
Glória E P
GE
Souza
D000818:Animals; D001419:Bacteria / Q000302:isolation & purification; D001424:Bacterial Infections / Q000401:mortality / Q000503:physiopathology*; D058491:Bacterial Load; D001769:Blood / Q000382:microbiology; D002432:Cecum / Q000293:injuries*; D016207:Cytokines / Q000097:blood / Q000378:metabolism*; D015232:Dinoprostone / Q000134:cerebrospinal fluid / Q000378:metabolism*; D004195:Disease Models, Animal; D005334:Fever / Q000139:chemically induced*; D006801:Humans; D008026:Ligation; D008297:Male; D010537:Peritoneum / Q000382:microbiology; D010538:Peritonitis / Q000401:mortality / Q000503:physiopathology*; D011677:Punctures; D051381:Rats; D017208:Rats, Wistar; D016019:Survival Analysis
D016207:Cytokines; D015232:Dinoprostone