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Mechanisms and mediators involved in the integration of fever and inflammatory responses


A local inflammatory response frequently triggers a network of inter-related events collectively known as the 'acute phase reaction' (APR). The occurrence of APR depends essentially on both the quality and intensity of the inflammatory stimulus, since these factors will determine the relative contribution of various mediators to the overall process. Cytokines, generated locally by resident cells (e.g. macrophages), play a major in the APR by stimulating the recruitment of other cells and the release of several vasoactive and hyperalgesic mediators, such as bradykinin (BK), endothelins (ETs) and Prostaglandins (PGs). Such substances may then diffuse into the circulation to act on various target organs to cause the APR, which includes fever as one of its most outstanding signs. There is considerable evidence for a participation of ETs and BK in the network of mediators involved in inflammatory and febrile responses. Inflammatory stimuli such as bacterial endotoxin (lipopolysaccha dde - LPS) can increase plasma levels of ET-1 and the expression of BK-B, receptors. Moreover, both ETs and BK can stimulate the production of inflammatory and pyrogenic cytokines, such as interleukin (IL)-lo, IL -6, IL -8, tumour necrosis factor a (TNF-a), macrophage inflammatory protein-1 (MIP-1) from different cell types. In addition, these cytokines can stimulate the release of these peptides. In view of such considerations, the present research project aims to investigate: a) the possible participation of ETs and BK in the cell migration, hyperalgesia and fever induced by LPS in rats and/or mice; b) the relationships between local peripheral inflammation and the development of systemic signs of inflammation, by assessing the correlation between LPS-induced neutrophil infiltration into the peritoneal or air-pouch cavities, production of cytokines, ETs, BK and PGE2/PGF2., (locally and centrally), activation of the HPA axis (via measurement of changes in plasma corticosterone levels) and the development of the febrile response; the possible mechanisms underlying the actions of ETs and BK in these phenomena, by observing their susceptibility to be blocked by selective inhibitors of cyclooxygenase-2 (e.g. meloxicam and others), or glucocorticoids (dexamethasone), and various inhibitory cytokines (IL-4, IL-1 0 and IL-1 3). The participation of endogenous glucocorticoids in the control of fever and cell migration induced by LPS, ETs, BK and cytokines in animals treated with inhibitory cytokines also will be investigated; d) the importance of vagal transmission in the mediation of fever triggered by peripheral inflammation, trying to establish the possible relative contributions of cell migration and/or local production of cytokines, ETs and BK towards triggering vagally-mediated fever; e) if meloxicam, dipyrone and paracetamol, well known antipyretic and antialgesic drugs, differentially affect fever and hyperalgesia induced by LPS, ETs and BK, as well as the levels of PGs in the cerebrospinal fluid during fever. The involvement of ETs and cytokines in the hyperalgesia induced by capsaicin will also be assessed; D finally, we shall examine the participation of arginine vasopressin in the antipyretic effects of these drugs. (AU)

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Scientific publications (11)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
SOARES, DENIS MELO; OTT, DANIELA; MELO, MIRIAM C. C.; SOUZA, GLORIA E. P.; ROTH, JOACHIM. Chemokine ligand (CCL)-3 promotes an integrated febrile response when injected within pre-optic area (POA) of rats and induces calcium signaling in cells of POA microcultures but not TNF-alpha or IL-6 synthesis. BRAIN BEHAVIOR AND IMMUNITY, v. 34, p. 120-129, . (08/10323-3, 97/09837-6)
SOARES, DENIS MELO; FIGUEIREDO, MARIA JOSE; MARTINS, JULIANO MANVAILER; MACHADO, RENES RESENDE; KANASHIRO, ALEXANDRE; MALVAR, DAVID DO CARMO; PESSINI, ANDREA CARLA; ROTH, JOACHIM; PETTO SOUZA, GLORIA EMILIA. CCL3/MIP-1 alpha is not involved in the LPS-induced fever and its pyrogenic activity depends on CRF. Brain Research, v. 1269, p. 54-60, . (97/09837-6)
SOARES, DENIS M.; CRISTOFOLETTI, RODRIGO; MELO, MIRIAM C. C.; LINDSEY, CHARLES J.; VEIGA-SOUZA, FABIANE H.; FABRICIO, ALINE S. C.; SOUZA, GLORIA E. P.. Cyclooxygenase-independent mechanism of ibuprofen-induced antipyresis: the role of central vasopressin V-1 receptors. FUNDAMENTAL & CLINICAL PHARMACOLOGY, v. 25, n. 6, p. 670-681, . (08/10323-3, 99/12466-5, 97/09837-6)
DE SOUZA‚ GEP; CARDOSO‚ RA; MELO‚ MCC; FABRICIO‚ ASC; SILVA‚ VMS; LORA‚ M.; DE BRUM-FERNANDES‚ AJ; RAE‚ GA; FERREIRA‚ SH; ZAMPRONIO‚ AR. A comparative study of the antipyretic effects of indomethacin and dipyrone in rats. Inflammation Research, v. 51, n. 1, p. 24-32, . (97/09837-6)
SOARES, DENIS DE MELO; SANTOS, DANIELLE R.; RUMMEL, CHRISTOPH; OTT, DANIELA; MELO, MIRIAM C. C.; ROTH, JOACHIM; CALIXTO, JOAO B.; SOUZA, GLORIA E. P.. The relevance of kalikrein-kinin system via activation of B-2 receptor in LPS-induced fever in rats. Neuropharmacology, v. 126, p. 84-96, . (08/10323-3, 97/09837-6)
WERNER‚ MFP; FRAGA‚ D.; MELO‚ MCC; SOUZA‚ GEP; ZAMPRONIO‚ AR. Importance of the vagus nerve for fever and neutrophil migration induced by intraperitoneal LPS injection. Inflammation Research, v. 52, n. 7, p. 291-296, . (97/09837-6)
ZAMPRONIO‚ AR; HOADLEY‚ ME; LUHESHI‚ G.; ROTHWELL‚ NJ; DE SOUZA‚ G.E.P.; HOPKINS‚ SJ; OTHERS. Interleukin (IL)-6 release and fever induced by a pre-formed pyrogenic factor (PFPF) derived from LPS-stimulated macrophages. EUROPEAN CYTOKINE NETWORK, v. 11, n. 4, p. 589-596, . (97/09837-6)
ZAMPRONIO‚ AR; MELO‚ MCC; HOPKINS‚ SJ; SOUZA‚ GEP. Involvement of CRH in fever induced by a distinct pre-formed pyrogenic factor (PFPF). Inflammation Research, v. 49, n. 9, p. 473-479, . (97/09837-6)
SOARES‚ D.M.; HIRATSUKA VEIGA-SOUZA‚ F.; SUELI COELHO FABRÍCIO‚ A.; JAVIER MIÑANO‚ F.; PETTO SOUZA‚ G.E.. CCL3/Macrophage inflammatory protein-1α induces fever and increases prostaglandin E2 in cerebrospinal fluid of rats: Effect of antipyretic drugs. Brain Research, v. 1109, n. 1, p. 83-92, . (97/09837-6)
MACHADO‚ R.R.; SOARES‚ D.M.; PROUDFOOT‚ A.E.; SOUZA‚ G.E.P.. CCR1 and CCR5 chemokine receptors are involved in fever induced by LPS ( E. coli) and RANTES in rats. Brain Research, v. 1161, p. 21-31, . (97/09837-6)
SOARES‚ D.M.; MACHADO‚ R.R.; YAMASHIRO‚ L.H.; MELO‚ M.C.C.; SOUZA‚ G.E.P.. Cytokine-induced neutrophil chemoattractant (CINC)-1 induces fever by a prostaglandin-dependent mechanism in rats. Brain Research, v. 1233, p. 79-88, . (97/09837-6)

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