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Vascular inflammation: pathophysiological mechanisms of induction and pathways of cellular activation


The activation of the leukocytes and other inflammatory cells, and their consequent adhesion to the endothelium, play a key role in the initiation and propagation of vascular inflammation and may result in endothelial activation, vascular damage and even obstruction of microcirculatory blood flow with subsequent tissue damage. These mechanisms play a central role in the pathophysiology of several diseases that are characterized by acute or chronic vascular inflammation, such as atherosclerosis, sickle cell anemia, stroke and transfusion-related acute lung injury (TRALI). Therefore, understanding the mechanisms that result in the activation and adhesion of blood cells to the vascular wall should assist in developing new strategies for the prevention and treatment of chronic inflammatory diseases. The current project aims to further unravel the signaling pathway by which TNF-± causes the adhesion of neutrophils, as well as determine how the statin, simvastatin, inhibits this pathway. Furthermore, we plan to investigate the effects of hemolysis and the presence of plasma free hemoglobin / heme on the activity of inflammatory cells, observing the formation and activation of inflamassomes, and the adhesive properties of leukocytes and platelets in vivo and in vitro. These objectives will be studied using techniques developed in our laboratory during the last 3-4 years; the Venaflux platform will be used for the study of cell adhesion in vitro and intravital microscopy will be employed to observe cell recruitment in the microcirculation of mice. Understanding the mechanisms involved in the induction of activation and adhesion of inflammatory cells and the signaling pathways by which these cells become adhesive and activated, remains one of the challenges in the search for therapeutic targets for the development of approaches for the prevention and reversal of vascular inflammation. (AU)

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Scientific publications (5)
(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)
SILVEIRA, ANGELICA A. A.; MAHON, OLWYN R.; CUNNINGHAM, CLARE C.; CORR, EMMA M.; MENDONCA, RAFAELA; SAAD, SARA T. O.; COSTA, FERNANDO F.; DUNNE, AISLING; CONRAN, NICOLA. S100A8 acts as an autocrine priming signal for heme-induced human M phi pro-inflammatory responses in hemolytic inflammation. Journal of Leukocyte Biology, v. 106, n. 1, p. 35-43, . (12/22048-2, 14/19173-5, 14/23170-1)
CONRAN, NICOLA; BELCHER, JOHN D.. Inflammation in sickle cell disease. CLINICAL HEMORHEOLOGY AND MICROCIRCULATION, v. 68, n. 2-3, p. 263-299, . (14/19173-5)
GOTARDO, ERICA M. F.; BRITO, PAMELA L.; GUSHIKEN, LUCAS F. S.; CHWEIH, HANAN; LEONARDO, FLAVIA C.; COSTA, FERNANDO F.; CONRAN, NICOLA. Molecular and cellular effects of in vivo chronic intravascular hemolysis and anti-inflammatory therapeutic approaches. VASCULAR PHARMACOLOGY, v. 150, p. 12-pg., . (16/10542-3, 14/19173-5)
ANTONIELLIS SILVEIRA, ANGELICA APARECIDA; DOMINICAL, VENINA MARCELA; ALMEIDA, CAMILA BONONI; CHWEIH, HANAN; FERREIRA, JR., WILSON ALVES; VICENTE, CRISTINA PONTES; MARANHAO COSTA, FABIO TRINDADE; WERNECK, CLAUDIO C.; COSTA, FERNANDO FERREIRA; CONRAN, NICOLA. TNF induces neutrophil adhesion via formin-dependent cytoskeletal reorganization and activation of beta-integrin function. Journal of Leukocyte Biology, v. 103, n. 1, p. 87-98, . (12/22048-2, 10/19916-7, 14/19173-5)
ANTONIELLIS SILVEIRA, ANGELICA APARECIDA; DOMINICAL, VENINA MARCELA; VITAL, DAIANA MORELLI; FERREIRA, JR., WILSON ALVES; MARANHAO COSTA, FABIO TRINDADE; WERNECK, CLAUDIO C.; COSTA, FERNANDO FERREIRA; CONRAN, NICOLA. Attenuation of TNF-induced neutrophil adhesion by simvastatin is associated with the inhibition of Rho-GTPase activity, p50 activity and morphological changes. International Immunopharmacology, v. 58, p. 160-165, . (12/22048-2, 10/19916-7, 14/19173-5)

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