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Sepsis and LPS tolerance - LPS tolerance role on oxidative stress and mithocondrial function, proteic nytrosilation and DNA damage

Abstract

Sepsis, SIRS and septic shock are responsible for 30-45% of death in ICU. The treatment is based only in hemodynamic support and source control. The cytokines induces the release of many others inflammatory mediators, as for instance reactive oxygen species, and nitric oxide. Toll-like (TLR) inhibitors, antinflammatory cytokines and changes in TLR signaling are the mechanism that control the extension and duration of the induced inflammation. These events are directed related to tolerance phenomenon that cause a state called hyporresponsivity to LPS. However, the regulation gene expression through TLR involves hundred of genes with several functions regulated in many different ways after TLR activation. This adaptation of immune innate response is related to epigenetic mechanism, it means the specific regulation is not regulated by the specific signal but by gene-specific through chromatin modifications. The role of nitric oxide in the tolerance has been approached in several papers that shown a dependence between tolerance effects and NO. Zingarelli and col suggested that the sustained activity of nitric oxide synthase may be a beneficial mechanism for tolerance induction to LPS. Other study showed that the beneficial effects produced by LPS tolerance were blocked with nitric oxide synthase inhibition. The antioxidant capacity in tolerance can be a cellular protection mechanism and resistance to metabolic aggression during sepsis, on the other hand tolerance can induce adaptations of mitochondrial activity. Oxidative stress of sepsis can lead to DNA damage, we will investigate if sepsis commits the size of telomere which also have correlations with the metabolic state. Sepsis and tolerance induce production of NO and H 2 S that can induce epigenetic alterations and regulation in inflammatory response. The main objectives (called sub projects) of this thematic project cover these subjects cited, in order to get deepest in the understanding of cell damage and protection mechanism and at the same time trying to find reliable and useful therapeutic for this disease. (AU)

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Scientific publications
(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)
PIMENTEL, ROSANGELA NASCIMENTO; PETRONI, RICARDO COSTA; BARBEIRO, HERMES VIEIRA; BARBEIRO, DENISE FREDIANI; ANDRADE, MARIANA MACEDO; ARIGA, SUELY KUMINI; SORIANO, FRANCISCO GARCIA. Hypertonic solution-induced preconditioning reduces inflammation and mortality rate. Journal of Inflammation-London, v. 16, JUL 3 2019. Web of Science Citations: 0.
LORIGADOS, CLARA B.; ARIGA, SUELY K. K.; DE LIMA, THAIS M.; BARBEIRO, DENISE F.; KRIEGER, JOSE E.; SORIANO, FRANCISCO G. BONE MARROW CELLS TRANSPLANT IN SEPTIC MICE MODULATES SYSTEMIC INFLAMMATORY RESPONSE VIA CELL-CELL CONTACT. Shock, v. 51, n. 3, p. 381-388, MAR 2019. Web of Science Citations: 2.

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