Sepsis - the role of inflammatory response: cell signaling; immune system action in sepsis; LPS tolerance and therapeutic

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. SIRS causes tissue and organ damage even in organs not involved in the infectious process, vasodilatation, myocardic depression, and tissular hupoperfusion, disseminated intravascular coagulation state known as severe sepsis and septic shock. The cytokines induces the release of many others inflammatory mediators, as for instance reactive oxygen species, and nitric oxide. Toll-like (TLR) inhibitors, ant inflammatory 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 an 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. Taken together these information we think that the important questions to be studied in sepsis are the following: a- the role of the different immune cells in the regulation of the inflammatory response; b- the mechanism of auto-regulation of gene expression in the cells of immune system in the inflammatory period; c- therapeutic strategies to reduce cell and tissue damage. 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)