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Role of liver X Receptor-LXRs in the modulation of local and systemic response during sepsis

Grant number: 09/07651-1
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): September 01, 2009
Effective date (End): November 30, 2012
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal researcher:Fernando de Queiroz Cunha
Grantee:Fabrício Oliveira Souto
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:07/51247-5 - Mediators involved in the genesis of pain and the migration of leukocytes and in sepsis, AP.TEM


Sepsis is a systemic inflammatory response to infection that results from the inability of the immune system to control a local infection. In this context, data from our laboratory demonstrated that during severe sepsis occurs a failure of neutrophils migration to the infected site, resulting in bacterial dissemination, failure of multiple organs and death. Although the mechanisms involved in the failure of neutrophils migration are not fully elucidated, our studies show that high levels of cytokines in the circulation, with subsequent release of nitric oxide (NO), part of this process. Parallel to this, recent data from the literature suggest the involvement of nuclear receptors in the modulation of immune response during inflammatory processes, such as dermatitis, arthritis, endotoxemia. Among the nuclear receptors, the LXRs (liver X receptors, LXR-alpha and LXR-beta) are related to the negative regulation of genes associated with inflammatory response, as the synthesis of NO, cytokines and transcription factor NF-kappaB. In fact, data of literature show that activation of LXRs by synthetic agonists, during endotoxemia, was able to restrict the growth of local and systemic proinflammatory mediators, besides providing a protection of hepatic injury. Furthermore, the role of these receptors in sepsis is still poorly explored. Thus, the central hypothesis of this study is that activation of LXRs may control the exacerbation of the systemic inflammatory response, leading the neutrophils migration to the infected site and thus increase the survival of animals subjected to severe sepsis. The objective of this project will determine the role of LXRs in local and systemic response during experimental sepsis. Moreover, it will be assessed the role of LXRs in the chemotactic activity of neutrophils from septic patients. (AU)

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(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)
SOUTO, FABRICIO O.; CASTANHEIRA, FERNANDA V. S.; TREVELIN, SILVIA C.; LIMA, BRAULIO H. F.; MARTELOSSI CEBINELLI, GUILHERME CESAR; TURATO, WALTER M.; AUXILIADORA-MARTINS, MARIA; BASILE-FILHO, ANIBAL; ALVES-FILHO, JOSE CARLOS; CUNHA, FERNANDO Q. Liver X Receptor Activation Impairs Neutrophil Functions and Aggravates Sepsis. Journal of Infectious Diseases, v. 221, n. 9, p. 1542-1553, MAY 1 2020. Web of Science Citations: 0.

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