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Development of hypothermia in systemic inflammation: the brain hypoxia hypothesis

Grant number: 20/09399-7
Support Opportunities:Scholarships in Brazil - Post-Doctorate
Effective date (Start): September 01, 2020
Effective date (End): August 31, 2023
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal Investigator:Alexandre Alarcon Steiner
Grantee:Eduardo Hermogenes Moretti
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:18/03418-0 - Hypothermia in Sepsis: causes and consequences, AP.TEM

Abstract

A change in body temperature is a hallmark of systemic inflammation. Although fever (rise in body temperature) is the most prevalent and studied response, hypothermia (decrease in body temperature) occurs in the most severe cases. Recent studies indicate that hypothermia does not result from thermoregulatory failure. On the contrary, it appears to be a regulated response with biological value when the costs of fever exceed its benefits. However, the mechanisms that govern the shift from fever to hypothermia remain unclear. Here, we will test the hypothesis that a slight drop in regional blood flow and, consequently, brain oxygenation is the trigger for brain-driven reductions in metabolic rate and body temperature. This hypothesis will be tested in rats pre-implanted with sensors for PO2, blood flow and brown adipose tissue temperature, in addition to electrodes for recording sympathetic activity. Systemic inflammation will be induced by moderate and high doses of LPS at an ambient temperature that is suitable for the development of hypothermia. If the hypothesis is correct, the hypothermic response is expected to be preceded by a drop in brain perfusion and oxygenation. Likewise, the drop in brain oxygenation should precede the inhibition of the sympathetic nerves that innervate the brown adipose tissue. Granger's causality tests will be used to statistically evaluate the temporal relationship between these variables. In subsequent experiments, we will assess whether the manipulation of brain oxygenation can impact the development of LPS-induced hypothermia. Brain oxygenation will be manipulated using strategies that increase global oxygenation (erythropoietin, hypoxia acclimation and perfluoroalkanes), in combination with partial occlusion of the carotid arteries.

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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)
CASTRO, ERIQUE; VIEIRA, THAYNA S.; OLIVEIRA, TIAGO E.; ORTIZ-SILVA, MILENE; ANDRADE, MAYNARA L.; TOMAZELLI, CAROLINE A.; PEIXOTO, ALBERT S.; SOBRINHO, CLEYTON R.; MORENO, MAYARA F.; GILIO, GUSTAVO R.; et al. Adipocyte-specific mTORC2 deficiency impairs BAT and iWAT thermogenic capacity without affecting glucose uptake and energy expenditure in cold-acclimated mice. AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, v. 321, n. 5, p. E592-E605, . (16/23169-9, 19/25943-1, 17/23040-9, 15/13508-8, 17/17582-3, 18/03418-0, 17/17403-1, 17/12260-8, 19/01763-4, 19/17660-0, 15/19530-5, 20/09399-7, 19/04271-5, 12/25317-4)
ALBERCA, RICARDO W.; GOMES, ELIANE; MORETTI, EDUARDO H.; RUSSO, MOMTCHILO; STEINER, ALEXANDRE A.. Naturally occurring hypothermia promotes survival in severe anaphylaxis. Immunology Letters, v. 237, p. 27-32, . (20/09399-7, 18/08699-7, 13/24694-1, 18/03418-0, 16/16602-8)
FONSECA, MONIQUE T.; MORETTI, EDUARDO H.; MARQUES, LUCAS M. M.; MACHADO, BIANCA F.; BRITO, CAMILA F.; GUEDES, JADY T.; KOMEGAE, EVILIN N.; VIEIRA, THAYNA S.; FESTUCCIA, WILLIAM T.; LOPES, NORBERTO P.; et al. A leukotriene-dependent spleen-liver axis drives TNF production in systemic inflammation. Science Signaling, v. 14, n. 679, . (16/23540-9, 18/03418-0, 17/17403-1, 17/13350-0, 15/19530-5, 16/04921-1, 20/09399-7, 14/50265-3, 14/03719-9, 18/00849-0)

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