Hypothermia in Sepsis: causes and consequences

• Grant number: 18/03418-0
• Support Opportunities: Research Projects - Thematic Grants
• Start date: October 01, 2018
• End date: September 30, 2025
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Alexandre Alarcon Steiner
• Grantee: Alexandre Alarcon Steiner
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: André Fujita ; Chao Yun Irene Yan ; Flávio Vieira Loures ; Luiz Antonio Baccalá ; Marcelo Nicolas Muscara ; Niels Olsen Saraiva Câmara ; Norberto Peporine Lopes ; Thiago dos Santos Moreira ; Vera Lucia Garcia Calich ; William Tadeu Lara Festuccia ; Wilson Araújo da Silva Junior
• Associated research grant(s): 19/01944-9 - Multi-User Equipment approved in grant 2018/03418-0: Oxylite System, AP.EMU
• Associated scholarship(s): 23/15804-0 - Immunomodulatory role of the spleen-liver axis: the influence of post-splenectomy time and LPS dose., BP.IC; 23/07357-3 - Sympathetic immunomodulation of the microbicidal action of macrophages and neutrophils, BP.MS; 22/13206-5 - Relationship between viral infections and subsequent predisposition to bacterial infections: role of splanchnic nerves, BP.IC; + associated scholarships 22/13467-3 - Relationship between COX-1 and proinflammatory cytokines in systemic inflammation, BP.IC; 22/07213-9 - Methods to evaluate the relationship among brain oxygenation, cardiac output and thermogenesis., BP.TT; 20/09399-7 - Development of hypothermia in systemic inflammation: the brain hypoxia hypothesis, BP.PD; 19/26164-6 - Thermal regulation of acquired immune response against Paracoccidioides brasiliensis, BP.MS; 20/00631-4 - Development of hypothermia in systemic inflammation: the signaling hypothesis cryogenic, BP.DD; 19/16851-6 - Thermal modulation of antigen presenting cells interaction with T lymphocytes, BP.TT; 19/11818-0 - Thermal modulation of lymphocyte function in P. brasiliensis infection, BP.TT; 19/12032-0 - Thermal modulation of the dendritic cell profile in P. brasiliensis infection, BP.IC; 17/13350-0 - The temperature negatively regulates the microbicidal activity of macrophages: why do they kill more in hypothermia?, BP.PD; 18/21521-2 - Thermal modulation of lung function in P. brasiliensis infection, BP.IC - associated scholarships

Abstract

Sepsis (systemic inflammation in the setting of infection) is a leading cause of mortality in Brazil and worldwide. A switch in thermal state from fever to hypothermia occurs in the most severe cases of Sepsis, which has led to the perception that hypothermia reflects organ failure and is detrimental. We argue that this perception may be premature and incorrect, since there is evidence indicating that such hypothermia is a regulated phenomenon that aids the infected host better than fever in the most severe cases of Sepsis. However, in spite of this evidence, the mechanisms involved remain unknown. Here, we propose to study the causes and consequences of hypothermia in experimental models of systemic inflammation and Sepsis. In specific aim I, we will test the hypothesis that, during systemic inflammation, a discrete fall in regional blood flow to the brain triggers reflex inhibition of the sympathetic drive to brown fat thermogenesis, which consequently promotes the switch from fever to hypothermia. In specific aim II, we will employ phenotype-specific gene deletions to unravel the mechanisms by which the constitutive isoform of cyclooxygenase (COX-1) in the spleen and other peripheral tissues contributes to the development of hypothermia in acute systemic inflammation. In specific aim III, we will conduct experiments to elucidate the mechanisms underlying the opposite effects that a switch from fever-like to hypothermia-like temperatures exerts on the microbicidal actions of neutrophils versus macrophages, thus reprogramming the innate immune response. In specific aim IV, we will investigate whether and how hypothermia can be a burden for the development of acquired, lymphocyte-dependent immune responses, despite its benefits during the acute phase of systemic inflammation. (AU)

Scientific publications

(12)

(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)

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, APR 20 2021. (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)

CARVALHO, VANESSA F. M.; SALATA, GIOVANNA C.; DE MATOS, JENYFFER K. R.; COSTA-FERNANDEZ, SANDRA; CHORILLI, MARLUS; STEINER, ALEXANDRE A.; DE ARAUJO, GABRIEL L. B.; SILVEIRA, EDILBERTO R.; COSTA-LOTUFO, V, LETICIA; LOPES, LUCIANA B.. Optimization of composition and obtainment parameters of biocompatible nanoemulsions intended for intraductal administration of piplartine (piperlongumine) and mammary tissue targeting. International Journal of Pharmaceutics, v. 567, AUG 15 2019. (17/23213-0, 13/16617-7, 17/04174-4, 18/03418-0, 18/18813-1, 18/13877-1)

DARTORA, VANESSA F. C.; SALATA, GIOVANNA C.; PASSOS, JULIA S.; BRANCO, PAOLA C.; SILVEIRA, EDILBERTO; STEINER, ALEXANDRE A.; V. COSTA-LOTUFO, LETICIA; LOPES, LUCIANA B.. Hyaluronic acid nanoemulsions improve piplartine cytotoxicity in 2D and 3D breast cancer models and reduce tumor development after intraductal administration. International Journal of Biological Macromolecules, v. 219, p. 12-pg., 2022-08-05. (14/50928-2, 18/17679-0, 18/03418-0, 20/01208-8, 17/04174-4, 15/17177-6)

STEINER, ALEXANDRE A.; ROMANOVSKY, ANDREJ A.. Energy Trade-offs in Host Defense: Immunology Meets Physiology. TRENDS IN ENDOCRINOLOGY AND METABOLISM, v. 30, n. 12, p. 4-pg., 2019-12-01. (18/03418-0, 12/03831-8, 16/04921-1)

PEIXOTO, ALBERT S.; MORENO, MAYARA F.; CASTRO, ERIQUE; PERANDINI, LUIZ A.; BELCHIOR, THIAGO; OLIVEIRA, TIAGO E.; VIEIRA, THAYNA S.; GILIO, GUSTAVO R.; TOMAZELLI, CAROLINE A.; LEONARDI, BIANCA F.; et al. Hepatocellular carcinoma induced by hepatocyte Pten deletion reduces BAT UCP-1 and thermogenic capacity in mice, despite increasing serum FGF-21 and iWAT browning. JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY, v. N/A, p. 13-pg., 2023-07-05. (17/12260-8, 21/14419-0, 19/17660-0, 20/10215-8, 15/19530-5, 20/04159-8, 19/04271-5, 18/03418-0, 22/02123-1, 17/17582-3, 17/23040-9, 19/01763-4, 15/22983-1, 20/09399-7)

KOMEGAE, EVILIN N.; FONSECA, MONIQUE T.; CRUZ-MACHADO, SANSERAY DA SILVEIRA; TURATO, WALTER M.; FILGUEIRAS, LUCIANO R.; MARKUS, REGINA P.; STEINER, ALEXANDRE A.. Site-Specific Reprogramming of Macrophage Responsiveness to Bacterial Lipopolysaccharide in Obesity. FRONTIERS IN IMMUNOLOGY, v. 10, JUN 28 2019. (12/03831-8, 18/03418-0, 14/03719-9, 13/13691-1, 15/04557-5, 16/04921-1, 17/13350-0, 14/17407-9)

MORETTI, EDUARDO H.; RODRIGUES, ABNER C.; MARQUES, BRUNO V.; TOTOLA, LEONARDO T.; FERREIRA, CAROLINE B.; BRITO, CAMILA F.; MATOS, CAROLINE M.; DA SILVA, FILIPE A.; SANTOS, ROBSON A. S.; LOPES, LUCIANA B.; et al. Autoregulation of blood flow drives early hypotension in a rat model of systemic inflammation induced by bacterial lipopolysaccharide. PNAS NEXUS, v. 2, n. 2, p. 13-pg., 2023-02-01. (18/13877-1, 20/00631-4, 18/03418-0, 20/09399-7, 15/23376-1, 18/21934-5)

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, SEP 2021. (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, p. 12-pg., 2021-04-20. (18/00849-0, 16/23540-9, 17/13350-0, 16/04921-1, 18/03418-0, 15/19530-5, 14/03719-9, 20/09399-7, 17/17403-1, 14/50265-3)

STEINER, ALEXANDRE A.. Should we let fever run its course in the early stages of COVID-19?. JOURNAL OF THE ROYAL SOCIETY OF MEDICINE, v. 113, n. 10, p. 3-pg., 2020-09-15. (18/03418-0, 12/03831-8, 16/04921-1)

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, NOV 2021. (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)

CHAVES-FILHO, ADRIANO B.; PEIXOTO, ALBERT S.; CASTRO, ERIQUE; OLIVEIRA, TIAGO E.; PERANDINI, LUIZ A.; MOREIRA, RAFAEL J.; DA SILVA, RAILMARA P.; DA SILVA, BEATRIZ P.; MORETTI, EDUARDO H.; STEINER, ALEXANDRE A.; et al. Futile cycle of beta-oxidation and de novo lipogenesis are associated with essential fatty acids depletion in lipoatrophy. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, v. 1868, n. 3, p. 14-pg., 2022-12-20. (16/23169-9, 17/23040-9, 20/04159-8, 18/03418-0, 20/09399-7, 20/12969-0, 19/26473-9, 13/07937-8, 15/19530-5, 18/11156-5, 19/17660-0)