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Multi-User Equipment approved in grant 2018/03418-0: Oxylite System


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 immunity. (AU)

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