Dr Julie CONTENTI-LIPRANDI

Research team

Microbial virulence and inflammatory signaling in disease (VIRINFLAM)

Hypoxie et sepsis: bench to bedside

Abstract:

Oxygen is a molecule essential to our survival, its primary role being to supply energy to all the body's cells. Oxygen levels in the tissues vary from 2 to 9% depending on the organs, and below these values we speak of hypoxia. When oxygen is insufficient, a protein complex called Hypoxia-inducible Factor (HIF) accumulates in almost every cell in the body, and regulates almost 2% of the human genome. Tissue hypoxia can be caused by different mechanisms: (i) low oxygen levels in the blood (hypoxaemia), reduced oxygen consumption in tissues (histotoxic hypoxia) or reduced and/or stopped blood flow. These mechanisms are found in various pathological situations frequently encountered in emergency medicine (sepsis, shock, cardiac arrest).

From the start of my academic career, my clinical work has focused on tissue hypoxia during sepsis, in particular through the use of a biomarker commonly used in clinical practice: lactate. In particular, I analysed the correlation between different lactate sampling sites (arterial, venous and capillary), its value as a diagnostic and/or prognostic marker in patients with suspected infection, and variations in lactate concentration as a function of beta-blocker treatment during sepsis.

In parallel, my research has enabled me to gain a better understanding of the impact of hypoxia on endothelial dysfunction, using an experimental model of arteriovenous fistula. I also studied the impact of hypoxia through different metabolic pathways (glycolysis and oxidative phosphorylation, regeneration of cytosolic NAD+) in an experimental paediatric tumour model (medulloblastoma). In this work, I demonstrated that a subgroup of medulloblastomas used mitochondrial glycerophosphate dehydrogenase (mGPDH) and malate-aspartate (MAS) shuttles differently for the regeneration of cytosolic NAD+. I also demonstrated that Hypoxia-Inducible Factor-1 alpha (HIF-1α), a subunit of the transcription factor HIF-1 that regulates the cellular response to hypoxia, was modified in a subgroup of medulloblastoma, leaving HIF-2 alone in the activation of metabolic signalling pathways under hypoxic conditions.

Future prospects include analysing the hypoxic signature induced by HIF-1 in patients presenting to emergency departments with an infection, and investigating whether some of these signatures can predict the development of organ failure. I would also like to continue working on the metabolic origin of the hyperlactataemia found in septic states, in order to understand whether the prognostic contribution of this biomarker may differ depending on the origin of its production.

Keywords: 

Hypoxia, metabolism, sepsis, biomarkers