Combined glucocorticoid resistance and hyperlactatemia contributes to lethal shock in sepsis

Published: 16 July 2021| Version 3 | DOI: 10.17632/xy8bnhgzfx.3
Contributors:
jolien vandewalle,
Steven Timmermans,
Ville Paakinaho,
Lies Vancraeynest,
Liza Dewyse,
Tineke Vanderhaeghen,
Charlotte Wallaeys,
Lise Van Wyngene,
Kelly Van Looveren,
Melanie Eggermont,
Sylviane Dewaele,
Tiago Velho,
Luis Ferreira Moita,
Sebastian Weis,
Christoph Sponholz,
Leo van Grunsven,
Mieke Dewerchin,
Peter Carmeliet,
Karolien De Bosscher,
Johan Vandevoorde,
Jorma Palvimo,
Claude Libert

Description

Sepsis is a potentially lethal syndrome resulting from a maladaptive response to infection. Upon infection, glucocorticoids are produced as a part of the compensatory response to tolerate sepsis. This tolerance is, however, mitigated in sepsis due to a quickly induced glucocorticoid resistance at the level of the glucocorticoid receptor. Here, we show that defects in the glucocorticoid receptor signaling pathway aggravate sepsis pathophysiology by lowering lactate clearance and sensitizing mice to lactate-induced toxicity. The latter is exerted via an uncontrolled production of vascular endothelial growth factor, resulting in vascular leakage and collapse with severe hypotension, organ damage, and death, all being typical features of a lethal form of sepsis. In conclusion, sepsis leads to glucocorticoid receptor failure and hyperlactatemia, which collectively leads to a lethal vascular collapse.

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Health Sciences, Glucocorticoid Receptor, Sepsis

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