Combined glucocorticoid resistance and hyperlactatemia contributes to lethal shock in sepsis.

Vandewalle J, Timmermans S, Paakinaho V, Vancraeynest L, Dewyse L, Vanderhaeghen T, Wallaeys C, Van Wyngene L, Van Looveren K, Nuyttens L, Eggermont M, Dewaele S, Velho TR, Moita LF, Weis S, Sponholz C, van Grunsven LA, Dewerchin M, Carmeliet P, De Bosscher K, Van de Voorde J, Palvimo JJ, Libert C (2021) Combined glucocorticoid resistance and hyperlactatemia contributes to lethal shock in sepsis. Cell Metab 33(9), 1763-1776.

Abstract

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.

Leibniz-HKI-Authors

Sebastian Weis

Identifier

doi: 10.1016/j.cmet.2021.07.002

PMID: 34302744