Combined glucocorticoid resistance and hyperlactatemia contributes to lethal shock in sepsis

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.