Highlights
- •Autophagy inhibition blocks the cytokine storm and vascular leakage that occur during sepsis.
- •Autophagy inhibition promotes the uptake and clearance of E. coli by leukocytes.
- •Hydroxychloroquine (HCQ) treatment protects E. coli-infected mice from lethality.
- •However, pretreatment of mice with HCQ before infection causes opposite outcome.
Summary
Objectives
Sepsis is an overwhelming systemic inflammatory response for which no satisfactory
therapeutic drug is available. Previous studies have shown that autophagy is involved
in the cytokine storm and vascular leakage that occur during sepsis. Therefore, we
aimed to evaluate the therapeutic potential of autophagy inhibitors against bacterial
infection-induced sepsis.
Methods
Cytokine production and phagocytosis of bacteria by human leukocytes and the permeability
of endothelial cells were determined after the co-incubation of cells with lipopolysaccharide
(LPS) or Escherichia coli in the presence or absence of autophagy inhibitors in vitro. Furthermore, the therapeutic effects of the autophagy inhibitors in E. coli-infected mice were analysed.
Results
In the presence of the autophagy inhibitors, the LPS-triggered cytokine secretion
of human leucocytes and LPS (or LPS-conditioned medium from leucocytes)-induced endothelial
hyperpermeability were significantly reduced. Moreover, the inhibition of autophagy
enhanced the clearance of E. coli by leucocytes in vitro. Finally, we demonstrated that post-treatment but not pretreatment with an autophagy
inhibitor (hydroxychloroquine) completely protected mice against E. coli infection-induced lethality by simultaneously reducing cytokine production and vascular
leakage and enhancing bacterial clearance.
Conclusions
These results suggest that autophagy plays an important role in the pathogenesis of
sepsis and could serve as a potential therapeutic target for sepsis.
Keywords
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Article info
Publication history
Published online: January 14, 2019
Accepted:
December 17,
2018
Received in revised form:
October 24,
2018
Received:
August 1,
2018
Identification
Copyright
© 2019 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
