Inhibition of autophagy protects against sepsis by concurrently attenuating the cytokine storm and vascular leakage

Liang Hsuan Lu, Chiao Hsuan Chao, Trai-Ming Yeh

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)178-186
Number of pages9
JournalJournal of Infection
Volume78
Issue number3
DOIs
Publication statusPublished - 2019 Mar 1

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Autophagy
Blood Vessels
Sepsis
Cytokines
Lipopolysaccharides
Leukocytes
Escherichia coli
Hydroxychloroquine
Escherichia coli Infections
Therapeutic Uses
Conditioned Culture Medium
Phagocytosis
Bacterial Infections
Permeability
Therapeutics
Endothelial Cells
Bacteria
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Microbiology (medical)
  • Infectious Diseases

Cite this

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title = "Inhibition of autophagy protects against sepsis by concurrently attenuating the cytokine storm and vascular leakage",
abstract = "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.",
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Inhibition of autophagy protects against sepsis by concurrently attenuating the cytokine storm and vascular leakage. / Lu, Liang Hsuan; Chao, Chiao Hsuan; Yeh, Trai-Ming.

In: Journal of Infection, Vol. 78, No. 3, 01.03.2019, p. 178-186.

Research output: Contribution to journalArticle

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