Enhancing autophagy with activated protein C and rapamycin protects against sepsis-induced acute lung injury

Yu-Ting Yen, Horng-Ren Yang, Hung-Chieh Lo, Ya-Ching Hsieh, Shih-Chang Tsai, Chia-Wen Hong, Chi-Hsun Hsieh

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

Background: Autophagy plays distinct roles in apoptosis and the inflammatory process. Understanding the role of autophagy in sepsis-induced acute lung injury (ALI) may provide new insights into developing novel therapeutic strategies for this group of patients. The aim of this study was to investigate the regulation of autophagy in the septic lung and to use pharmacologic agents to modulate autophagy to study its functional significance. Methods: Mice were subjected to cecal ligation and puncture (CLP) or a sham operation. At 1 hour after CLP, mice were treated with vehicle, activated protein C (APC), rapamycin, or bafilomycin A1. Mice were humanely killed at 4 or 24 hours after the operation or were observed for ≤7 days. Results: CLP induced a systemic inflammatory response and significantly decreased survival. In lung tissue, increased leukocyte infiltration, inflammation, and apoptosis were observed. In contrast, autophagy was suppressed after CLP such that the expression of LC3II, Atg5, and Rab7 were downregulated. Rapamycin activated autophagy, limited the CLP-induced proinflammatory response, and downregulated apoptotic activity after CLP. The administration of APC after CLP had an effect similar to that of rapamycin. Both medications significantly improved survival 7 days after CLP. Conclusion: The downregulation of autophagy may lead to systemic inflammation and ALI after sepsis. The direct or indirect modification of autophagy using rapamycin or APC, respectively, resulted in improved survival. Enhancing or restoring autophagy early after sepsis seems to be a potential strategy for the treatment of sepsis-induced ALI. © 2013 Mosby, Inc. All rights reserved.
Original languageEnglish
Pages (from-to)689-698
Number of pages10
JournalSurgery (United States)
Volume153
Issue number5
DOIs
Publication statusPublished - 2013
Externally publishedYes

Keywords

  • activated protein C
  • autophagy protein 5
  • bafilomycin A1
  • Rab7 protein
  • rapamycin
  • acute lung injury
  • animal cell
  • animal experiment
  • animal model
  • animal tissue
  • apoptosis
  • article
  • autophagy
  • cell infiltration
  • controlled study
  • dose response
  • down regulation
  • human
  • human cell
  • inflammation
  • leukocyte
  • lung parenchyma
  • male
  • mouse
  • nonhuman
  • priority journal
  • sepsis
  • sham procedure
  • survival rate
  • upregulation
  • Acute Lung Injury
  • Animals
  • Anti-Bacterial Agents
  • Apoptosis
  • Autophagy
  • Biological Markers
  • Blotting, Western
  • Cecum
  • Cells, Cultured
  • Cytokines
  • Humans
  • Immunohistochemistry
  • Ligation
  • Macrolides
  • Male
  • Mice
  • Mice, Inbred C3H
  • Protein C
  • Sepsis
  • Sirolimus

Fingerprint Dive into the research topics of 'Enhancing autophagy with activated protein C and rapamycin protects against sepsis-induced acute lung injury'. Together they form a unique fingerprint.

  • Cite this