title: Lc3 over-expression improves survival and attenuates lung injury through increasing autophagosomal clearance in septic mice.
abstract: OBJECTIVE
  To clarify the role of autophagy in sepsis-induced lung injury.
  
  
  BACKGROUND
  The role of autophagy as a protective or maladaptive response in lung cells during sepsis has not yet been determined. The lack of specificity of the autophagic process has driven the development of new approaches that assess autophagosomes from formation to fusion with lysosomes.
  
  
  METHODS
  Sepsis was induced by cecal ligation and puncture (CLP). The autophagic process was manipulated using the pharmacological inhibitors of the autophagy pathway. Green fluorescent protein (GFP)-microtubule-associated protein 1 light chain 3 (LC3) transgenic mice were further used to determine the role of autophagy.
  
  
  RESULTS
  The formation of autophagosomal protein LC3-II progressively accumulated in the lungs over 24 hours after CLP, with the Lc3 gene expression returning to baseline levels at 24 hours. Autophagosome-lysosome fusion, however, gradually decreased from 8 to 24 hours after CLP, suggesting impaired clearance of autophagosomes rather than upregulation of autophagy in the septic lung. In contrast, transgenic mice overexpressing the Lc3 gene exhibited increased clearance of autophagosomes and improved survival after CLP. This protective effect was also seen in decreased cell death, inflammatory responses, neutrophil accumulation, albumin leakage, and edema formation. However, blockade of autophagosome-lysosome fusion with bafilomycin A1 abolished the protective effects in transgenic mice. This indicates that Lc3 transgene attenuates lung injury/inflammation in sepsis, possibly through increasing the clearance of autophagosomes.
  
  
  CONCLUSIONS
  Autophagy in the septic lung represents a protective response. However, autophagy, by virtue of excessive autophagosome accumulation, may play a maladaptive role in the late stage of sepsis, leading to acute lung injury.
authors.affiliation: Department of Plastic and Reconstructive Surgery, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan, Republic of China.
authors.forename: Steven
authors.initials: S
authors.lastname: Lo
authors.forename: Shyng-Shiou F
authors.initials: SS
authors.lastname: Yuan
authors.forename: Chin
authors.initials: C
authors.lastname: Hsu
authors.forename: Yu-Jen
authors.initials: YJ
authors.lastname: Cheng
authors.forename: Ya-Fang
authors.initials: YF
authors.lastname: Chang
authors.forename: Hsiang-Wei
authors.initials: HW
authors.lastname: Hsueh
authors.forename: Po-Huang
authors.initials: PH
authors.lastname: Lee
authors.forename: Ya-Ching
authors.initials: YC
authors.lastname: Hsieh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001343:Autophagy / Q000276:immunology*; D016923:Cell Death; D004791:Enzyme Inhibitors / Q000494:pharmacology; D055370:Lung Injury / Q000276:immunology / Q000378:metabolism* / Q000401:mortality*; D008247:Lysosomes / Q000502:physiology; D018942:Macrolides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D014617:Vacuoles / Q000648:ultrastructure
chemical_list: D004791:Enzyme Inhibitors; D018942:Macrolides; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; C057620:bafilomycin A