title: Defective autophagy impairs ATF3 activity and worsens lung injury during endotoxemia.
abstract: Autophagy has emerged as a key regulator of the inflammatory response. To examine the role of autophagy in the development of organ dysfunction during endotoxemia, wild-type and autophagy-deficient (Atg4b-null) mice were challenged with lipopolysaccharide. Animals lacking Atg4b showed increased mortality after endotoxemia. Among the different organs studied, only the lungs showed significant differences between genotypes, with increased damage in mutant animals. Autophagy was activated in lungs from wild-type, LPS-treated mice. Similarly, human bronchial cells show an increased autophagy when exposed to serum from septic patients. We found an increased inflammatory response (increased neutrophilic infiltration, higher levels of Il6, Il12p40, and Cxcl2) in the lungs from knockout mice and identified perinuclear sequestration of the anti-inflammatory transcription factor ATF3 as the putative mechanism responsible for the differences between genotypes. Finally, induction of autophagy by starvation before LPS exposure resulted in a dampened pulmonary response to LPS in wild-type, but not knockout, mice. Similar results were found in human bronchial cells exposed to LPS. Our results demonstrate the central role of autophagy in the regulation of the lung response to endotoxemia and sepsis and its potential modulation by nutrition.
  
  
  CONCLUSIONS
  Endotoxemia and sepsis trigger autophagy in lung tissue. Defective autophagy increases mortality and lung inflammation after endotoxemia. Impairment of autophagy results is perinuclear ATF3 sequestration. Starvation ameliorates lung injury by an autophagy-dependent mechanism.
authors.affiliation: Departamento de Biología Funcional, Área de Fisiología, IUOPA, Universidad de Oviedo, Oviedo, Spain.
authors.forename: Alina
authors.initials: A
authors.lastname: Aguirre
authors.forename: Inés
authors.initials: I
authors.lastname: López-Alonso
authors.forename: Adrián
authors.initials: A
authors.lastname: González-López
authors.forename: Laura
authors.initials: L
authors.lastname: Amado-Rodríguez
authors.forename: Estefanía
authors.initials: E
authors.lastname: Batalla-Solís
authors.forename: Aurora
authors.initials: A
authors.lastname: Astudillo
authors.forename: Jorge
authors.initials: J
authors.lastname: Blázquez-Prieto
authors.forename: Alvaro F
authors.initials: AF
authors.lastname: Fernández
authors.forename: José A
authors.initials: JA
authors.lastname: Galván
authors.forename: Claudia C
authors.initials: CC
authors.lastname: dos Santos
authors.forename: Guillermo M
authors.initials: GM
authors.lastname: Albaiceta
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D000071183:Autophagy-Related Proteins; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism; D019446:Endotoxemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D055370:Lung Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged
chemical_list: D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D000071183:Autophagy-Related Proteins; C582881:Atg4b protein, mouse; D003546:Cysteine Endopeptidases