title: Aspirin-induced gastrointestinal damage is associated with an inhibition of epithelial cell autophagy.
abstract: BACKGROUND
  Aspirin (ASA) causes gastrotoxicity by hampering the epithelial defense against luminal contents through cyclooxygenase inhibition. Since cell survival in tough conditions may depend on rescue mechanisms like autophagy, we analyzed whether epithelial cells rely on this process to defend themselves from aspirin's damaging action.
  
  
  METHODS
  Rats received a single dose of ASA (150 mg/kg, p.o.) with or without pretreatment with the autophagy inhibitor 3-methyladenine, and gastric injury and epithelial autophagy were evaluated 3 h later. The effects of ASA on cell viability and autophagy were also evaluated in gastric epithelial AGS cells.
  
  
  RESULTS
  Basal autophagy in the gastric mucosa was inhibited by ASA as demonstrated by increased levels of p62 and ubiquitinated proteins and total LC3 and a reduced LC3-II/LC3-I ratio. Similarly, ASA increased p62 and decreased LC3-II accumulation and the number of EmGFP/LC3B puncta in AGS cells. ASA activated the PI3K/Akt-GSK3-mTOR pathway, which phosphorylates ULK1 to prevent autophagy initiation, changes that were inhibited by the PI3K-inhibitor wortmannin. Autophagy inhibition seems to enhance the vulnerability of gastric epithelial cells as a combination of ASA with 3-methyladenine exacerbated rat gastric damage and AGS cell apoptosis.
  
  
  CONCLUSIONS
  Our data highlight the importance of autophagy in the gastric mucosa as a protective mechanism when the epithelium is injured. In the stomach, aspirin induces mucosal damage and reduces autophagy, thus, eliminating a protective mechanism that epithelial cells could use to escape death. We hypothesize that the combination of aspirin with drugs that activate autophagy could protect against gastric damage.
authors.affiliation: Departamento de Farmacología and CIBER, Facultad de Medicina, Universidad de Valencia, Av. Blasco Ibáñez, 15, 46010, Valencia, Spain. carlos.hernandez-saez@uv.es.|FISABIO, Hospital Dr. Peset, Av. Cataluña, 21, 46020, Valencia, Spain. carlos.hernandez-saez@uv.es.
authors.forename: Carlos
authors.identifier: http://orcid.org/0000-0001-8536-429X
authors.initials: C
authors.lastname: Hernández
authors.affiliation: Departamento de Farmacología and CIBER, Facultad de Medicina, Universidad de Valencia, Av. Blasco Ibáñez, 15, 46010, Valencia, Spain.
authors.forename: Maria Dolores
authors.initials: MD
authors.lastname: Barrachina
authors.affiliation: Departamento de Farmacología and CIBER, Facultad de Medicina, Universidad de Valencia, Av. Blasco Ibáñez, 15, 46010, Valencia, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Vallecillo-Hernández
authors.affiliation: Departamento de Farmacología and CIBER, Facultad de Medicina, Universidad de Valencia, Av. Blasco Ibáñez, 15, 46010, Valencia, Spain.|Fundación General Universidad de Valencia, Calle Amadeo de Saboya, 4, 46010, Valencia, Spain.
authors.forename: Ángeles
authors.initials: Á
authors.lastname: Álvarez
authors.affiliation: Departamento de Farmacología and CIBER, Facultad de Medicina, Universidad de Valencia, Av. Blasco Ibáñez, 15, 46010, Valencia, Spain.
authors.forename: Dolores
authors.initials: D
authors.lastname: Ortiz-Masiá
authors.affiliation: Departamento de Farmacología and CIBER, Facultad de Medicina, Universidad de Valencia, Av. Blasco Ibáñez, 15, 46010, Valencia, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Cosín-Roger
authors.affiliation: Departamento de Farmacología and CIBER, Facultad de Medicina, Universidad de Valencia, Av. Blasco Ibáñez, 15, 46010, Valencia, Spain.|FISABIO, Hospital Dr. Peset, Av. Cataluña, 21, 46020, Valencia, Spain.
authors.forename: Juan Vicente
authors.initials: JV
authors.lastname: Esplugues
authors.affiliation: Departamento de Farmacología and CIBER, Facultad de Medicina, Universidad de Valencia, Av. Blasco Ibáñez, 15, 46010, Valencia, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Calatayud
mesh_terms: D000818:Animals; D001241:Aspirin / Q000009:adverse effects / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects*; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016861:Cyclooxygenase Inhibitors; D001241:Aspirin
keywords: Aspirin; Autophagy; Epithelial cells; Gastric damage; NSAID