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Aspirin-induced gastrointestinal damage is associated with an inhibition of epithelial cell autophagy

  • Original Article—Alimentary Tract
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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.

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Abbreviations

3-MA:

3-Methyladenine

ASA:

Acetylsalicylic acid, aspirin

CQ:

Chloroquine

NSAIDs:

Non-steroidal anti-inflammatory agents

Veh:

Vehicle

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Acknowledgments

We thank Brian Normanly for his English language editing. This work was supported by Ministerio de Ciencia e Innovación [grant numbers SAF2010-20231, SAF2010-16030, SAF2013-43441-P and RYC-2011-09571], Ministerio de Sanidad y Consumo [Grant Number PI11/00327], CIBERehd [Grant Number CB06/04/0071] and Generalitat Valenciana [Grant Number PROMETEOII/2014/035]. Carlos Hernandez acknowledges support from the ‘Ramon y Cajal’ program from Ministerio de Ciencia e Innovación of Spain (RYC-2011-09571). Jesús Cosín-Roger is supported by FPU fellowships from Ministerio de Educación, Cultura y Deporte. The support received had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. Departamento de Farmacología and CIBER, Facultad de Medicina, Universidad de Valencia, Av. Blasco Ibáñez, 15, 46010, Valencia, Spain

    Carlos Hernández, Maria Dolores Barrachina, Jorge Vallecillo-Hernández, Ángeles Álvarez, Dolores Ortiz-Masiá, Jesús Cosín-Roger, Juan Vicente Esplugues & Sara Calatayud

  2. FISABIO, Hospital Dr. Peset, Av. Cataluña, 21, 46020, Valencia, Spain

    Carlos Hernández & Juan Vicente Esplugues

  3. Fundación General Universidad de Valencia, Calle Amadeo de Saboya, 4, 46010, Valencia, Spain

    Ángeles Álvarez

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  1. Carlos Hernández
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Correspondence to Carlos Hernández.

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Hernández, C., Barrachina, M.D., Vallecillo-Hernández, J. et al. Aspirin-induced gastrointestinal damage is associated with an inhibition of epithelial cell autophagy. J Gastroenterol 51, 691–701 (2016). https://doi.org/10.1007/s00535-015-1137-1

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  • DOI: https://doi.org/10.1007/s00535-015-1137-1

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