Evitar (l-Alanyl-l-Glutamine) Regulates Key Signaling Molecules in the Pathogenesis of Postoperative Tissue Fibrosis

Reprod Sci. 2019 Jun;26(6):724-733. doi: 10.1177/1933719118789511. Epub 2018 Sep 5.


Aims: Hypoxia and the resulting oxidative stress play a major role in postoperative tissue fibrosis. The objective of this study was to determine the effect of l-alanyl-l-glutamine (Ala-Gln) on key markers of postoperative tissue fibrosis: hypoxia-inducible factor (HIF) 1α and type I collagen.

Methods: Primary cultures of human normal peritoneal fibroblasts (NPF) established from normal peritoneal tissue were treated with increasing doses of Ala-Gln (0, 1, 2, or 10 mM) with hypoxia ([2% O2] 0-48 hours; continuous hypoxia) or after hypoxia (0.5, 1, 2, 4 hours) and restoration of normoxia (episodic hypoxia) with immediate treatment with Ala-Gln. Hypoxia-inducible factor 1α and type 1 collagen levels were determined by enzyme-linked immunosorbent assay. Data were analyzed with 1-way analysis of variance followed by Tukey tests with Bonferroni correction.

Results: Hypoxia-inducible factor 1α and type I collagen levels increased in untreated controls by 3- to 4-fold in response to continuous and episodic hypoxia in human NPF. Under continuous hypoxia, HIF-1α and type I collagen levels were suppressed by Ala-Gln in a dose-dependent manner. l-alanyl-l-glutamine treatment after episodic hypoxia also suppressed HIF-1α and type I collagen levels for up to 24 hours for all doses and up to 48 hours at the highest dose, regardless of exposure time to hypoxia.

Conclusions: l-alanyl-l-glutamine significantly suppressed hypoxia-induced levels of key tissue fibrosis (adhesion) phenotype markers under conditions of continuous as well as episodic hypoxia in vitro. This effect of glutamine on molecular events involved in the cellular response to insult or injury suggests potential therapeutic value for glutamine in the prevention of postoperative tissue fibrosis.

Keywords: -alanyl--glutamine; HIF-1α; adhesions; hypoxia; postoperative tissue fibrosis; type I collagen.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers / analysis
  • Cell Hypoxia
  • Cells, Cultured
  • Collagen Type I / analysis
  • Dipeptides / administration & dosage
  • Dipeptides / pharmacology*
  • Fibroblasts / chemistry
  • Fibroblasts / drug effects
  • Fibroblasts / physiology
  • Fibrosis / metabolism*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / analysis
  • Peritoneum / cytology
  • Postoperative Complications / metabolism*
  • Signal Transduction / drug effects*
  • Tissue Adhesions / prevention & control*


  • Biomarkers
  • Collagen Type I
  • Dipeptides
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • alanylglutamine