The Pathogenesis of Alcohol-Induced Airflow Limitation in Acetaldehyde Dehydrogenase 2-Deficient Mice

Int Arch Allergy Immunol. 2016;171(3-4):276-284. doi: 10.1159/000452709. Epub 2017 Jan 4.

Abstract

Background: In Japanese patients, alcohol-induced asthma is attributed to elevated plasma concentrations of acetaldehyde following alcohol consumption because of an acetaldehyde dehydrogenase 2 gene (ALDH2) polymorphism. The resulting increase in plasma histamine concentrations seems to trigger the onset of asthma symptoms. However, the specific pathogenic mechanism underlying this response remains unclear. ALDH2-deficient mice were therefore generated to investigate the pathogenesis of alcohol-induced asthma.

Methods: ALDH2-deficient mice were generated using embryonic stem cells that were derived from C57BL/6 mice. The resulting mice were backcrossed into the BALB/c mice background. Exon 1 of ALDH2 was replaced with the Neo cassette. Pure ethanol was orally administered to ALDH2-deficient and wild-type mice, and the plasma concentrations of ethanol, acetaldehyde, and histamine, in addition to enhanced pause (Penh) values, were determined and compared between the 2 groups.

Results: We established an ALDH2-deficient mouse line to compare responses between wild-type and ALDH2-deficient mice receiving orally administered ethanol. The results showed that the plasma concentrations of acetaldehyde (p < 0.0001) and histamine (p < 0.005) were significantly higher, and the Penh values (p < 0.01) were significantly greater in the ALDH2-deficient mice, although plasma ethanol levels were not different.

Conclusions: We studied the pathogenesis of alcohol-induced asthma using ALDH2-deficient mice. The results demonstrated that alcohol intake resulted in an increase in acetaldehyde levels, and a subsequent increase in histamine levels, which induced airway constriction. Alcohol consumption is known to be an important factor that exacerbates bronchial asthma, and studies investigating this factor are useful for the treatment of patients with alcohol-induced asthma.

MeSH terms

  • Alcohol Drinking / adverse effects*
  • Aldehyde Dehydrogenase, Mitochondrial / deficiency*
  • Aldehyde Dehydrogenase, Mitochondrial / genetics
  • Animals
  • Asthma / blood
  • Asthma / etiology*
  • Biomarkers
  • Disease Models, Animal
  • Disease Susceptibility
  • Ethanol / adverse effects*
  • Ethanol / metabolism
  • Gene Order
  • Gene Targeting
  • Genetic Loci
  • Genotype
  • Histamine / blood
  • Male
  • Mice
  • Mice, Knockout

Substances

  • Biomarkers
  • Ethanol
  • Histamine
  • Aldehyde Dehydrogenase, Mitochondrial