Genetic variation associates with susceptibility for cigarette smoke-induced neutrophilia in mice

Simon D. Pouwels, Irene H. Heijink, Uilke Brouwer, Renee Gras, Lisette E. den Boef, Hendrika Boezen, Ron Korstanje, Antoon J. M. van Oosterhout, Martijn C. Nawijn*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

15 Citations (Scopus)

Abstract

Neutrophilic airway inflammation is one of the major hallmarks of chronic obstructive pulmonary disease and is also seen in steroid resistant asthma. Neutrophilic airway inflammation can be induced by different stimuli including cigarette smoke (CS). Short-term exposure to CS induces neutrophilic airway inflammation in both mice and humans. Since not all individuals develop extensive neutrophilic airway inflammation upon smoking, we hypothesized that this CS-induced innate inflammation has a genetic component. This hypothesis was addressed by exposing 30 different inbred mouse strains to CS or control air for 5 consecutive days, followed by analysis of neutrophilic lung inflammation. By genomewide haplotype association mapping, we identified four susceptibility genes with a significant association to lung tissue levels of the neutrophil marker myeloperoxidase under basal conditions and an additional five genes specifically associated with CS-induced tissue MPO levels. Analysis of the expression levels of the susceptibility genes by quantitative RT-PCR revealed that three of the four genes associated with CS-induced tissue MPO levels had CS-induced changes in gene expression levels that correlate with CS-induced airway inflammation. Most notably, CS exposure induces an increased expression of the coiled-coil domain containing gene, Ccdc93, in mouse strains susceptible for CS-induced airway inflammation whereas Ccdc93 expression was decreased upon CS exposure in nonsusceptible mouse strains. In conclusion, this study shows that CS-induced neutrophilic airway inflammation has a genetic component and that several genes contribute to the susceptibility for this response.

Original languageEnglish
Pages (from-to)L693-L709
Number of pages17
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume308
Issue number7
DOIs
Publication statusPublished - 1-Apr-2015

Keywords

  • cigarette smoke
  • neutrophilic airway inflammation
  • Focad
  • Naip6
  • Ccdc93
  • OBSTRUCTIVE PULMONARY-DISEASE
  • CYTOCHROME-C-OXIDASE
  • ACUTE LUNG INJURY
  • AIRWAY INFLAMMATION
  • TUMOR-SUPPRESSOR
  • ASTHMA
  • COPD
  • INNATE
  • APOPTOSIS
  • IDENTIFICATION

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