title: Genetic variation associates with susceptibility for cigarette smoke-induced neutrophilia in mice.
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.
authors: University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Experimental Pulmonology and Inflammation Research, Groningen, The Netherlands; GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands;
authors: Simon D
authors: SD
authors: Pouwels
authors: University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Experimental Pulmonology and Inflammation Research, Groningen, The Netherlands; GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, Department of Pulmonology, Groningen, The Netherlands;
authors: Irene H
authors: IH
authors: Heijink
authors: University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Experimental Pulmonology and Inflammation Research, Groningen, The Netherlands; GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands;
authors: Uilke
authors: U
authors: Brouwer
authors: University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Experimental Pulmonology and Inflammation Research, Groningen, The Netherlands; GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands;
authors: Renee
authors: R
authors: Gras
authors: University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Experimental Pulmonology and Inflammation Research, Groningen, The Netherlands; GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands;
authors: Lisette E
authors: LE
authors: den Boef
authors: GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, The Netherlands; and.
authors: H Marike
authors: HM
authors: Boezen
authors: The Jackson Laboratory, Bar Harbor, Maine.
authors: Ron
authors: R
authors: Korstanje
authors: University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Experimental Pulmonology and Inflammation Research, Groningen, The Netherlands; GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands;
authors: Antoon J M
authors: AJ
authors: van Oosterhout
authors: University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Experimental Pulmonology and Inflammation Research, Groningen, The Netherlands; GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; m.c.nawijn@umcg.nl.
authors: Martijn C
authors: MC
authors: Nawijn
mesh_terms: D000818:Animals; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D007960:Leukocyte Disorders / Q000151:congenital* / Q000235:genetics / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D009195:Peroxidase / Q000378:metabolism; D011014:Pneumonia / Q000209:etiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012907:Smoking / Q000009:adverse effects*
chemical_list: D009195:Peroxidase
keywords: Ccdc93; Focad; Naip6; cigarette smoke; neutrophilic airway inflammation