Genetic Variance is Associated with Susceptibility for Cigarette Smoke-induced DAMP Release in Mice

Chronic obstructive pulmonary disease (COPD) is characterized by unresolved neutrophilic airway inflammation and is caused by chronic exposure to toxic gases, such as cigarette smoke (CS), in genetically susceptible individuals. Recent data indicate a role for damage-associated molecular patterns (DAMPs) in COPD. Here, we investigated the genetics of CS-induced DAMP release in 28 inbred mouse strains. Subsequently, in lung tissue from a subset of strains, the expression of the identified candidate genes was analyzed. We tested whether small interfering RNA-dependent knockdown of candidate genes altered the susceptibility of the human A549 cell line to CS-induced cell death and DAMP release. Furthermore, we tested whether these genes were differentially regulated by CS exposure in bronchial brushings obtained from individuals with a family history indicative of either the presence or absence of susceptibility for COPD. We observed that, of the four DAMPs tested, double-stranded DNA (dsDNA) showed the highest correlation with neutrophilic airway inflammation. Genetic analyses identified 11 candidate genes governing either CS-induced or basal dsDNA release in mice. Two candidate genes ( and ) showed differential expression in lung tissue on CS exposure between susceptible and nonsusceptible mouse strains. Knockdown of and in A549 cells altered susceptibility to CS extract-induced cell death and DAMP release. In bronchial brushings, CS-induced expression of and was significantly different between individuals susceptible or nonsusceptible for COPD. Our study shows that genetic variance in a mouse model is associated with CS-induced DAMP release, and that this might contribute to susceptibility for COPD.