Increased Expression of Beta-Defensin 1 (DEFB1) in Chronic Obstructive Pulmonary Disease

Abstract

On-going airway inflammation is characteristic for the pathophysiology of chronic obstructive pulmonary disease (COPD). However, the key factors determining the decrease in lung function, an important clinical parameter of COPD, are not clear. Genome-wide linkage analyses provide evidence for significant linkage to airway obstruction susceptibility loci on chromosome 8p23, the location of the human defensin gene cluster. Moreover, a genetic variation in the defensin beta 1 (DEFB1) gene was found to be associated with COPD. Therefore, we hypothesized that DEFB1 is differently regulated and expressed in human lungs during COPD progression. Gene expression of DEFB1 was assessed in bronchial epithelium and BAL fluid cells of healthy controls and patients with COPD and using bisulfite sequencing and ChIP analysis, the epigenetic control of DEFB1 mRNA expression was investigated. We can demonstrate that DEFB1 mRNA expression was significantly increased in bronchopulmonary specimen of patients with COPD (n = 34) vs. healthy controls (n = 10) (p<0.0001). Furthermore, a significant correlation could be detected between DEFB1 and functional parameters such as FEV1 (p = 0.0024) and the FEV1/VC ratio (p = 0.0005). Upregulation of DEFB1 mRNA was paralleled by changes in HDAC1-3, HDAC5 and HDAC8 mRNA expression. Whereas bisulfite sequencing revealed no differences in the methylation state of DEFB1 promoter between patients with COPD and controls, ChIP analysis showed that enhanced DEFB1 mRNA expression was associated with the establishment of an active histone code. Thus, expression of human DEFB1 is upregulated and related to the decrease in pulmonary function in patients with COPD.

pH modulates the activity and synergism of the airway surface liquid antimicrobials β-defensin-3 and LL-37

“…Polymorphisms in defensin genes are also associated with infections outside the lung (31)(32)(33). Also consistent with an important role in defense is the observation that airway insults and disease can increase defensin gene expression (34)(35)(36).…”

Genome-wide association study of lung function phenotypes in a founder population

“…There are three classes of defensins, but only the β-defensins are specifically expressed in epithelial cells, including those lining the respiratory tract. Genetic studies have implicated the β-defensin genes on chromosome 8p23 in lung function in patients with asthma 58 , chronic obstructive pulmonary disease (COPD) 59 and with cystic fibrosis (CF) 60 . In particular, DEFB1 mRNA in bronchial epithelial cell biopsies was significantly elevated in COPD patients compared to controls and significantly associated with both reduced FEV 1 and the FEV 1 /FVC ratio in COPD patients and controls 59 .…”

“…Genetic studies have implicated the β-defensin genes on chromosome 8p23 in lung function in patients with asthma 58 , chronic obstructive pulmonary disease (COPD) 59 and with cystic fibrosis (CF) 60 . In particular, DEFB1 mRNA in bronchial epithelial cell biopsies was significantly elevated in COPD patients compared to controls and significantly associated with both reduced FEV 1 and the FEV 1 /FVC ratio in COPD patients and controls 59 . The results of our studies would further suggest that all three clusters of β-defensin genes on chromosomes 8p23, 20p13, and 20q11 contribute to lung function in healthy, unselected subjects.…”

Epigenetic targets for novel therapies of lung diseases

“…Reduced HDAC expression correlated with elevated IL-8 expression and greater H4 pan-acetylation at the IL-8 promoter (Ito et al, 2005). Conversely elevated HDAC1 expression was observed in epithelial biopsies from patients with COPD and positively correlated with the expression of beta-defensin 1 (Andresen et al, 2011). Interestingly, smoking alone was sufficient to elevate H4 pan-acetylation and reduce the expression of some HDAC isoforms (Ito et al, 2005).…”