D108-12 Persistent Inactivation of the Interferon Alpha/Beta Signaling Pathway in Alveolar Macrophages of COPD Subjects Despite Smoking Cessation for Twelve Months

Rationale Lung infection is associated with accelerated lung function decline in COPD. Alveolar macrophages (AM) are activated in response to smoking and play a central role in COPD pathogenesis. Smoking cessation slows the smoking-related lung function decline, but less in quitters with COPD (COPD-Q) than in healthy quitters (S-Q). We previously reported that following 12 months of smoking cessation, in contrast to S-Q, some genes/pathways remain abnormal in COPD-Q. We hypothesize that non-reversible genes/pathways would identify potential causes of lung health deterioration in COPD-Q. Methods Gene expression in AM purified from bronchoalveolar lavage fluid was analyzed in n = 11 NS, n = 27 S, n = 22 COPD-S, n = 10 S-Q and n = 11 COPD-Q using Affymetrix HG-U133 Plus 2.0 microarrays (n = 239 samples). Persistent dysregulation of gene expression in healthy smokers (S) and COPD smokers (COPD-S) compared with nonsmokers (NS), and the effect of smoking cessation in S-Q and COPD-Q was evaluated at baseline, 3, 6 and 12 months. Dysregulated genes were identified using a 3-way repeated measures ANOVA model corrected for multiple testing (p < 0.05, fold-change ≥1.5). Ingenuity pathway analysis identified inactivation/activation of dysregulated pathways corrected for multiple testing (p < 0.05, |z score| >2). All subjects were males with normal alpha-1 antitrypsin levels matched for ethnicity and pack-yr history. Results At baseline, n = 566 genes were dysregulated and 49 pathways inactivated (92%)/activated (8%) in S vs NS. In COPD vs NS, n = 775 genes were dysregulated and 54 pathways inactivated (87%)/activated (13%). Top inactivated pathways in S and COPD-S vs NS included interferon alpha/beta signaling (z scores -4.47 and -3.96, respectively) and interferon gamma signaling (z scores -4.24 and -4.47, respectively). In COPD-Q, 33 genes and 1 pathway (interferon alpha/beta signaling) remained abnormal one year after cessation while all genes and pathways were normalized in S-Q. The alpha/beta signaling pathway was enriched with the interferon-stimulated host anti-viral response genes MX1, IFIT2, IFIT3 and XAF1, that remained down-regulated. Among the other 29 non-reversible genes, three additional interferon response genes, DDX60 (positive regulator of antiviral-sensor RIG-1), SAMD9 (viral RNA/DNA sensor and cytosolic antiviral granule organizer), and PARP9 (viral RNA sensor that both activates and is activated by interferon signaling), were down-regulated. Notably, IFIT3, MX1, DDX60, and PARP9 are differentially methylated genes that are hypermethylated in autoimmune diseases leading to decreased expression. Conclusions One year after smoking cessation, COPD-Q, but not S-Q, had persistent suppression of AM interferon signaling pathways, potentially contributing to increased susceptibility to infection. This abstract is funded by: R01 107882, P20 113443