Abstract 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
Rostami et al. (Fri,) studied this question.