Cigarette smoke contains numerous chemical compounds, including abundant reactive oxygen/nitrogen species and aldehydes, and many other carcinogens. Long-term cigarette smoking significantly increases the risk of various lung diseases, including chronic obstructive pulmonary disease and lung cancer, and contributes to premature death. Many in vitro and in vivo studies have elucidated mechanisms involved in cigarette smoke-induced inflammation, DNA damage, and autophagy, and the subsequent cell fates, including cell death, cellular senescence, and transformation. In this Translational Review, we summarize the known pathways underlying these processes in airway epithelial cells to help reveal future challenges and describe possible directions of research that could lead to better management and treatment of these diseases.

IFN-γ induces the interaction of HDAC1 and p53, leading to p53 deacetylation, which facilitates autophagy via Bmf suppression.

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RATIONALE:Both chronic obstructive pulmonary disease (COPD) and lung cancer are associated with cigarette smoke-induced chronic inflammation that is driven by the activation of nuclear factor (NF)-kB. Extensive inflammation in the lung results in epithelial cell hyperplasia and our studies have shown that resolution of this hyperplastic lesion is mediated by IFNg-induced cell death through the intrinsic apoptotic pathway. The purpose of this study was to identify BH3-only domain proteins of the BCL-2 family that regulate the inflammatory process and the resolution of epithelial cell hyperplasias and determine their clinical relevance. METHODS:We screened for IFNg-induced BH3-only proteins in human and mouse primary and immortalized airway epithelial cells. Immunoprecipitation, MALDI-TOF mass spectrometry, and GST pull-down were used to identify the interacting proteins. Overexpression or suppression of each component of the protein complex together with immunofluorescence, luciferase, and Multiplex Bead-based Luminex assays were used to investigate the roles of these proteins in NF-kB activation. Mice deficient in the crucial BH3-only domain protein were exposed to cigarette smoke to assess its role . In addition, single nucleotide polymorphisms (SNPs) in this crucial gene in vivo were tested for association with lung function decline in the Lovelace Smokers Cohort (LSC), a longitudinal study of current and former smokers. RESULTS: We found NOXA was dramatically induced by IFNg in a STAT1-dependent manner, and identified phosphorylated HSP27 as a protein that forms a complex with NOXA. Induced expression of NOXA inhibited TNFa-mediated nuclear translocation of NF-kB p65 subunit, NF-kB-dependent transcriptional activity, and related cytokine production. Both NOXA and phosphorylated HSP27 were essential for inhibition of NF-kB by stabilizing inhibitor of kB (IkBa) from ubiquitin-mediated degradation. This inhibition of NF-kB activation translated into a significant reduction in inflammatory cytokine expression and suppression of the anti-apoptotic protein, Bcl-x , and L enhanced the cell death of airway epithelial cells. Cigarette smoke-induced inflammation was significantly more extensive in Noxa -/compared to mice. In the LSC, a tag SNP (rs11152187) in a haplotypic block encompassing the gene was significantly Noxa +/+ NOXA associated with decline in lung function ( =0.0007). p CONCLUSIONS: This study demonstrates that NOXA modulates the canonical NF-kB signaling cascade and blocks the pro-inflammatory cytokine synthesis. These findings suggest that restoring NOXA expression may be of clinical significance, because Noxa inhibited cigarette smoke-induced inflammation in mice and the related SNP was associated with lung function decline in smokers.