Figure 2.

Molecular and cellular responses to tobacco smoke. (A) Tobacco smoke contains >70 classified carcinogens (Hecht and Szabo 2014); shown are five compounds strongly associated with mutagenesis: benzo(a)pyrene (BaP), nicotine-derived NNK, N-nitrosodimethylamine (NDMA), 4-aminobiphenyl (4-ABP), and N-nitrosonornicotine (NNN). Many of the compounds in tobacco smoke are metabolized by cytochrome P450, resulting in molecules with highly reactive electrophilic moieties. (Black bar) Representative molecular structures with electrophilic moieties produced from the chemicals metabolized by P450. Electrophilic moieties can readily interact with DNA to form DNA adducts. DNA adducts can be repaired to correct the obstacle and re-establish “normal” DNA; this is frequently achieved by the cell's repair machinery through a process called nucleotide excision repair (NER). However, if repair is unsuccessful and cells do not undergo apoptosis, permanent procancerous mutations may be established. (B) Epigenetic modification commonly refers to processes that do not directly alter genetic information encoded by DNA but rather alter availability of genes for transcription; for instance, by addition of reversible methyl or acetyl modifications to DNA or histones. Chronic exposure to tobacco smoke extensively modifies the epigenome of cells in the affected tissue, with characteristic modifications, including hypermethylation of CpG islands (regions with high occurrence of cytosine and guanine separated by only one phosphate group, frequently found near gene promotors). This hypermethylation, generally in the context of tobacco-induced mutations, leads to reduced expression of genes important for tumor suppression and has been shown to significantly contribute to lung tumor formation (Vaz et al. 2017). Methylated residues (filled black circles) are typically generated by the action of methyltransferase enzymes (e.g., DNMT1 and EZH2) and limit transcription of growth inhibitory proteins. (C) Tobacco smoke also induces an inflammatory response that involves both epithelial and immune cells. Chemicals in the smoke induce production of fibrosis-associated proteins, most prominently TGF-β (transforming growth factor β); a number of highly active cytokines and regulators of the immune system (e.g., IL-8, C-X-C motif chemokine proteins [CXC], TNF-α, and others); and the release of nitric oxide (NO). This induces fibrosis and remodeling of the extracellular matrix (ECM), creating a more favorable microenvironment for tumorigenesis. (MMPs) Matrix metalloproteinases; (LTB4) leukotriene B4.