Cigarette Smoke Induces Nucleic-Acid Oxidation in Lung Fibroblasts

Abstract

Oxidative stress is widely proposed as a pathogenic mechanism for chronic obstructive pulmonary disease (COPD), but the molecular pathway connecting oxidative damage to tissue destruction remains to be fully defined. We suggest that reactive oxygen species (ROS) oxidatively damage nucleic acids, and this effect requires multiple repair mechanisms, particularly base excision pathway components 8-oxoguanine-DNA glycosylase (OGG1), endonuclease III homologue 1 (NTH1), and single-strand-selective monofunctional uracil-DNA glycosylase 1 (SMUG1), as well as the nucleic acid-binding protein, Y-box binding protein 1 (YB1). This study was therefore designed to define the levels of nucleic-acid oxidation and expression of genes involved in the repair of COPD and in corresponding models of this disease. We found significant oxidation of nucleic acids localized to alveolar lung fibroblasts, increased levels of OGG1 mRNA expression, and decreased concentrations of NTH1, SMUG1, and YB1 mRNA in lung samples from subjects with very severe COPD compared with little or no COPD. Mice exposed to cigarette smoke exhibited a time-dependent accumulation of nucleic-acid oxidation in alveolar fibroblasts, which was associated with an increase in OGG1 and YB1 mRNA concentrations. Similarly, human lung fibroblasts exposed to cigarette smoke extract exhibited ROS-dependent nucleic-acid oxidation. The short interfering RNA (siRNA)-dependent knockdown of OGG1 and YB1 expression increased nucleic-acid oxidation at the basal state and after exposure to cigarette smoke. Together, our results demonstrate ROS-dependent, cigarette smoke-induced nucleic-acid oxidation in alveolar fibroblasts, which may play a role in the pathogenesis of emphysema.

IL-13–induced airway mucus production is attenuated by MAPK13 inhibition

“…Limited clinical information was available for non-COPD subjects, but the group of patients with very severe COPD was characterized by severe emphysema and symptoms of chronic bronchitis signified by excess mucus production (Supplemental Table 1). To address the relationship of CLCA1 expression to airway mucus production, we examined lung tissue core samples directed to airways based on computed tomography imaging (31). In these airway-rich core samples, we found a significant increase in CLCA1 and MUC5AC mRNA as well CLCA1 and MUC5AC protein levels in subjects with COPD compared with subjects without COPD (Supplemental Figure 4).…”

“…Control samples were obtained from donors without COPD (n = 11) using both lung explants that were otherwise not useable for transplantation and excess lung tissue that was resected for downsizing. For airway-specific analyses of gene and protein expression, computed tomography imaging and gross histologic examination was used to select airway-containing tissue cores in COPD explants (n = 11) and frozen lung tissues from donors without COPD (n = 7) as described previously (31). Each analysis consisted of samples from recipients with COPD with the same clinical characteristics (as summarized in Supplemental Table 1).…”

Neutrophil Elastase Differentially Regulates Interleukin 8 (IL-8) and Vascular Endothelial Growth Factor (VEGF) Production by Cigarette Smoke Extract

“…Lung inflammation caused by CS is generally associated with an influx of inflammatory cells such as neutrophils, macrophages, and CD8 ϩ T lymphocytes (9). CS itself contains a high concentration of reactive oxygen species, which causes tissue destruction and DNA damage (10). Moreover, CS triggers generation of additional reactive oxygen species, and reactive oxygen species amplify inflammation, suggesting cross-talk between oxidative stress and inflammation (6,11).…”

Polymerization and Oxidation of Alpha-1-Antitrypsin in Pathogenesis of Emphysema

“…Harmful effects of oxidative stress are numerous: inactivation of antiproteases, disregulation of cell proliferation, induction of apoptosis, modulation the immune system, direct damages of proteins, lipids, and nucleic acids. The products of lipid peroxidation, protein oxidation, and nucleic acid oxidation have been shown in emphysema (Mohsenin, 1991;Sahin et al, 2001;Hackett et al, 2010;Torres-Ramos et al, 2009;Deslee et al, 2009;Deslee et al, 2010).…”