8-hydroxy-2--deoxyguanosine and Emphysema

Chronic exposure to high levels of ozone induces emphysema and chronic inflammation in mice. We determined the recovery from ozone-induced injury and whether an antioxidant, N-acetylcysteine (NAC), could prevent or reverse the lung damage.. Mice were exposed to ozone (2.5 ppm, 3 hours/12 exposures, over 6 weeks) and studied 24 hours (24h) or 6 weeks (6W) later. Nac (100 mg/kg, intraperitoneally) was administered either before each exposure (preventive) or after completion of exposure (therapeutic) for 6 weeks.. After ozone exposure, there was an increase in functional residual capacity, total lung volume, and lung compliance, and a reduction in the ratio of forced expiratory volume at 25 and 50 milliseconds to forced vital capacity (FEV25/FVC, FEV50/FVC). Mean linear intercept (Lm) and airway hyperresponsiveness (AHR) to acetylcholine increased, and remained unchanged at 6W after cessation of exposure. Preventive NAC reduced the number of BAL macrophages and airway smooth muscle (ASM) mass. Therapeutic NAC reversed AHR, and reduced ASM mass and apoptotic cells.. Emphysema and lung function changes were irreversible up to 6W after cessation of ozone exposure, and were not reversed by NAC. The beneficial effects of therapeutic NAC may be restricted to the ASM.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acetylcysteine; Animals; Apoptosis; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Deoxyguanosine; Disease Models, Animal; Emphysema; Expectorants; Gene Expression; Lung; Malondialdehyde; Mice; Ozone; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests

Chronic obstructive pulmonary diseases (COPD) have been the major cause of mortality worldwide. Early identification of populations at risk allows us to prevent the occurrence and to reduce the cost of health care. In human studies, exposure to environmental tobacco smoke (ETS) and arsenic respectively increased the risk of chronic lung diseases, including COPD. We suspected that ETS and arsenic might enhance the risk of COPD. In our present study, we evaluated this hypothesis in mice and tried to identify early biomarkers for chemicals-induced lung lesions. Mice inhaled ETS and/or administrated arsenite via gavage for 4 weeks. At the end of experiment, exposure to ETS or arsenite alone failed to cause lung lesions or inflammation. However, co-exposure to ETS and arsenite significantly induced emphysema-like lesions, characterized with enlarged alveolar spaces and destruction of alveolar structure, although inflammation was not observed. Furthermore, co-exposure to ETS and arsenite significantly increased plasma 8-oxodeoxyguanosine (8-OHdG) levels. Our results indicated that co-exposure to ETS and arsenite induced emphysematous lesions, and plasma 8-OHdG might serve as an early biomarker for co-exposure of ETS and arsenite. With information about ETS and arsenic exposure in human populations, plasma 8-OHdG will help us to identify individuals at risk.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Arsenic; Bronchoalveolar Lavage Fluid; Deoxyguanosine; Emphysema; Gene Expression; Inhalation Exposure; L-Lactate Dehydrogenase; Lung; Male; Mice; Mice, Inbred ICR; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Tobacco Smoke Pollution

Although inflammation and protease/antiprotease imbalance have been postulated to be critical in cigarette smoke-induced (CS-induced) emphysema, oxidative stress has been suspected to play an important role in chronic obstructive pulmonary diseases. Susceptibility of the lung to oxidative injury, such as that originating from inhalation of CS, depends largely on its upregulation of antioxidant systems. Nuclear factor, erythroid-derived 2, like 2 (Nrf2) is a redox-sensitive basic leucine zipper protein transcription factor that is involved in the regulation of many detoxification and antioxidant genes. Disruption of the Nrf2 gene in mice led to earlier-onset and more extensive CS-induced emphysema than was found in wild-type littermates. Emphysema in Nrf2-deficient mice exposed to CS for 6 months was associated with more pronounced bronchoalveolar inflammation; with enhanced alveolar expression of 8-oxo-7,8-dihydro-2'-deoxyguanosine, a marker of oxidative stress; and with an increased number of apoptotic alveolar septal cells--predominantly endothelial and type II epithelial cells--as compared with wild-type mice. Microarray analysis identified the expression of nearly 50 Nrf2-dependent antioxidant and cytoprotective genes in the lung that may work in concert to counteract CS-induced oxidative stress and inflammation. The responsiveness of the Nrf2 pathway may act as a major determinant of susceptibility to tobacco smoke-induced emphysema by upregulating antioxidant defenses and decreasing lung inflammation and alveolar cell apoptosis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antioxidants; Apoptosis; Bronchoalveolar Lavage; Deoxyguanosine; DNA-Binding Proteins; Emphysema; Epithelial Cells; Genetic Predisposition to Disease; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Inflammation; Lung; Mice; Mice, Inbred ICR; Mice, Transgenic; Microscopy, Fluorescence; NF-E2-Related Factor 2; Oligonucleotide Array Sequence Analysis; Oxidation-Reduction; Phenotype; Pulmonary Alveoli; Smoking; Time Factors; Trans-Activators; Transcription, Genetic; Up-Regulation