Glutathione, the redox sensitive transcription factors AP-1 and NF-kB, and early one adenoviral protein in human lung in smoking related lung disease

Abstract

The major factor in the development of chronic obstructive airways disease (COPD) is cigarette smoking, although not all smokers develop chronic obstructive pulmonary disease. Inflammation and destruction has been shown in the lungs of smokers with chronic obstructive pulmonary disease. Oxidative stress, both from cigarette smoke and oxidants generated endogenously by cellular processes, contribute to the inflammation that occurs in the lungs in chronic obstructive pulmonary disease. It remains unclear why certain individuals appear susceptible to the effects of cigarette smoke and go on to develop inflammation and airflow limitation. The glutathione redox system is an important antioxidant protective system within the lungs, and this system may play a critical role in the development of inflammation. An alteration in the transcription of pro-inflammatory cytokines and mediators is also likely to contribute to the inflammation within the lung. Nuclear factor kappa-B (NF-kB) and activator protein-1 (AP-1) are both redox sensitive transcription factors, and are involved in the regulation of the gene transcription of many pro-inflammatory mediators. Activator protein-1 and nuclear factor kappa-B have a close relationship with y-glutamylcysteine synthetase (y-GCS) (glutamate cysteine ligase, GCL), the rate limiting enzyme in the synthesis of glutathione, with the y-glutamylcysteine synthetase gene containing various elements including an Activator protein-1 binding site. Susceptibility to the effects of cigarette smoke is likely to explain why certain individuals develop chronic obstructive pulmonary disease, and this susceptibility may arise from an earlier viral infection such as adenoviral infection that lies dormant, but which in the face of an oxidant stimulus such as cigarette smoke augments the inflammatory process.

The in vivo studies herein have examined glutathione and y-glutamylcysteine synthetase, gene transcription, oxidant/antioxidant imbalance, the redox sensitive transcription factors nuclear factor kappa-B and activator protein-1, and have assessed for the presence of the early one adenoviral protein in human lung in smokers and patients with COPD.

The results show similar levels of total glutathione in the lungs of patients with and without airflow obstruction, and decreased y-glutamylcysteine synthetase activity in patients with severe airflow obstruction who have undergone lung volume reduction surgery for emphysema compared to those with no airflow obstruction. Local lung oxidative stress as measured by malondialdehyde, and trolox equivalant antioxidant capacity a marker of systemic oxidative stress did not correlate with lung function. DNA binding of Nuclear factor kappa-B correlated with lung function as measured by percent predicted forced expiratory volume in one second (FEVi), however no such relationship was found with Activator protein-1 DNA binding. Examination for early one adenoviral gene and protein in human lung tissue failed to reveal conclusive results.

In conclusion levels of glutathione in human lung tissue, oxidative stress including both lung and systemic oxidative stress, and the DNA binding of activator protein-1 in lung are not related to the degree of airflow obstruction present.