A Vicious Downward Spiral of Air Pollution for Lung Aging and Respiratory Diseases

Reactive oxygen species (ROS) are chemically reactive molecules containing oxygen, which are produced directly or indirectly by exposure of diesel exhaust and kitchen/cigarette smoke. Although it has been widely accepted that the moderate concentrations of ROS have important roles in immune cell function and homeostasis, an excess or chronic exposure of ROS results in significant damage of cells and tissue, cellular senescence as well as inflammation, and thus often blamed for the development of severe asthma and chronic obstructive pulmonary disease (COPD), which is predicted to be the third leading cause of death worldwide by 2030, as well as lung cancer.

We previously found that global and also specific histone Histone(H)4 acetylation is increased in macrophages, epithelial cells and lung from asthma and COPD. Although H4 acetylation is also increased in culture airway epithelial cells after exposure of diesel particles or cigarette smoke, it did not last long as repair or resolution mechanisms exist. The main molecule involved in resolution of this histone acetylation is a histone deacetylase (HDAC). Eighteen HDACs are identified in human cells, but in particular HDAC2, sirtuin 1 (SIRT1) and SIRT6 are susceptible to oxidative stress and known to be reduced in asthma and COPD. The reduction of molecules leads amplified histone acetylation, causing persistent inflammatory gene expression. In addition, as these HDACs deacetylate DNA repair protein Ku86 and anti-oxidant transcription factors such as the large forkhead family of proteins (FOXO) and nuclear factor erythroid 2-related factor 2 (Nrf2) and known to regulate DNA repair and anti-oxidant capacity, these are called as anti-aging molecules. We also found these HDACs were dysregulated by ROS-induced activation of pro-aging phosphoinositide 3 kinase (PI3K) and increases in several microRNAs. This aberrant regulation of HDACs may play critical roles in accelerating lung aging and inflammation in airways as well as decreased anti-oxidant capacity, and further amplified oxidative stress worsens this situation.

Thus, this vicious downward spiral of oxidative stress from air pollution is a key factor of pathogenesis of chronic airway disease and accelerating lung aging, and this research will help to understand the mechanisms underlying adverse health effects by air pollution. In addition, various strategies to overcome oxidative stress-induced diseases or improve accelerating aging will be discussed.