Polycyclic Aromatic Hydrocarbons (PAHs), Arachidonic Acid, and Emphysema
D.V.M., Michigan State University
Ph.D., Michigan State University
Faculty Web Page
Cigarette smoking is the most significant risk factor in the development of emphysema, an advanced form of chronic obstructive pulmonary disease (COPD) that affects an estimated 16 million people in the United States each year. Emphysema is characterized by loss of lung function following the destruction of alveolar architecture, which greatly reduces the effective surface area required for gas exchange.
Recent studies demonstrate that cigarette smoke-induced apoptosis, or programmed cell death, plays an important role in the loss of alveolar architecture, the hallmark of emphysema. However, little is known about the components of cigarette smoke responsible or the signaling pathways involved in this effect.
Dr. Tithof’s group has demonstrated that specific compounds present in cigarette smoke in high concentrations induce apoptosis in epithelial cells. These compounds include three polycyclic aromatic hydrocarbons (PAHs) and the nitrosated derivative of nicotine, NNK. Moreover, they have identified the signal transduction pathways involved in this effect.
Dr. Tithof’s group found that PAHs and NNK induce endothelial apoptosis by activating the phospholipase A2 (PLA2)/arachidonic acid cascade, an important pathway that produces more than 100 biologically active lipid mediators that have important roles in a number of diseases, including coronary artery disease and emphysema. Dr. Tithof’s study was the first to link the exposure of endothelial cells to cigarette smoke with PLA2 activation, fatty acid release, and apoptosis.
Using eight PAHs that have been implicated in the pathogenesis of emphysema, Dr. Tithof’s group is working to determine the role of arachidonic acid in PAH-induced apoptosis of human pulmonary microvascular endothelial cells, and to identify the specific PLA2 isoforms and downstream metabolizing enzymes responsible for this effect.
Results of Dr. Tithof’s study will provide valuable insight into the smoking-induced mechanisms of emphysema.