Ambient air pollution particle (PM) is associated with increased morbidity and mortality resulting from acute and chronic cardiopulmonary injury including lung cancer. Recent investigations have demonstrated that PM is genotoxic to alveolar epithelial cell (AEC) by causing DMA damage and apoptosis. The extent of AEC injury and repair are critical determinants of the toxic potential of PM. The precise cellular and molecular mechanisms underlying the toxic pulmonary effects of PM are not fully established. However, the mechanisms may depend upon the ability of PM to interact with and modify a spectrum of biomolecules including DNA, lipids, and proteins. Accumulating evidence implicate PM induced DNA damage and apoptosis due to iron-derived reactive oxygen species (ROS) as important second messengers of toxicity due to a variety of particulates. It is known that various DNA-damaging agents such as oxidants generate signals that converge to either cell cycle arrest or apoptosis. Control of cell cycle progression in response to oxidative stress is linked to activation of a checkpoint mechanism operating before entry into the S phase of the cell cycle. A feedback control is activated that acts as a brake on the cell cycle to inhibit entry into the S phase until DNA repair is completed. Progression through the G1 phase and the G1-S transition involves sequential assembly and activation of key regulators of the cell cycle machinery, the Cyclins and cyclin-dependent kinases (CDKs). However, there is no information on airborne particulate matter induced regulation of this cell cycle machinery. Our preliminary data show that PM induces cell cycle arrest and alters regulation of G1 Cyclins and cyclin-dependent kinase in AEC.
The specific aims of this proposal are 1) To determine whether ambient air pollution particulates induce cell cycle arrest via altered regulation of G1 cyclins by generation of reactive oxygen species in AEC. 2) To determine whether iron derived free radicals mediate PM-induced altered expression and posttranslational modification of cell cycle regulatory target genes in AEC. 3) To determine whether PM-induced cell cycle arrest is mediated by altered regulation of G1 Cyclins and CDKs that activate mitochondria) death pathway. Our proposed work will enable us to understand the molecular and biological basis of pathophysiology of ambient airborne particulate induced lung diseases.
