Molecular mechanisms of asbestos-induced lung epithelial cell apoptosis.
Asbestos causes pulmonary fibrosis (asbestosis) and malignancies (bronchogenic lung cancer and mesothelioma) by mechanisms that are not fully elucidated. Accumulating evidence show that alveolar epithelial cell (AEC) apoptosis is a crucial initiating and perpetuating event in the development of pulmonary fibrosis following exposure to a wide variety of noxious stimuli, including asbestos. We review the important molecular mechanisms underlying asbestos-induced AEC apoptosis. Specifically, we focus on the role of asbestos in augmenting AEC apoptosis by the mitochondria- and p53-regulated death pathways that result from the production of iron-derived reactive oxygen species (ROS) and DNA damage. We summarize emerging evidence implicating the endoplasmic reticulum (ER) stress response in AEC apoptosis in patients with idiopathic pulmonary fibrosis (IPF), a disease with similarities to asbestosis. Finally, we discuss a recent finding that a mitochondrial oxidative DNA repair enzyme (8-oxoguanine DNA glycosylase; Ogg1) acts as a mitochondrial aconitase chaperone protein to prevent oxidant (asbestos and H(2)O(2))-induced AEC mitochondrial dysfunction and intrinsic apoptosis. The coupling of mitochondrial Ogg1 to mitochondrial aconitase is a novel mechanism linking metabolism to mitochondrial DNA that may be important in the pathophysiologic events resulting in oxidant-induced toxicity as seen in tumors, aging, and respiratory disorders (e.g. asbestosis, IPF). Collectively, these studies are illuminating the molecular basis of AEC apoptosis following asbestos exposure that may prove useful for developing novel therapeutic strategies. Importantly, the asbestos paradigm is elucidating pathophysiologic insights into other more common pulmonary diseases, such as IPF and lung cancer, for which better therapy is required.
Liu
Gang
G
Department of Medicine, Pulmonary & Critical Care Medicine, Jesse Brown VA Medical Center and Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Beri
Rohinee
R
Mueller
Amanda
A
Kamp
David W
DW
D000818:Animals; D017209:Apoptosis; D001194:Asbestos / Q000633:toxicity*; D001195:Asbestosis / Q000473:pathology*; D002273:Carcinogens / Q000378:metabolism; D004847:Epithelial Cells / Q000473:pathology*; D006801:Humans; D008168:Lung / Q000473:pathology*
D002273:Carcinogens; D001194:Asbestos