Asbestos-induced pulmonary toxicity: role of DNA damage and apoptosis.
Asbestos causes asbestosis and various malignancies by mechanisms that are not clearly defined. Here, we review the accumulating evidence showing that asbestos is directly genotoxic by inducing DNA strand breaks (DNA-SB) and apoptosis in relevant lung target cells. Although the exact mechanisms by which asbestos causes DNA damage and apoptosis are not firmly established, some of the implicated mechanisms include the generation of iron-derived reactive oxygen species (ROS) as well as reactive nitrogen species (RNS), alteration in the mitochondrial function, and activation of the death receptor pathway. We focus on the accumulating evidence implicating ROS. DNA repair mechanisms have a key role in limiting the extent of DNA damage. Recent studies show that asbestos activates DNA repair enzymes such as apurinic/apyrimidinic endonuclease (APE) and poly (ADP-ribose) polymerase (PARP). Asbestos-induced neoplastic transformation may result in the setting where DNA damage overwhelms DNA repair in the face of a persistent proliferative signal. Strategies aimed at limiting asbestos-induced oxidative stress may reduce DNA damage and, as such, prevent malignant transformation.
Upadhyay
Daya
D
Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
Kamp
David W
DW
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001194:Asbestos / Q000009:adverse effects* / Q000737:chemistry; D001195:Asbestosis / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D004249:DNA Damage / Q000502:physiology*; D004260:DNA Repair; D004789:Enzyme Activation / Q000187:drug effects; D004798:Enzymes / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D004798:Enzymes; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D001194:Asbestos; D007501:Iron