Neutrophils and respiratory tract DNA damage and mutagenesis: a review.
Inflammation has been recognized as an important factor in cancer development. For the lung, experimental studies with rats, as well as molecular epidemiological studies in humans, have provided evidence that the influx of neutrophils into the airways may be an important process linking inflammation with carcinogenesis. Currently it is believed that the genotoxic capacity of neutrophils is a crucial aetiological factor in this carcinogenic response. In the present review we discuss two major pathways of neutrophil-induced genotoxicity: (i) induction of oxidative DNA damage through release of reactive oxygen species (ROS) and (ii) myeloperoxidase (MPO)-related metabolic activation of chemical carcinogens. So far, direct evidence for a role of neutrophils in pulmonary genotoxicity has largely been derived from in vitro studies using co-cultures of activated neutrophils and target cells. Current evidence from in vivo studies is primarily indirect and additional animal studies are needed to substantiate causality. A further challenge will be to extrapolate results from such studies to humans. Taken together, this will provide a better insight into the role of neutrophils in pulmonary carcinogenicity and may, hence, lead to novel approaches for cancer prevention strategies.
Knaapen
Ad M
AM
Nutrition and Toxicology Research Institute, Department of Health Risk Analysis and Toxicology, Maastricht University, Maastricht, The Netherlands. a.knaapen@GRAT.unimaas.nl
Güngör
Nejla
N
Schins
Roel P F
RP
Borm
Paul J A
PJ
Van Schooten
Frederik J
FJ
D000818:Animals; D018920:Coculture Techniques; D004249:DNA Damage; D006801:Humans; D007249:Inflammation; D008954:Models, Biological; D008956:Models, Chemical; D016296:Mutagenesis; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D018375:Neutrophil Activation; D009504:Neutrophils / Q000378:metabolism / Q000502:physiology*; D018384:Oxidative Stress; D009195:Peroxidase / Q000378:metabolism; D017382:Reactive Oxygen Species; D012137:Respiratory System / Q000378:metabolism*
D017382:Reactive Oxygen Species; D009195:Peroxidase