Genotoxic effects of neutrophils and hypochlorous acid

Abstract

Chronic inflammation has been recognized as a contributing factor in the pathogenesis of lung cancer. In this process, reactive oxygen species released by neutrophils may play an important role. The aim of the present study was to investigate the capacity of the major neutrophilic oxidant hypochlorous acid (HOCl), which is formed by myeloperoxidase (MPO), to induce DNA damage and mutagenicity in lung cells. HOCl was mutagenic in lung epithelial A549 cells in vitro, showing at physiological concentrations a significant induction of mutations in the HPRT gene. We studied three major types of DNA lesions that could be relevant for this HOCl-induced mutagenicity. Single strand DNA breakage and 8-oxo-7,8-dihydro-2'-deoxyguanosine were not found to be increased following HOCl treatment. On the other hand, HOCl caused a significant increase in the formation of 3-(2-deoxy-beta-D-erythro-pentofuranosyl)pyrimido[1,2-alpha]purin-10(3H)-one (M(1)dG), which can be formed by either malondialdehyde (MDA) or base propenals. We observed an increased MDA formation upon exposure of A549 cells to HOCl, but a role of base propenals cannot be excluded. In line with this, we observed 4-fold increased M(1)dG adduct levels in mice that were intratracheally instilled with lipopolysaccharide to induce a pulmonary inflammation with neutrophil influx. Depletion of circulating neutrophils significantly reduced pulmonary MPO activity as well as M(1)dG adducts levels, thereby providing a causal link between neutrophils/HOCl and pulmonary genotoxicity in vivo. Taken together, these data indicate that MPO catalysed formation of HOCl during lung inflammation should be considered as a significant source of neutrophil-induced genotoxicity.

Formaldehyde-induced toxicity in the nasal epithelia of workers of a plastic laminate plant

“…53,55 FA exposure also leads to inflammation and to a consequent excess of ROS. 31,56 ROS, as hydrogen peroxide and hypochlorite acid, are indeed generated from the oxidative burst of activated alveolar macrophages and neutrophils. 31 The genomic mechanisms of instability and the cellular tolerance pathways associated with FA exposure seem to be a key point in the mutation arising, even if it is not fully characterized.…”

“…31,56 ROS, as hydrogen peroxide and hypochlorite acid, are indeed generated from the oxidative burst of activated alveolar macrophages and neutrophils. 31 The genomic mechanisms of instability and the cellular tolerance pathways associated with FA exposure seem to be a key point in the mutation arising, even if it is not fully characterized. 57 Many studies have shown that FA is genotoxic and mutagenic in vitro in various kinds of mammalian cells including cultured human blood and human nasal epithelial cells.…”

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…Indeed, neutrophils were shown to directly promote tumorigenesis by causing genomic instability [257]. Neutrophil-induced genotoxicity has been related to induction of oxidative DNA damage through release of ROS and myeloperoxidase-related metabolites [258][259][260]. In addition, neutrophils were shown to promote experimental chronic colitis-associated carcinogenesis in mice [261].…”

CXCL-8/IL8 Produced by Diffuse Large B-cell Lymphomas Recruits Neutrophils Expressing a Proliferation-Inducing Ligand APRIL

“…Neutrophils have been reported to increase cancer genetic instability by their production of nitric oxide derivatives and reactive oxygen species (5), to promote angiogenesis by their secretion of pro-angiogenic factors (6,7), and also to produce immunosuppressive factors, such as IL-10 (8). For all these reasons, neutrophil infiltration of several solid tumors has been associated with a poorer outcome for patients (9).…”