Comparisons of the pro-oxidant and proinflammatory effects of organic diesel exhaust particle chemicals in bronchial epithelial cells and macrophages

Division of Clinical Immunology and Allergy, Department of Medicine, University of California-Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
The Journal of Immunology (Impact Factor: 5.36). 11/2002; 169(8):4531-41. DOI: 10.4049/jimmunol.169.8.4531
Source: PubMed

ABSTRACT Inhaled diesel exhaust particles (DEP) exert proinflammatory effects in the respiratory tract. This effect is related to the particle content of redox cycling chemicals and is involved in the adjuvant effects of DEP in atopic sensitization. We demonstrate that organic chemicals extracted from DEP induce oxidative stress in normal and transformed bronchial epithelial cells, leading to the expression of heme oxygenase 1, activation of the c-Jun N-terminal kinase cascade, IL-8 production, as well as induction of cytotoxicity. Among these effects, heme oxygenase 1 expression is the most sensitive marker for oxidative stress, while c-Jun N-terminal kinase activation and induction of apoptosis-necrosis require incremental amounts of the organic chemicals and increased levels of oxidative stress. While a macrophage cell line (THP-1) responded in similar fashion, epithelial cells produced more superoxide radicals and were more susceptible to cytotoxic effects than macrophages. Cytotoxicity is the result of mitochondrial damage, which manifests as ultramicroscopic changes in organelle morphology, a decrease in the mitochondrial membrane potential, superoxide production, and ATP depletion. Epithelial cells also differ from macrophages in not being protected by a thiol antioxidant, N-acetylcysteine, which effectively protects macrophages against cytotoxic DEP chemicals. These findings show that epithelial cells exhibit a hierarchical oxidative stress response that differs from that of macrophages by more rapid transition from cytoprotective to cytotoxic responses. Moreover, epithelial cells are not able to convert N-acetylcysteine to cytoprotective glutathione.

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    • "After the particles or pathogens have eluded or overwhelmed the epithelial barrier of the upper airways, they come into contact with the dedicated antigen presenting dendritic cells (DCs) (e.g. Steinman and Cohn, 1973; Nicod, 1997; Lipscomb and Masten, 2002; Holt, 2005) which are highly phagocytic (Dreher et al., 2001; Kiama et al., 2001, 2006; Walter et al., 2001). If they reach the alveolar surface, they are dealt with by the PSMs (e.g. "
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    • "While activation of p38 MAPK was analyzed 2 and 4 h after the addition of OE, COX-2 protein was determined at the 16-h time point [16] [21] [27]. Cell lysate preparation, protein assay and western blot were performed as previously described [15] [27] [28]. HO-1, phosphorylated p38, total p38, COX- 2, and ␤-actin proteins were detected using respective primary Abs (1:1000) followed by horseradish peroxidaseconjugated secondary Abs (1:1000). "
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    Toxicology Reports 12/2014; 1. DOI:10.1016/j.toxrep.2014.09.015
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    • "Interestingly, co-treatment with a physiologic dose (500 mM) of NAC markedly lowered the cytogenotoxic effects of PbNO3in vitro. Other studies indicated that NAC protects macrophage cell line (THP-1) against diesel exhaust particle chemicals [17]. Yang and his co-workers [41] also reported that NAC lowers DNA damage produced by water-soluble cigarette smoke in human lymphoid cells containing Epstein-Barr virus episomes. "
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    ABSTRACT: The investigation of the environmental contribution for developmental neurotoxicity is very critical. Many environmental chemical exposures are now thought to contribute to the development of neurological disorders, especially in children. Results from animal studies may guide investigations of human populations towards identifying either environmental toxicants that cause or drugs that protect from neurotoxicity and may help in treatment of neurodevelopmental disorders. To study both the protective and therapeutic effects of N-acetyl cysteine on brain intoxication induced by propionic acid (PPA) in rats. Twenty-eight young male Western Albino rats were enrolled in the present study. They were grouped into four equal groups, each of 7 animals. Group 1: control group, orally received only phosphate buffered saline; Group 2: PPA-treated group, received a neurotoxic dose of of PPA of 250 mg/kg body weight/day for 3 days; Group 3: protective group, received a dose of 50 mg/kg body weight/day N-acetyl-cysteine for one week followed by a similar dose of PPA for 3 days; and Group 4: therapeutic group, treated with the same dose of N-acetyl cysteine after being treated with the toxic dose of PPA. Serotonin, interferon gamma (IFN-γ), and glutathione-s-transferase activity, together with Comet DNA were assayed in the brain tissue of rats in all different groups. The obtained data showed that PPA caused multiple signs of brain toxicity as measured by depletion of serotonin (5HT), increase in IFN-γ and inhibition of glutathione-s-transferase activity as three biomarkers of brain dysfunction. Additionally Comet DNA assay showed remarkably higher tail length, tail DNA % damage and tail moment. N-acetyl-cysteine was effective in counteracting the neurotoxic effects of PPA. The low dose and the short duration of N-acetyl-cysteine treatment tested in the present study showed much more protective rather than therapeutic effects on PPA-induced neurotoxicity in rats, as there was a remarkable amelioration in the impaired biochemical parameters representing neurochemical, inflammatory, detoxification and DNA damage processes.
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