Chlorinated Benzenes Cause Concomitantly Oxidative Stress and Induction of Apoptotic Markers in Lung Epithelial Cells (A549) at Nonacute Toxic Concentrations

Mörbt, Nora; Tomm, Janina M.; Feltens, Ralph; Mögel, Iljana; Kalkhof, Stefan; Murugesan, Kalaimathi; Wirth, Henry; Vogt, Carsten; Binder, Hans; Lehmann, Irina; Bergen, Martin von

doi:10.1021/pr1005718

Cited by 32 publications

(24 citation statements)

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“…The proteomic profiling of Jurkat T-leukemia cells either left untreated or treated with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) known to induce ROS and subsequently autophagy demonstrated an altered expression pattern of enzymes involved in the energy metabolism, the cellular redox control and anti-oxidative proteins [16]. A similar response pattern was also found in hepatoma or lung carcinoma cells challenged with the carcinogen benzo(a)pyrene or chlorinated benzenes, respectively, leading to massive oxidative stress [27], [28]. This data suggest that massive oxidative stress might rather trigger common response pattern, almost independent from the initiating stimuli.…”

Section: Discussionmentioning

confidence: 90%

Comparative Expression Profiling of Distinct T Cell Subsets Undergoing Oxidative Stress

et al. 2012

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The clinical outcome of adoptive T cell transfer-based immunotherapies is often limited due to different escape mechanisms established by tumors in order to evade the hosts' immune system. The establishment of an immunosuppressive micromilieu by tumor cells along with distinct subsets of tumor-infiltrating lymphocytes is often associated with oxidative stress that can affect antigen-specific memory/effector cytotoxic T cells thereby substantially reducing their frequency and functional activation. Therefore, protection of tumor-reactive cytotoxic T lymphocytes from oxidative stress may enhance the anti-tumor-directed immune response. In order to better define the key pathways/proteins involved in the response to oxidative stress a comparative 2-DE-based proteome analysis of naïve CD45RA+ and their memory/effector CD45RO+ T cell counterparts in the presence and absence of low dose hydrogen peroxide (H2O2) was performed in this pilot study. Based on the profiling data of these T cell subpopulations under the various conditions, a series of differentially expressed spots were defined, members thereof identified by mass spectrometry and subsequently classified according to their cellular function and localization. Representative targets responding to oxidative stress including proteins involved in signaling pathways, in regulating the cellular redox status as well as in shaping/maintaining the structural cell integrity were independently verified at the transcript and protein level under the same conditions in both T cell subsets. In conclusion the resulting profiling data describe complex, oxidative stress-induced, but not strictly concordant changes within the respective expression profiles of CD45RA+ and CD45RO+ T cells. Some of the differentially expressed genes/proteins might be further exploited as potential targets toward modulating the redox capacity of the distinct lymphocyte subsets thereby providing the basis for further studies aiming at rendering them more resistant to tumor micromilieu-induced oxidative stress.

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Section: Discussionmentioning

confidence: 90%

Comparative Expression Profiling of Distinct T Cell Subsets Undergoing Oxidative Stress

et al. 2012

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“…Multiple post-translational modifications of NPM are known, including acetylation, phosphorylation (≥ 6 sites), SUMOylation, ubiquitination, and poly-(ADP-ribosyl)-ation, and are variously associated with specific functions and/or subcellular localizations of NPM. Cellular levels of NPM increase three-fold upon exposure of human lung epithelial cells to chlorobenzene and 1,2-dichlorobenzene (both of which are significantly hepatotoxic as well as pneumotoxic) (59). NPM is one of several proteins that become glutathionylated in 3T3 cells upon treatment with a nitric-oxide releasing prodrug, and this covalent modification was linked to the activation of kinases associated with stress response and cell death pathways including p38, JNK and c-jun (60).…”

Section: Resultsmentioning

confidence: 99%

Identification of Protein Targets of Reactive Metabolites of Tienilic Acid in Human Hepatocytes

Koen

Sarma²,

Williams³

et al. 2012

Chem. Res. Toxicol.

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Tienilic acid (TA) is a uricosuric diuretic that was withdrawn from the market only months after its introduction because of reports of serious incidents of drug-induced liver injury including some fatalities. Its hepatotoxicity is considered to be primarily immunoallergic in nature. Like other thiophene compounds, TA undergoes biotransformation to a S-oxide metabolite which then reacts covalently with cellular proteins. To identify protein targets of TA metabolites, we incubated [14C]-TA with human hepatocytes, separated cellular proteins by 2D gel electrophoresis, and analyzed proteins in 36 radioactive spots by tryptic digestion followed by LC-MS/MS. Thirty one spots contained at least one identifiable protein. Sixteen spots contained only one of 14 non-redundant proteins which were thus considered to be targets of TA metabolites. Six of the 14 were also found in other radioactive spots that contained from 1 to 3 additional proteins. Eight of the 14 had not been reported to be targets for any reactive metabolite other than TA. The other 15 spots each contained from 2–4 identifiable proteins, many of which are known targets of other chemically reactive metabolites, but since adducted peptides were not observed, the identity of the adducted protein(s) in these spots is ambiguous. Interestingly, all the radioactive spots corresponded to proteins of low abundance, while many highly abundant proteins in the mixture showed no radioactivity. Furthermore, of approximately 16 previously reported protein targets of TA in rat liver (Methogo, R., Dansette, P. and Klarskov, K. (2007) Int. J. Mass Spectrom., 268, 284–295), only one (fumarylacetoacetase) is among the 14 targets identified in this work. One reason for this difference may be statistical, given that each study identified a small number of targets from among thousands present in hepatocytes. Another may be the species difference (i.e. rat vs. human), and still another may be the method of detection of adducted proteins (i.e. Western blot vs. C-14). Knowledge of human target proteins is very limited. Of more than 350 known protein targets of reactive metabolites, only 42 are known from human and only 21 of these are known to be targets for more than one chemical. Nevertheless, the demonstration that human target proteins can be identified using isolated hepatocytes in vitro should enable the question of species differences to be addressed more fully in the future.

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“…Several in vitro studies using human alveolar epithelial cells have shown that exposure to single aromatic VOCs induces an inflammatory response via oxidative stress and NFκB activation [15], [26], [48], [49]. Oxidative stress, the imbalance between reactive oxygen species (ROS) and antioxidants, has been shown to play an important role in the pathogenesis of asthma and airway inflammation [50].…”

Section: Discussionmentioning

confidence: 99%

Volatile Organic Compounds Enhance Allergic Airway Inflammation in an Experimental Mouse Model

et al. 2012

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BackgroundEpidemiological studies suggest an association between exposure to volatile organic compounds (VOCs) and adverse allergic and respiratory symptoms. However, whether VOCs exhibit a causal role as adjuvants in asthma development remains unclear.MethodsTo investigate the effect of VOC exposure on the development of allergic airway inflammation Balb/c mice were exposed to VOCs emitted by new polyvinylchloride (PVC) flooring, sensitized with ovalbumin (OVA) and characterized in acute and chronic murine asthma models. Furthermore, prevalent evaporated VOCs were analyzed and mice were exposed to selected single VOCs.ResultsExposure of mice to PVC flooring increased eosinophilic lung inflammation and OVA-specific IgE serum levels compared to un-exposed control mice. The increased inflammation was associated with elevated levels of Th2-cytokines. Long-term exposure to PVC flooring exacerbated chronic airway inflammation. VOCs with the highest concentrations emitted by new PVC flooring were N-methyl-2-pyrrolidone (NMP) and 2,2,4-trimethyl-1,3-pentanediol diisobutyrate (TXIB). Exposure to NMP or TXIB also increased the allergic immune response in OVA-sensitized mice. In vitro or in vivo exposure to NMP or TXIB reduced IL-12 production in maturing dendritic cells (DCs) and enhanced airway inflammation after adoptive DC transfer into Balb/c mice. At higher concentrations both VOCs induced oxidative stress demonstrated by increased isoprostane and glutathione-S-transferase-pi1 protein levels in the lung of non-sensitized mice. Treatment of PVC flooring-exposed mice with N-acetylcysteine prevented the VOC-induced increase of airway inflammation.ConclusionsOur results demonstrate that exposure to VOCs may increase the allergic immune response by interfering with DC function and by inducing oxidative stress and has therefore to be considerate as risk factor for the development of allergic diseases.

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Chlorinated Benzenes Cause Concomitantly Oxidative Stress and Induction of Apoptotic Markers in Lung Epithelial Cells (A549) at Nonacute Toxic Concentrations

Cited by 32 publications

References 93 publications

Comparative Expression Profiling of Distinct T Cell Subsets Undergoing Oxidative Stress

Comparative Expression Profiling of Distinct T Cell Subsets Undergoing Oxidative Stress

Identification of Protein Targets of Reactive Metabolites of Tienilic Acid in Human Hepatocytes

Volatile Organic Compounds Enhance Allergic Airway Inflammation in an Experimental Mouse Model

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