Oxidative stress (OS) has been implicated in the pathogenesis of autoimmune diseases (ADs), including systemic lupus erythematosus (SLE), and a large number of environmental chemicals are known to cause OS. Our long-term goal is to elucidate the role of OS in the development of ADs that are induced by environmental chemicals, and use this information to design preventive or therapeutic strategies. Trichloroethene (TCE) has been implicated in causing ADs, including SLE-like diseases in humans. Previously, we have established an association between TCE-mediated OS and autoimmune response/SLE. This competitive continuation application is based on the premise that TCE exposure affects diverse OS-responsive pathways to lead to a pathogenic response. We hypothesize that TCE-induced oxidative stress causes impairment in PARP-1 and Nrf-2 expression, leading to a harmful inflammatory/autoimmune response. Furthermore, lipid-derived reactive aldehydes (LDRAs) cause structural modifications to endogenous proteins, resulting in the formation of neoantigens which, via lymphocyte activation, contribute to ADs. To test our hypothesis, the following specific aims are proposed:
Aim 1 will define the role of PARP-1 activation in TCE-mediated autoimmunity/SLE and will test the hypothesis that TCE-induced activation of PARP-1 leads to a pro-inflammatory response and confers higher susceptibility for SLE/autoimmunity. Studies in this aim will establish a clear link between PARP-1 activation and TCE-mediated autoimmunity/SLE, determine that modulation of PARP-1 abrogates TCE- mediated autoimmune response, and examine PARP-1's potential to act as a coactivator of NF-kB-mediated transcription of pro-inflammatory mediators/cytokines.
Aim 2 will determine that impaired Nrf2 expression plays a critical role in the pathogenesis of TCE-mediated SLE, and will test the hypothesis that reduced expression of Nrf2 exacerbates the development of TCE-mediated lupus nephritis. Nrf2 activation will likely attenuate inflammation and disease pathogenesis. Studies in this aim will establish that absence of Nrf2 exacerbates TCE-mediated autoimmune response, and also determine that antioxidant sulforaphane (SFN) ameliorates TCE-mediated SLE by upregulating Nrf2.
Aim 3 will elucidate that lipid-derived reactive aldehydes (LDRAs) contribute to TCE-mediated SLE, and will test the hypothesis that LDRA modification of endogenous proteins results in the formation of neo-antigens, which by activating lymphocytes can elicit an autoimmune response. We will determine that LDRA-protein adducts aggravate T cell proliferation, especially Th17 cells, and induce inflammatory cytokines. Furthermore, we will characterize LDRA-protein adducts (proteomic approaches) and determine their autoimmune potential. Our studies will firmly establish a role for OS in the induction and/or exacerbation of autoimmunity/SLE, will delineate novel mechanisms of pathogenesis, and will serve as a stepping stone to translational strategies to prevent autoimmune responses to TCE and other chemicals/drugs known to cause toxicity via OS.

Public Health Relevance

Trichloroethene (TCE) is an extensively used organic solvent, especially for degreasing metals. A sizable human population is continuously exposed to this chemical both environmentally and occupationally. TCE has been implicated in causing autoimmune diseases, including lupus (SLE)-like diseases in humans. The goal of this proposal is to dissect pathways, especially responsive to oxidative stress, that contribute to TCE-mediated autoimmune diseases. The proposed work will present opportunities for new therapeutics that particularly target oxidative stress-responsive novel pathways.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Systemic Injury by Environmental Exposure (SIEE)
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Humble, Michael C
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University of Texas Med Br Galveston
Schools of Medicine
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Khan, M Firoze; Wang, Gangduo (2018) Environmental Agents, Oxidative Stress and Autoimmunity. Curr Opin Toxicol 7:22-27
Wang, Gangduo; Wakamiya, Maki; Wang, Jianling et al. (2015) iNOS null MRL+/+ mice show attenuation of trichloroethene-mediated autoimmunity: contribution of reactive nitrogen species and lipid-derived reactive aldehydes. Free Radic Biol Med 89:770-6
Fan, Xiuzhen; Wang, Gangduo; English, Robert D et al. (2014) Proteomic identification of carbonylated proteins in the kidney of trichloroethene-exposed MRL+/+ mice. Toxicol Mech Methods 24:21-30
Wang, Gangduo; Wang, Jianling; Luo, Xuemei et al. (2014) Nitrosative stress and nitrated proteins in trichloroethene-mediated autoimmunity. PLoS One 9:e98660
Wang, Gangduo; Wang, Jianling; Ma, Huaxian et al. (2013) N-Acetylcysteine protects against trichloroethene-mediated autoimmunity by attenuating oxidative stress. Toxicol Appl Pharmacol 273:189-95
Wang, Gangduo; Li, Hui; Firoze Khan, M (2012) Differential oxidative modification of proteins in MRL+/+ and MRL/lpr mice: Increased formation of lipid peroxidation-derived aldehyde-protein adducts may contribute to accelerated onset of autoimmune response. Free Radic Res 46:1472-81
Wang, Gangduo; Wang, Jianling; Fan, Xiuzhen et al. (2012) Protein adducts of malondialdehyde and 4-hydroxynonenal contribute to trichloroethene-mediated autoimmunity via activating Th17 cells: dose- and time-response studies in female MRL+/+ mice. Toxicology 292:113-22
Wang, Gangduo; Pierangeli, Silvia S; Papalardo, Elizabeth et al. (2010) Markers of oxidative and nitrosative stress in systemic lupus erythematosus: correlation with disease activity. Arthritis Rheum 62:2064-72
Wang, Gangduo; Wang, Jianling; Ma, Huaxian et al. (2009) Increased nitration and carbonylation of proteins in MRL+/+ mice exposed to trichloroethene: potential role of protein oxidation in autoimmunity. Toxicol Appl Pharmacol 237:188-95
Wang, Gangduo; Konig, Rolf; Ansari, G A S et al. (2008) Lipid peroxidation-derived aldehyde-protein adducts contribute to trichloroethene-mediated autoimmunity via activation of CD4+ T cells. Free Radic Biol Med 44:1475-82

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