Unfolded Protein Response Signaling and MAP Kinase Pathways Underlie Pathogenesis of Arsenic-Induced Cutaneous Inflammation

Li, Changzhao; Xu, Jiang; Li, Fugui; Chaudhary, Sandeep; Weng, Zhiping; Wen, Ji; Elmets, Craig A.; Ahsan, Habibul; Athar, Mohammad

doi:10.1158/1940-6207.capr-11-0343

Cited by 54 publications

(53 citation statements)

References 22 publications

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“…32 Earlier, we also found that the UPR pathway underlies the pathogenesis of subacute arseniteinduced mild inflammatory responses in the skin. 13 Therefore, together this provides a likely scenario that trivalent arsenic released from metabolic degradation of lewisite may play a significant role in the induction of ER stress. Interestingly, ER stresseregulated pathogenesis is not unique to the toxic manifestations of arsenicals but is important in the pathobiology of multiple diseases.…”

Section: Discussionmentioning

confidence: 99%

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Molecular Mechanism Underlying Pathogenesis of Lewisite-Induced Cutaneous Blistering and Inflammation

Srivastavá

Weng

et al. 2016

The American Journal of Pathology

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Lewisite is a potent arsenic-based chemical warfare agent known to induce painful cutaneous inflammation and blistering. Only a few modestly effective antidotes have so far been described in the literature. However, the discovery of effective antidotes for lewisite was hampered by the paucity of the exact molecular mechanism underlying its cutaneous pathogenesis. We investigated the molecular mechanism underlying lewisite-induced cutaneous blistering and inflammation and describe its novel antidotes. On the basis of our initial screening, we used a highly sensitive murine model that recapitulates the known human pathogenesis of arsenicals-induced cutaneous inflammation and blistering. Topically administered lewisite induced potent acute inflammation and microvesication in the skin of Ptch1 þ/À /SKH-1 mice. Even at a very low dose, lewisite up-regulates unfolded protein response signaling, inflammatory response, and apoptosis. These cutaneous lesions were associated with production of reactive oxygen species and extensive apoptosis of the epidermal keratinocytes. We confirmed that activation of reactive oxygen speciesedependent unfolded protein response signaling is the underlying molecular mechanism of skin damage. Similar alterations were noticed in lewisitetreated cultured human skin keratinocytes. We discovered that chemical chaperone 4ephenyl butyric acid and antioxidant N-acetylcysteine, which significantly attenuate lewisite-mediated skin injury, can serve as potent antidotes. These data reveal a novel molecular mechanism underlying the cutaneous pathogenesis of lewisite-induced lesions. We also identified novel potential therapeutic targets for lewisite-mediated cutaneous injury.

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Section: Discussionmentioning

confidence: 99%

“…13 Briefly, first-strand cDNA synthesis was performed using RT 2 First Strand kit (SABiosciences). PCR was performed with mouse inflammatory cytokines and receptor PCR Arrays on a 7500 fast real-time PCR system (Applied Biosystems, Foster City, CA) using RT 2 qPCR Master Mix.…”

Section: Pcr Arraymentioning

confidence: 99%

Molecular Mechanism Underlying Pathogenesis of Lewisite-Induced Cutaneous Blistering and Inflammation

Srivastavá

Weng

et al. 2016

The American Journal of Pathology

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“…Western blots were performed as previously described (25). The integrated density of bands was measured with ImageJ software (http://rsb.…”

Section: Western Blotmentioning

confidence: 99%

“…ROS levels in lung tissues were measured using the chloromethyl derivative of 29,79-dichlorodihydrofluorescein diacetate (CM-H2DCFDA, c6827; Invitrogen Life Technologies, Grand Island, NY) as described previously (25).…”

Section: Measurements Of Rosmentioning

confidence: 99%

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Chlorine Induces the Unfolded Protein Response in Murine Lungs and Skin

Li¹,

Weng²,

Doran

et al. 2013

Am J Respir Cell Mol Biol

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Chlorine (Cl 2 ) is an important industrial chemical. Accidental full body exposure to Cl 2 poses an environmental, occupational, and public health hazard characterized mainly by injury to the lung, skin, and ocular epithelia. The cellular mechanisms underlying its acute toxicity are incompletely understood. This study examined whether whole body exposure of BALB/c mice to Cl 2 in environmental chambers leads to the up-regulation of the unfolded protein response (UPR) in their lungs and skin. Shaved BALB/c mice were exposed to a sublethal concentration of Cl 2 (400 ppm for 30 min) and returned to room air for 1 or 6 hours and killed. IL-6 and TNF-a were increased significantly at 1 and 6 hours after Cl 2 exposure in the lungs and at 6 hours in the skin. These changes were accompanied by increased UPR signaling (i.e., activation of protein kinase RNA-like endoplasmic reticulum kinase, inositol-requiring enzyme 1 a, and activating transcription factor 6a) at these time points. The expression of hepcidin, which regulates tissue accumulation and mobilization of iron, was increased in the skin and lungs of Cl 2 -exposed mice. The data shown herein indicate for the first time the up-regulation of UPR signaling and hepcidin in the skin and lungs of Cl 2 -exposed mice, which persisted when the mice were returned to room air for 6 hours.Key words: hepcidin; inflammation; unfolded protein response; TNF-a; IL-6Chlorine gas (Cl 2 ) is an important industrial chemical (1). In the United States, Europe, and other parts of the world, several million tons of Cl 2 are produced annually. Its accidental release in the atmosphere may cause significant mortality and morbidity to humans and animals. Its exposure primarily leads to pulmonary edema and to restrictive and obstructive lung diseases. Other clinical symptoms include dyspnea, cough, pneumonitis, cyanosis, nausea, vomiting, and loss of consciousness (2-6).Cl 2 is a strong oxidant. Its exposure rapidly augments reactive oxygen species (ROS) generation and depletes tissue antioxidants such as glutathione and ascorbic acid (7-9). It manifests its toxicity via oxidative damage to lung epithelial cells, leading to egress of plasma proteins from the vascular to the alveolar spaces, production of inflammatory mediators, influxes of neutrophils into lung tissue, and reactive airway disease syndrome (10-13). Systemic injury, characterized by inflammation and inactivation of nitric oxide synthase, has also been reported (14). Postexposure administration of ascorbate and deferoxamine in mice exposed to 600 ppm Cl 2 for 45 minutes decreased mortality, injury to the bloodgas barrier, and lipid peroxidation (2, 9). Similarly, postexposure administration of AEOL10150, a peroxynitrite scavenger, in Cl 2 -treated mice decreased airway hyperresponsiveness, inflammation, and 4-hydroxynonenal level, a marker of lipid peroxidation (15).Many groups have investigated the molecular mechanisms of Cl 2 toxicity in humans and in experimental animals, with the goal of developing novel and molecular tar...

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