Endothelial response to stress from exogenous Zn<sup>2+</sup> resembles that of NO-mediated nitrosative stress, and is protected by MT-1 overexpression

Wiseman, Dean A.; Wells, Sandra M.; Wilham, Jason M.; Hubbard, Maryann; Welker, Jonathan E.; Black, Stephen M.

doi:10.1152/ajpcell.00509.2005

Cited by 69 publications

(72 citation statements)

References 57 publications

(71 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We demonstrated that apical exposure to ZnO NPs for 24 hours reduced mitochondrial activity ( Figure 12). Mitochondrial dysfunction is partly associated with depletion of sulfhydryl groups in metallothionein-1 proteins caused by excess Zn 21 arising from dissolved ZnO NPs (43,44). Our data suggest that excess free Zn 21 (from dissolved ZnO NPs) disrupts zincprotein interactions in mitochondria, leading to disruption of mitochondrial redox state and an increase in intracellular ROS levels, resulting in cell plasma membrane damage and cell injury.…”

Section: Discussionmentioning

confidence: 79%

“…Excess Zn 21 in mammalian cells is toxic, although a trace amount of Zn 21 serves as an effective antioxidant and a critical structural and functional component of zinc-binding proteins (40,41). Impaired mitochondrial function due to increased intracellular Zn 21 causes elevated intracellular ROS, leading to apoptotic or necrotic cell death (42)(43)(44). Recently, Nel and colleagues (30) reported that cytotoxicity of ZnO NPs may be directly related to dissolution of ZnO NPs suspended in bathing medium of RAW 264.7 and BEAS-2B cells, and Lin and colleagues (24) showed that viability of A549 cells is reduced in a dose-and time-dependent manner after apical exposure to ZnO NPs.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Alveolar Epithelial Cell Injury Due to Zinc Oxide Nanoparticle Exposure

Kim¹,

Fazlollahi²,

Kennedy³

et al. 2010

Am J Respir Crit Care Med

View full text Add to dashboard Cite

Rationale: Although inhalation of zinc oxide (ZnO) nanoparticles (NPs) is known to cause systemic disease (i.e., metal fume fever), little is known about mechanisms underlying injury to alveolar epithelium. Objectives: Investigate ZnO NP-induced injury to alveolar epithelium by exposing primary cultured rat alveolar epithelial cell monolayers (RAECMs) to ZnO NPs. Methods: RAECMs were exposed apically to ZnO NPs or, in some experiments, to culture fluid containing ZnCl 2 or free Zn released from ZnO NPs. Transepithelial electrical resistance (R T ) and equivalent short-circuit current (I EQ ) were assessed as functions of concentration and time. Morphologic changes, lactate dehydrogenase release, cell membrane integrity, intracellular reactive oxygen species (ROS), and mitochondrial activity were measured. Measurements and Main Results: Apical exposure to 176 mg/ml ZnO NPs decreased R T and I EQ of RAECMs by 100% over 24 hours, whereas exposure to 11 mg/ml ZnO NPs had little effect. Changes in R T and I EQ caused by 176 mg/ml ZnO NPs were irreversible. ZnO NP effects on R T yielded half-maximal concentrations of approximately 20 mg/ml. Apical exposure for 24 hours to 176 mg/ml ZnO NPs induced decreases in mitochondrial activity and increases in lactate dehydrogenase release, permeability to fluorescein sulfonic acid, increased intracellular ROS, and translocation of ZnO NPs from apical to basolateral fluid (most likely across injured cells and/or damaged paracellular pathways). Conclusions: ZnO NPs cause severe injury to RAECMs in a dose-and time-dependent manner, mediated, at least in part, by free Zn released from ZnO NPs, mitochondrial dysfunction, and increased intracellular ROS.Keywords: epithelial monolayers; zinc toxicity; reactive oxygen species; mitochondrial damage; plasma membrane integrity Nanoparticles (NPs) are used in many commercial products and new applications in biomedicine, yet their fate, potential toxicity, and mechanisms of translocation in biological cells, tissues, and organs (including the lung) have not been well defined. Some, but not all, inhaled NPs (including ambient ultrafine particulates that overlap in size with NPs) have been reported to be associated with adverse health effects (1, 2). There is evidence that measurable amounts of these inhaled NPs are found in end organs (e.g., liver, spleen, and heart) after inhalation (3-6), possibly leading to thrombosis, atherogenesis, and cardiac dysrhythmias (3,7,8). NPs found in end organs after inhalation are most likely to enter the systemic circulation across the epithelia of the lung, especially the alveolar epithelium, which constitutes a very thin biological barrier (z0.5 mm) and affords greater than 95% of the surface area (z100 m 2 in humans) in distal airspaces of the lung.Of the NPs and ambient ultrafine particulates studied to date, several metal (e.g., Fe, Zn, V, and Ni) and metal oxide (Fe 2 O 3, ZnO, V 2 O 5 , and NiO) NPs have the potential to cause inflammation and injury in lungs (9-12). Among metal and metal oxide NPs i...

show abstract

Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Alveolar Epithelial Cell Injury Due to Zinc Oxide Nanoparticle Exposure

Kim¹,

Fazlollahi²,

Kennedy³

et al. 2010

Am J Respir Crit Care Med

View full text Add to dashboard Cite

show abstract

“…The identification of Zn 2ϩ as a potent intracellular TRPA1 activator makes it likely that cellular stressors that increase [Zn 2ϩ ] i (44,45) will activate TRPA1 and affect the excitability of neurons. Our results also raise the possibility that TRPA1 can be activated indirectly in response to Zn 2ϩ entry through other neuronal ion channels, such as L-type Ca 2ϩ and AMPA/kainate channels (23,46), which are expressed by DRG neurons (47)(48)(49).…”

Section: Discussionmentioning

confidence: 99%

Clioquinol and pyrithione activate TRPA1 by increasing intracellular Zn ²⁺

Andersson

Gentry²,

Moss³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

122

109

View full text Add to dashboard Cite

The antifungal and amoebicidal drug clioquinol (CQ) was withdrawn from the market when it was linked to an epidemic of subacute myelo-optico-neuropathy (SMON). Clioquinol exerts its anti-parasitic actions by acting as a Cu/Zn chelator and ionophore. Here we show that local injections of CQ produce mechanical hyperalgesia and cold hypersensitivity through a mechanism involving TRPA1 in mice. We also show that CQ activates TRPA1 in a Zn 2؉ pain ͉ sensory neurons ͉ TRP channels ͉ zinc T he antifungal and amoebicidal drug clioquinol (CQ) was once widely used to treat gastrointestinal disorders, but was withdrawn from oral preparations when CQ was linked to an epidemic of subacute myelo-optico-neuropathy (SMON) in Japanese patients. Patients with SMON suffer from sensory and motor disorders and visual impairment. Thirty years after the ban of oral CQ, 40% of patients with SMON are unable to walk independently and approximately 7% suffer from visual impairment. The most common complaints, however, have been different forms of sensory impairments, such as tactile hypo-and hypersensitivity (almost 90% of patients) and dysesthesias (97%) (1). Notably, almost 50% of patients experience pain and 40% have cold sensitivity. CQ also has acute sensory effects, and studies on isolated nociceptive fibers in dogs demonstrated that CQ recruited normally quiescent fibers to become sensitive to hyperosmotic stimuli and cold (2), suggesting a direct effect on sensory nerves.CQ exerts its anti-parasitic actions by acting as a moderate affinity Cu/Zn chelator and ionophore. The ionophore activity of CQ contributes to its neurotoxicity (3, 4), but also makes it a useful drug for the treatment of acrodermatitis enteropathica, a rare genetic disorder characterized by insufficient Zn 2ϩ uptake (5, 6). More recently CQ has been shown to reduce Cu/Zn deposits and beta-amyloid accumulation in transgenic mouse models of Alzheimer's disease (7,8), findings that have led to clinical trials of CQ in Alzheimer's patients (9, 10).TRPA1 is expressed in a subpopulation of dorsal root ganglion (DRG) neurons, where it acts as a sensory receptor for environmental irritants and both oxidation and thiol-reactive compounds, some of which are produced endogenously during oxidative stress (11-15). Furthermore, TRPA1 can be activated by increasing the osmolarity of the extracellular solution (16).Transgenic mice lacking TRPA1 have a reduced sensitivity to cold stimuli and punctate mechanical stimulation (17), in addition to a reduced chemical sensitivity to irritants and oxidants (11,12,17,18). The similarity between the modalities affected by CQ in nociceptive fibers (increased sensitivity to cold stimulation and hyperosmotic solutions) and the behavioral deficits of mice lacking TRPA1 (reduced sensitivity to painful cold and mechanical stimuli) led us to examine whether CQ can induce pain behavior acutely in mice through the activation of TRPA1. ResultsPronociceptive Effects of Clioquinol. Tactile and cold hypersensitivity are very common symptoms in pati...

show abstract

“…9). These considerations suggest that when the proton pump is disabled accumulation of Zn 2ϩ during different forms of cellular stress (38,43) could lead to undue or untimely accumulation of Zn 2ϩ in the cytoplasm, and thence to a variety of disturbances in cell viability and function (36,37).…”

Section: Discussionmentioning

confidence: 99%