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Dr. Andrij Holian
University of Montana Missoula, Department of Biomedical and Pharmaceutical Sciences, Missoula, MT 59812, USA

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0 Asbestos
0 Innate Immunity
0 Nanoparticles
0 Silica
0 Particulate Matter

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Silica
Alveolar macrophages
Asbestos
NLRP3 inflammasome
Particulate Matter
Nanoparticles
Lysosomes
Innate Immunity
Macrophage receptors

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Journal article
Published: 07 May 2021 in Methods and Applications in Fluorescence
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ACS Style

Matthew J Sydor; Donald S Anderson; Harmen B B Steele; J B Alexander Ross; Andrij Holian. Fluorescence lifetime imaging microscopy and time-resolved anisotropy of nanomaterial-induced changes to red blood cell membranes. Methods and Applications in Fluorescence 2021, 9, 035002 .

AMA Style

Matthew J Sydor, Donald S Anderson, Harmen B B Steele, J B Alexander Ross, Andrij Holian. Fluorescence lifetime imaging microscopy and time-resolved anisotropy of nanomaterial-induced changes to red blood cell membranes. Methods and Applications in Fluorescence. 2021; 9 (3):035002.

Chicago/Turabian Style

Matthew J Sydor; Donald S Anderson; Harmen B B Steele; J B Alexander Ross; Andrij Holian. 2021. "Fluorescence lifetime imaging microscopy and time-resolved anisotropy of nanomaterial-induced changes to red blood cell membranes." Methods and Applications in Fluorescence 9, no. 3: 035002.

Journal article
Published: 26 March 2021 in Particle and Fibre Toxicology
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Background A very pure multi-walled carbon nanotube (MWCNT) that was shown to have very low toxicity in vitro, was evaluated for lung and systemic effects and distribution following inhalation exposure. Methods B6C3F1/N mice were exposed to varying doses (0, 0.06, 0.2, and 0.6 mg/m3) of the (99.1% carbon) MWCNT by inhalation for 30 days (excluding weekends). Ten days following the last exposure, the lungs and spleen were harvested and processed for histology and immune cell population assessment. In addition, lung lavage cells and fluid were analyzed. Stimulated Raman scattering (SRS) was used to identify particles in the lungs, spleen, kidneys, liver, mediastinal and brachial lymph nodes, and olfactory bulb. Splenic tissue sections were stained with hematoxylin and eosin (H&E) for light microscopic histopathology assessment. Blood plasma was analyzed for cytokines and cathepsins. A section of the spleen was processed for RNA isolation and relative gene expression for 84 inflammation-related cytokines/chemokines. Results Following MWCNT exposure, particles were clearly evident in the lungs, spleens, lymph nodes and olfactory bulbs, (but not livers or kidneys) of exposed mice in a dose-dependent manner. Examination of the lavaged lung cells was unremarkable with no significant inflammation indicated at all particle doses. In contrast, histological examination of the spleen indicated the presence of apoptotic bodies within T cells regions of the white pulp area. Isolated splenic leukocytes had significant changes in various cells including an increased number of proinflammatory CD11b+Ly6C+ splenic cells. The gene expression studies confirmed this observation as several inflammation-related genes were upregulated particularly in the high dose exposure (0.6 mg/m3). Blood plasma evaluations showed a systemic down-regulation of inflammatory cytokines and a dose-dependent up-regulation of lysosomal cathepsins. Conclusions The findings in the lungs were consistent with our hypothesis that this MWCNT exposure would result in minimal lung inflammation and injury. However, the low toxicity of the MWCNT to lung macrophages may have contributed to enhanced migration of the MWCNT to the spleen through the lymph nodes, resulting in splenic toxicity and systemic changes in inflammatory mediators.

ACS Style

Christopher T. Migliaccio; Raymond F. Hamilton; Pamela K. Shaw; Joseph F. Rhoderick; Sanghamitra Deb; Rohit Bhargava; Jack R. Harkema; Andrij Holian. Respiratory and systemic impacts following MWCNT inhalation in B6C3F1/N mice. Particle and Fibre Toxicology 2021, 18, 1 -21.

AMA Style

Christopher T. Migliaccio, Raymond F. Hamilton, Pamela K. Shaw, Joseph F. Rhoderick, Sanghamitra Deb, Rohit Bhargava, Jack R. Harkema, Andrij Holian. Respiratory and systemic impacts following MWCNT inhalation in B6C3F1/N mice. Particle and Fibre Toxicology. 2021; 18 (1):1-21.

Chicago/Turabian Style

Christopher T. Migliaccio; Raymond F. Hamilton; Pamela K. Shaw; Joseph F. Rhoderick; Sanghamitra Deb; Rohit Bhargava; Jack R. Harkema; Andrij Holian. 2021. "Respiratory and systemic impacts following MWCNT inhalation in B6C3F1/N mice." Particle and Fibre Toxicology 18, no. 1: 1-21.

Journal article
Published: 25 February 2021 in International Journal of Molecular Sciences
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Lysosomal membrane permeabilization (LMP) has been proposed to precede nanoparticle-induced macrophage injury and NLRP3 inflammasome activation; however, the underlying mechanism(s) of LMP is unknown. We propose that nanoparticle-induced lysosomal hyperpolarization triggers LMP. In this study, a rapid non-invasive method was used to measure changes in lysosomal membrane potential of murine alveolar macrophages (AM) in response to a series of nanoparticles (ZnO, TiO2, and CeO2). Crystalline SiO2 (micron-sized) was used as a positive control. Changes in cytosolic potassium were measured using Asante potassium green 2. The results demonstrated that ZnO or SiO2 hyperpolarized the lysosomal membrane and decreased cytosolic potassium, suggesting increased lysosome permeability to potassium. Time-course experiments revealed that lysosomal hyperpolarization was an early event leading to LMP, NLRP3 activation, and cell death. In contrast, TiO2- or valinomycin-treated AM did not cause LMP unless high doses led to lysosomal hyperpolarization. Neither lysosomal hyperpolarization nor LMP was observed in CeO2-treated AM. These results suggested that a threshold of lysosomal membrane potential must be exceeded to cause LMP. Furthermore, inhibition of lysosomal hyperpolarization with Bafilomycin A1 blocked LMP and NLRP3 activation, suggesting a causal relation between lysosomal hyperpolarization and LMP.

ACS Style

Tahereh Ziglari; Zifan Wang; Andrij Holian. Contribution of Particle-Induced Lysosomal Membrane Hyperpolarization to Lysosomal Membrane Permeabilization. International Journal of Molecular Sciences 2021, 22, 2277 .

AMA Style

Tahereh Ziglari, Zifan Wang, Andrij Holian. Contribution of Particle-Induced Lysosomal Membrane Hyperpolarization to Lysosomal Membrane Permeabilization. International Journal of Molecular Sciences. 2021; 22 (5):2277.

Chicago/Turabian Style

Tahereh Ziglari; Zifan Wang; Andrij Holian. 2021. "Contribution of Particle-Induced Lysosomal Membrane Hyperpolarization to Lysosomal Membrane Permeabilization." International Journal of Molecular Sciences 22, no. 5: 2277.

Review article
Published: 28 January 2021 in Inhalation Toxicology
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Lysosomes offer a unique arrangement of degradative, exocytic, and signaling capabilities that make their continued function critical to cellular homeostasis. Lysosomes owe their function to the activity of lysosomal ion channels and transporters, which maintain concentration gradients of H+, K+, Ca2+, Na+, and Cl− across the lysosomal membrane. This review examines the contributions of lysosomal ion channels to lysosome function, showing how ion channel function is integral to degradation and autophagy, maintaining lysosomal membrane potential, controlling Ca2+ signaling, and facilitating exocytosis. Evidence of lysosome dysfunction in a variety of disease pathologies creates a need to understand how lysosomal ion channels contribute to lysosome dysfunction. For example, the loss of function of the TRPML1 Ca2+ lysosome channel in multiple lysosome storage diseases leads to lysosome dysfunction and disease pathogenesis while neurodegenerative diseases are marked by lysosome dysfunction caused by changes in ion channel activity through the TRPML1, TPC, and TMEM175 ion channels. Autoimmune disease is marked by dysregulated autophagy, which is dependent on the function of multiple lysosomal ion channels. Understanding the role of lysosomal ion channel activity in lysosome membrane permeability and NLRP3 inflammasome activation could provide valuable mechanistic insight into NLRP3 inflammasome-mediated diseases. Finally, this review seeks to show that understanding the role of lysosomal ion channels in lysosome dysfunction could give mechanistic insight into the efficacy of certain drug classes, specifically those that target the lysosome, such as cationic amphiphilic drugs.

ACS Style

Rebekah L. Kendall; Andrij Holian. The role of lysosomal ion channels in lysosome dysfunction. Inhalation Toxicology 2021, 33, 41 -54.

AMA Style

Rebekah L. Kendall, Andrij Holian. The role of lysosomal ion channels in lysosome dysfunction. Inhalation Toxicology. 2021; 33 (2):41-54.

Chicago/Turabian Style

Rebekah L. Kendall; Andrij Holian. 2021. "The role of lysosomal ion channels in lysosome dysfunction." Inhalation Toxicology 33, no. 2: 41-54.

Article
Published: 17 August 2020 in Journal of Applied Polymer Science
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Stimuli‐responsive electrospun fibers loaded with therapeutic agents for smart delivery are attractive biomedical applications. However, development of such fibers requires the use of complex chemical processes that can induce toxicity, reduce fiber quality, or prohibit fiber electrospinnablity. To address these challenges, core‐shell structured fibers capable of temperature‐controlled delivery of nanoparticles were developed. The fiber core contained an aqueous suspension of poly(n‐isopropylacrylamide) (PNIPAM) microgel particles and silver nanoparticles (model antibacterial drug). A novel use of ball‐milling was applied to produce microgel particles with an average hydrodynamic diameter of 511 ± 100 nm. The ball‐milling technique was developed to avoid the current complex chemical processes for syntheses of microgels, and to address the need for high‐yield techniques in industrial manufacturing. The results show that the thermoresponsive properties of the PNIPAM hydrogel particles were preserved during the ball‐milling process. The fiber shell formed a strong structure matrix, regulated the nanoparticles release pathway (through open pores formed via selective dissolution of porogen), and served as a barrier to prevent direct contact of microgel particles with tissues. This core‐shell fiber design allows for the future application of various therapeutic agents, including fragile and bioactive agents, and microgel particles with special properties.

ACS Style

Zahra Mahdieh; Andrij Holian. Electrospun fibers loaded with ball‐milled poly(n‐isopropylacrylamide) microgel particles for smart delivery applications. Journal of Applied Polymer Science 2020, 137, 1 .

AMA Style

Zahra Mahdieh, Andrij Holian. Electrospun fibers loaded with ball‐milled poly(n‐isopropylacrylamide) microgel particles for smart delivery applications. Journal of Applied Polymer Science. 2020; 137 (44):1.

Chicago/Turabian Style

Zahra Mahdieh; Andrij Holian. 2020. "Electrospun fibers loaded with ball‐milled poly(n‐isopropylacrylamide) microgel particles for smart delivery applications." Journal of Applied Polymer Science 137, no. 44: 1.

Cover image
Published: 17 August 2020 in Journal of Polymer Science
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The image created by Andrij Holian and Zahra Mahdieh shows the scanned electron micrograph of coreshell electrospun fibers developed for thermoresponsive delivery of nanoparticles. Poly(n‐isopropylacrylamide) microgel particles in an aqueous solution with silver nanoparticles were loaded inside the core. Increasing the temperature above the phase transition will result in the microgel particles transition thus shrinking and releasing of the silver nanoparticles from the core. This technique can be used for smart delivery of nanoparticles in various applications such as antibacterial agents triggered by temperature increases due to infection. Various microgel particles can be loaded inside the core for different applications through the described simple, versatile, and nontoxic method of ball‐milling. DOI: 10.1002/app.49786

ACS Style

Zahra Mahdieh; Andrij Holian. Cover Image, Volume 137, Issue 44. Journal of Polymer Science 2020, 137, 1 .

AMA Style

Zahra Mahdieh, Andrij Holian. Cover Image, Volume 137, Issue 44. Journal of Polymer Science. 2020; 137 (44):1.

Chicago/Turabian Style

Zahra Mahdieh; Andrij Holian. 2020. "Cover Image, Volume 137, Issue 44." Journal of Polymer Science 137, no. 44: 1.

Research article
Published: 05 August 2020 in ACS Applied Polymer Materials
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Electrospun fiber meshes with controlled drug delivery properties have great potential for applications such as wound dressings, tissue engineering, and cancer treatment. However, controlling the drug release, especially from core-shell fibers, remains the main challenge. In this study, core-shell fibers were developed with silver nanoparticles (Ag NP, as an antibacterial agent) loaded inside the core. Fiber shell was composed of polycaprolactone (PCL, shell matrix), polyethylene glycol (PEG, porogen), and zinc oxide nanoparticles (ZnO NP). ZnO NP were used in this study to improve the structure of pores in the shell (which serve as diffusion pathway for Ag NP) and thus to control the release rate. ZnO NP associated with PCL resulting in formation of PEG phase deeper in the fiber shell during the electrospinning process. Moreover, the diffusion/release rate of Ag NP from electrospun fibers was fine-tuned with variation in particle size. Fibers were loaded with three size compositions of 20 nm, 110 nm, or a mix of the two Ag NP inside the fiber core. Release studies showed fast, slow, and intermediate delivery rates obtained with the defined Ag NP. Fine-tuned release of Ag NP confirmed the formation of open pores within a stable shell structure because controlling the release rate was only possible through this well-defined release pathway. Furthermore, tensile strength analysis revealed excellent mechanical stability of the fibers after pore formation.

ACS Style

Zahra Mahdieh; Somenath Mitra; Andrij Holian. Core–Shell Electrospun Fibers with an Improved Open Pore Structure for Size-Controlled Delivery of Nanoparticles. ACS Applied Polymer Materials 2020, 2, 1 .

AMA Style

Zahra Mahdieh, Somenath Mitra, Andrij Holian. Core–Shell Electrospun Fibers with an Improved Open Pore Structure for Size-Controlled Delivery of Nanoparticles. ACS Applied Polymer Materials. 2020; 2 (9):1.

Chicago/Turabian Style

Zahra Mahdieh; Somenath Mitra; Andrij Holian. 2020. "Core–Shell Electrospun Fibers with an Improved Open Pore Structure for Size-Controlled Delivery of Nanoparticles." ACS Applied Polymer Materials 2, no. 9: 1.

Journal article
Published: 05 May 2020 in Immunobiology
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Macrophages fuse into multinucleated giant cells (MGC) in many pathological conditions. Despite MGC correlations with granulomas, their functional contribution to inflammation is relatively unknown. An in vitro mouse model of IL-4-induced bone marrow-derived macrophage fusion and microfiltration were used to generate enriched MGC and macrophage populations. Phenotypes were compared in response to well-known inflammatory stimuli, including lipopolysaccharide and crocidolite asbestos. Surface markers were assessed by flow cytometry: CD11b, CD11c, F4/80, and MHC II. Secreted cytokines were assessed by multiplex immunoassay: IFN-γ, IL-1β, IL-6, TNF-α, IL-10, IL-13, and IL-33. Results show that MGC maintained macrophage surface protein expression but lost the ability to produce a cytokine response. This suggests a potentially beneficial role of MGC in isolating the host from a foreign body without contributing to excessive inflammation. This study and future research using other stimulants and environments are important to gaining a fundamental MGC cell biology understanding. This will inform approaches to controlling the foreign body response to particle exposure, medical implants, and many diseases associated with granulomas.

ACS Style

Kevin Trout; Andrij Holian. Multinucleated giant cell phenotype in response to stimulation. Immunobiology 2020, 225, 151952 -151952.

AMA Style

Kevin Trout, Andrij Holian. Multinucleated giant cell phenotype in response to stimulation. Immunobiology. 2020; 225 (3):151952-151952.

Chicago/Turabian Style

Kevin Trout; Andrij Holian. 2020. "Multinucleated giant cell phenotype in response to stimulation." Immunobiology 225, no. 3: 151952-151952.

Journal article
Published: 03 May 2020 in Current Research in Toxicology
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Multinucleated giant cells (MGC) are formed by fusion of macrophages in pathological conditions. These are often studied in the context of the foreign body response to biomaterial implants, but MGC formation is rarely assessed in response to inorganic particles in the lungs. Therefore, a major objective of this study was to quantitatively compare in vivo macrophage fusion resulting from exposure to a spectrum of micron- and nano-sized particles from both environmental and engineered origin, including crystalline silica, multiwalled carbon nanotubes, titanium nanobelts, and crocidolite asbestos. Groups of C57Bl/6 mice were instilled with inorganic particles or PBS control. Lung cells were collected by lavage after one week for cell differentials, quantification of macrophage fusion, and microscopic observation of particle uptake. MGC were present in lungs of all mice exposed to particles; no MGC were found in control mice. Asbestos exposure resulted in significant macrophage fusion, which coincided with significantly increased total lavage cells and percent neutrophils. Microscopic observations show particle internalization in MGC and a unique case of potential heterotypic fusion of macrophages with neutrophils. MGC can form in the lungs of mice within a relatively short one-week time period after particle exposure. The number of MGC was sufficient for quantification and statistical analysis, indicating that MGC formation was more than simply a rare chance occurrence. Observations of particles within MGC warrants further investigation of MGC involvement in inflammation and particle clearance.

ACS Style

Kevin L. Trout; Andrij Holian. Macrophage fusion caused by particle instillation. Current Research in Toxicology 2020, 1, 42 -47.

AMA Style

Kevin L. Trout, Andrij Holian. Macrophage fusion caused by particle instillation. Current Research in Toxicology. 2020; 1 ():42-47.

Chicago/Turabian Style

Kevin L. Trout; Andrij Holian. 2020. "Macrophage fusion caused by particle instillation." Current Research in Toxicology 1, no. : 42-47.

Preprint content
Published: 30 April 2020
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Unique characteristics of electrospun fiber meshes have demonstrated their potential applications for wound dressing, tissue engineering, surgical mesh, and drug delivery systems. In drug delivery applications, researchers are developing stimuli-responsive fiber meshes loaded with drugs for deliveries triggered by stimuli such as temperature or pH. However, such systems require the

ACS Style

Zahra Mahdieh; Andrij Holian. Temperature responsive drug delivery from core-shell structured electrospun fibers. 2020, 1 .

AMA Style

Zahra Mahdieh, Andrij Holian. Temperature responsive drug delivery from core-shell structured electrospun fibers. . 2020; ():1.

Chicago/Turabian Style

Zahra Mahdieh; Andrij Holian. 2020. "Temperature responsive drug delivery from core-shell structured electrospun fibers." , no. : 1.

Preprint content
Published: 30 April 2020
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Unique characteristics of electrospun fiber meshes have demonstrated their potential applications for wound dressing, tissue engineering, surgical mesh, and drug delivery systems. In drug delivery applications, researchers are developing stimuli-responsive fiber meshes loaded with drugs for deliveries triggered by stimuli such as temperature or pH. However, such systems require the

ACS Style

Zahra Mahdieh; Andrij Holian. Temperature responsive drug delivery from core-shell structured electrospun fibers. 2020, 1 .

AMA Style

Zahra Mahdieh, Andrij Holian. Temperature responsive drug delivery from core-shell structured electrospun fibers. . 2020; ():1.

Chicago/Turabian Style

Zahra Mahdieh; Andrij Holian. 2020. "Temperature responsive drug delivery from core-shell structured electrospun fibers." , no. : 1.

Preprint content
Published: 30 April 2020
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Unique characteristics of electrospun fiber meshes have demonstrated their potential applications for wound dressing, tissue engineering, surgical mesh, and drug delivery systems. In drug delivery applications, researchers are developing stimuli-responsive fiber meshes loaded with drugs for deliveries triggered by stimuli such as temperature or pH. However, such systems require the

ACS Style

Zahra Mahdieh; Andrij Holian. Temperature responsive drug delivery from core-shell structured electrospun fibers. 2020, 1 .

AMA Style

Zahra Mahdieh, Andrij Holian. Temperature responsive drug delivery from core-shell structured electrospun fibers. . 2020; ():1.

Chicago/Turabian Style

Zahra Mahdieh; Andrij Holian. 2020. "Temperature responsive drug delivery from core-shell structured electrospun fibers." , no. : 1.

Journal article
Published: 15 April 2020 in Biochimica et Biophysica Acta (BBA) - Biomembranes
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Engineered nano-materials (ENM) have been reported to affect lipid membrane permeability in cell models, but a mechanistic understanding of how these materials interact with biological membranes has not been described. To assess mechanisms of permeability, liposomes composed of DOPC, DOPS, or POPC, with or without cholesterol, were used as model membranes for measuring ENM-induced changes to lipid order to improve our understanding of ENM effects on membrane permeability. Liposomes were treated with either titanium dioxide (TiO2) or zinc oxide (ZnO) ENM, and changes to lipid order were measured by time-resolved fluorescence anisotropy of a lipophilic probe, Di-4-ANEPPDHQ. Both ENM increased lipid order in two lipid models differing in headgroup charge. TiO2 increased lipid order of POPC liposomes (neutral charge), while ZnO acted primarily on DOPS liposomes (negative charge). Addition of cholesterol to these models significantly increased lipid order while in some cases attenuated ENM-induced changes to lipid order. To assess the ability of ENM to induce membrane permeability, liposomes composed of the above lipids were assayed for membrane permeability by calcein leakage in response to ENM. Both ENM caused a dose-dependent increase in permeability in all liposome models tested, and the addition of cholesterol to the liposome models neither blocked nor reduced calcein leakage. Together, these experiments show that ENM increased permeability of small molecules (calcein) from model liposomes, and that the magnitude of the effect of ENM on lipid order depended on ENM surface charge, lipid head group charge and the presence of cholesterol in the membrane.

ACS Style

Matthew J. Sydor; Donald S. Anderson; Harmen B.B. Steele; J.B. Alexander Ross; Andrij Holian. Effects of titanium dioxide and zinc oxide nano-materials on lipid order in model membranes. Biochimica et Biophysica Acta (BBA) - Biomembranes 2020, 1862, 183313 .

AMA Style

Matthew J. Sydor, Donald S. Anderson, Harmen B.B. Steele, J.B. Alexander Ross, Andrij Holian. Effects of titanium dioxide and zinc oxide nano-materials on lipid order in model membranes. Biochimica et Biophysica Acta (BBA) - Biomembranes. 2020; 1862 (9):183313.

Chicago/Turabian Style

Matthew J. Sydor; Donald S. Anderson; Harmen B.B. Steele; J.B. Alexander Ross; Andrij Holian. 2020. "Effects of titanium dioxide and zinc oxide nano-materials on lipid order in model membranes." Biochimica et Biophysica Acta (BBA) - Biomembranes 1862, no. 9: 183313.

Chapter
Published: 31 January 2020 in Molecular and Integrative Toxicology
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The potential health effects associated with the widespread use of engineered nanomaterials are broadly concerning to developers, researchers, and policy-makers alike. While extensive studies have been undertaken to understand the immediate consequences of exposure to these materials, the long-term effects associated with potential translocation to secondary and even tertiary organs are less well understood. Further, mechanisms underlying the toxic properties of nanomaterials after translocating to distal organs, if any, are largely unknown at this time. Here, we describe the current state of knowledge regarding translocation of commonly studied and primarily nonmedical engineered nanomaterials following exposure and discuss potential mechanisms and consequences to health outcomes. Current evidence suggests that nanomaterials are redistributed, at least in part, to secondary organs throughout the body. While the properties associated with any given nanomaterial may influence its redistribution, the most likely explanation for adverse effects following translocation involves increased inflammation leading to pathology. Whether more persistent nanomaterials will eventually be cleared from the body after exposure remains an important question. Further, information regarding the effects of systemic trafficking on the basic characteristics of nanomaterials would help predict whether nanomaterials will accumulate in specific organs and/or cause pathologies in secondary or even tertiary locations.

ACS Style

Melisa Bunderson-Schelvan; Andrij Holian; Kevin Trout; Raymond F. Hamilton. Translocation, Biodistribution, and Fate of Nanomaterials in the Body. Molecular and Integrative Toxicology 2020, 99 -125.

AMA Style

Melisa Bunderson-Schelvan, Andrij Holian, Kevin Trout, Raymond F. Hamilton. Translocation, Biodistribution, and Fate of Nanomaterials in the Body. Molecular and Integrative Toxicology. 2020; ():99-125.

Chicago/Turabian Style

Melisa Bunderson-Schelvan; Andrij Holian; Kevin Trout; Raymond F. Hamilton. 2020. "Translocation, Biodistribution, and Fate of Nanomaterials in the Body." Molecular and Integrative Toxicology , no. : 99-125.

Research article
Published: 28 January 2020 in Inhalation Toxicology
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Background: While the role of lysosomal membrane permeabilization (LMP) in NP-induced inflammatory responses has been recognized, the underlying mechanism of LMP is still unclear. The assumption has been that zinc oxide (ZnO)-induced LMP is due to Zn2+; however, little is known about the role of ZnO nanoparticles (NP) in toxicity.Methods: We examined the contribution of intact ZnO NP on membrane permeability using red blood cells (RBC) and undifferentiated THP-1 cells as models of particle-membrane interactions to simulate ZnO NP-lysosomal membrane interaction. The integrity of plasma membranes was evaluated by transmission electron microscopy (TEM) and confocal microscopy. ZnO NP dissolution was determined using ZnAF-2F, Zn2+ specific probe. The stability of ZnO NP inside the phagolysosomes of phagocytic cells, differentiated THP-1, alveolar macrophages, and bone marrow-derived macrophages, was determined.Results: ZnO NP caused significant hemolysis and cytotoxicity under conditions of negligible dissolution. Fully ionized Zn2SO4 caused slight hemolysis, while partially ionized ZnO induced significant hemolysis. Confocal microscopy and TEM images did not reveal membrane disruption in RBC and THP-1 cells, respectively. ZnO NP remained intact inside the phagolysosomes after a 4 h incubation with phagocytic cells.Conclusions: These studies demonstrate the ability of intact ZnO NP to induce membrane permeability and cytotoxicity without the contribution of dissolved Zn2+, suggesting that ZnO NP toxicity does not necessarily depend upon Zn2+. The stability of ZnO NP inside the phagolysosomes suggests that LMP is the result of the toxic effect of intact ZnO NP on phagolysosomal membranes.

ACS Style

Tahereh Ziglari; Donald S. Anderson; Andrij Holian. Determination of the relative contribution of the non-dissolved fraction of ZnO NP on membrane permeability and cytotoxicity. Inhalation Toxicology 2020, 32, 86 -95.

AMA Style

Tahereh Ziglari, Donald S. Anderson, Andrij Holian. Determination of the relative contribution of the non-dissolved fraction of ZnO NP on membrane permeability and cytotoxicity. Inhalation Toxicology. 2020; 32 (2):86-95.

Chicago/Turabian Style

Tahereh Ziglari; Donald S. Anderson; Andrij Holian. 2020. "Determination of the relative contribution of the non-dissolved fraction of ZnO NP on membrane permeability and cytotoxicity." Inhalation Toxicology 32, no. 2: 86-95.

Research article
Published: 02 January 2020 in Inhalation Toxicology
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Objective: In this study, we compared in vitro and in vivo bioactivity of nitrogen-doped multi-walled carbon nanotubes (NDMWCNT) to MWCNT to test the hypothesis that nitrogen doping would alter bioactivity. Materials and Methods: High-resolution transmission electron microscopy (TEM) confirmed the multilayer structure of MWCNT with an average layer distance of 0.36 nm, which was not altered by nitrogen doping: the nanomaterials had similar widths and lengths. In vitro studies with THP-1 cells and alveolar macrophages from C57BL/6 mice demonstrated that NDMWCNT were less cytotoxic and stimulated less IL-1β release compared to MWCNT. For in vivo studies, male C57BL/6J mice received a single dose of dispersion medium (DM), 2.5, 10 or 40 µg/mouse of NDMWCNT, or 40 µg/mouse of MWCNT by oropharyngeal aspiration. Animals were euthanized between 1 and 7 days post-exposure for whole lung lavage (WLL) studies. Results and Discussion: NDMWCNT caused time- and dose-dependent pulmonary inflammation. However, it was less than that caused by MWCNT. Activation of the NLRP3 inflammasome was assessed in particle-exposed mice by determining cytokine production in WLL fluid at 1 day post-exposure. Compared to DM-exposed mice, IL-1β and IL-18 were significantly increased in MWCNT- and NDMWCNT-exposed mice, but the increase caused by NDMWCNT was less than MWCNT. At 56 days post-exposure, histopathology determined lung fibrosis in MWCNT-exposed mice was greater than NDMWCNT-exposed mice. Conclusions: These data indicate nitrogen doping of MWCNT decreases their bioactivity, as reflected with lower in vitro and in vivo toxicity inflammation and lung disease. The lower activation of the NLRP3 inflammasome may be responsible. Abbreviations: NDMWCNT: nitrogen-doped multi-walled carbon nanotubes; MWCNT: multi-walled carbon nanotubes; TEM: transmission electron microscopy; HRTEM: high resolution transmission electron microscopy; IL-1ß: interleukin-1ß; DM: dispersion medium; WLL: whole lung lavage; IL-18: interleukin-18; GSD: geometric standard deviation; XPS: X-ray photoelectron spectroscopy; SEM: standard error of the mean; PMA: phorbol 12-myristate 13-acetate; LPS: lipopolysacharride; LDH: lactate dehydrogenase; AM: alveolar macrophage; PMN: polymorphonuclear leukocyte

ACS Style

Dale W. Porter; Marlene Orandle; Peng Zheng; Nianqiang Wu; Raymond F. Hamilton Jr; Andrij Holian; Bean T. Chen; Michael Andrew; Michael G. Wolfarth; Lori Battelli; Shuji Tsuruoka; Mauricio Terrones; Vince Castranova. Mouse pulmonary dose- and time course-responses induced by exposure to nitrogen-doped multi-walled carbon nanotubes. Inhalation Toxicology 2020, 32, 24 -38.

AMA Style

Dale W. Porter, Marlene Orandle, Peng Zheng, Nianqiang Wu, Raymond F. Hamilton Jr, Andrij Holian, Bean T. Chen, Michael Andrew, Michael G. Wolfarth, Lori Battelli, Shuji Tsuruoka, Mauricio Terrones, Vince Castranova. Mouse pulmonary dose- and time course-responses induced by exposure to nitrogen-doped multi-walled carbon nanotubes. Inhalation Toxicology. 2020; 32 (1):24-38.

Chicago/Turabian Style

Dale W. Porter; Marlene Orandle; Peng Zheng; Nianqiang Wu; Raymond F. Hamilton Jr; Andrij Holian; Bean T. Chen; Michael Andrew; Michael G. Wolfarth; Lori Battelli; Shuji Tsuruoka; Mauricio Terrones; Vince Castranova. 2020. "Mouse pulmonary dose- and time course-responses induced by exposure to nitrogen-doped multi-walled carbon nanotubes." Inhalation Toxicology 32, no. 1: 24-38.

Original research article
Published: 13 December 2019 in Frontiers in Immunology
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Exposure of lupus-prone female NZBWF1 mice to respirable crystalline silica (cSiO2), a known human autoimmune trigger, initiates loss of tolerance, rapid progression of autoimmunity, and early onset of glomerulonephritis. We have previously demonstrated that dietary supplementation with the ω-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) suppresses autoimmune pathogenesis and nephritis in this unique model of lupus flaring. In this report, we utilized tissues from prior studies to test the hypothesis that DHA consumption interferes with upregulation of critical genes associated with cSiO2-triggered murine lupus. A NanoString nCounter platform targeting 770 immune-related genes was used to assess the effects cSiO2 on mRNA signatures over time in female NZBWF1 mice consuming control (CON) diets compared to mice fed diets containing DHA at an amount calorically equivalent to human consumption of 2 g per day (DHA low) or 5 g per day (DHA high). Experimental groups of mice were sacrificed: (1) 1 d after a single intranasal instillation of 1 mg cSiO2 or vehicle, (2) 1 d after four weekly single instillations of vehicle or 1 mg cSiO2, and (3) 1, 5, 9, and 13 weeks after four weekly single instillations of vehicle or 1 mg cSiO2. Genes associated with inflammation as well as innate and adaptive immunity were markedly upregulated in lungs of CON-fed mice 1 d after four weekly cSiO2 doses but were significantly suppressed in mice fed DHA high diets. Importantly, mRNA signatures in lungs of cSiO2-treated CON-fed mice over 13 weeks reflected progressive amplification of interferon (IFN)- and chemokine-related gene pathways. While these responses in the DHA low group were suppressed primarily at week 5, significant downregulation was observed at weeks 1, 5, 9, and 13 in mice fed the DHA high diet. At week 13, cSiO2 treatment of CON-fed mice affected 214 genes in kidney tissue associated with inflammation, innate/adaptive immunity, IFN, chemokines, and antigen processing, mostly by upregulation; however, feeding DHA dose-dependently suppressed these responses. Taken together, dietary DHA intake in lupus-prone mice impeded cSiO2-triggered mRNA signatures known to be involved in ectopic lymphoid tissue neogenesis, systemic autoimmunity, and glomerulonephritis.

ACS Style

Abby D. Benninghoff; Melissa A. Bates; Preeti Chauhan; Kathryn Wierenga; Kristen N. Gilley; Andrij Holian; Jack R. Harkema; James J. Pestka. Docosahexaenoic Acid Consumption Impedes Early Interferon- and Chemokine-Related Gene Expression While Suppressing Silica-Triggered Flaring of Murine Lupus. Frontiers in Immunology 2019, 10, 2851 .

AMA Style

Abby D. Benninghoff, Melissa A. Bates, Preeti Chauhan, Kathryn Wierenga, Kristen N. Gilley, Andrij Holian, Jack R. Harkema, James J. Pestka. Docosahexaenoic Acid Consumption Impedes Early Interferon- and Chemokine-Related Gene Expression While Suppressing Silica-Triggered Flaring of Murine Lupus. Frontiers in Immunology. 2019; 10 ():2851.

Chicago/Turabian Style

Abby D. Benninghoff; Melissa A. Bates; Preeti Chauhan; Kathryn Wierenga; Kristen N. Gilley; Andrij Holian; Jack R. Harkema; James J. Pestka. 2019. "Docosahexaenoic Acid Consumption Impedes Early Interferon- and Chemokine-Related Gene Expression While Suppressing Silica-Triggered Flaring of Murine Lupus." Frontiers in Immunology 10, no. : 2851.

Journal article
Published: 01 November 2019 in Immunobiology
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Macrophages fuse together to form multinucleated giant cells (MGC) in granulomas associated with various pathological conditions. Improved in vitro methods are required to better enable investigations of MGC biology and potential contribution to disease. There is a need for standardization of MGC quantification, purification of MGC populations, and characterization of how cell culture variables influence MGC formation. This study examined solutions to address these needs while providing context with other current and alternative methods. Primary mouse bone marrow-derived macrophages were treated with interleukin-4, a cytokine known to induce fusion into MGC. This model was used to systematically assess the influence of cell stimulant timing, cell seeding density, colony stimulating factors, and culture vessel type. Results indicated that MGC formation is greatly impacted by alterations in certain culture variables. An assessment of previously published research showed that these culture conditions varied widely between different laboratories, which may explain inconsistencies in the literature. A particularly novel and unexpected observation was that MGC formation appears to be greatly increased by silicone, which is a component of a chamber slide system commonly used for MGC studies. The most successful quantification method was fluorescent staining with semi-automated morphological evaluation. The most successful enrichment method was microfiltration. Overall, this study takes steps toward standardizing in vitro methods, enhancing replicability, and guiding investigators attempting to culture, quantify, and enrich MGC.

ACS Style

Kevin Trout; Andrij Holian. Factors influencing multinucleated giant cell formation in vitro. Immunobiology 2019, 224, 834 -842.

AMA Style

Kevin Trout, Andrij Holian. Factors influencing multinucleated giant cell formation in vitro. Immunobiology. 2019; 224 (6):834-842.

Chicago/Turabian Style

Kevin Trout; Andrij Holian. 2019. "Factors influencing multinucleated giant cell formation in vitro." Immunobiology 224, no. 6: 834-842.

Advanced review
Published: 30 September 2019 in WIREs Nanomedicine and Nanobiotechnology
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The use of engineered nanomaterials within various applications such as medicine, electronics, and cosmetics has been steadily increasing; therefore, the rate of occupational and environmental exposures has also increased. Inhalation is an important route of exposure to nanomaterials and has been shown to cause various respiratory diseases in animal models. Human lung disease frequently presents with a sex/gender‐bias in prevalence or severity, but investigation of potential sex‐differences in the adverse health outcomes associated with nanoparticle inhalation is greatly lacking. Only ~20% of basic research in the general sciences use both male and female animals and a substantial percentage of these do not address differences between sexes within their analyses. This has prevented researchers from fully understanding the impact of sex‐based variables on health and disease, particularly the pathologies resulting from the inhalation of particles. The mechanisms responsible for sex‐differences in respiratory disease remain unclear, but could be related to a number of variables including sex‐differences in hormone signaling, lung physiology, or respiratory immune function. By incorporating sex‐based analysis into respiratory nanotoxicology and utilizing human data from other relevant particles (e.g., asbestos, silica, particulate matter), we can improve our understanding of sex as a biological variable in nanoparticle exposures. This article is categorized under: Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials

ACS Style

Jessica L. Ray; Paige Fletcher; Rachel Burmeister; Andrij Holian. The role of sex in particle‐induced inflammation and injury. WIREs Nanomedicine and Nanobiotechnology 2019, 12, e1589 .

AMA Style

Jessica L. Ray, Paige Fletcher, Rachel Burmeister, Andrij Holian. The role of sex in particle‐induced inflammation and injury. WIREs Nanomedicine and Nanobiotechnology. 2019; 12 (2):e1589.

Chicago/Turabian Style

Jessica L. Ray; Paige Fletcher; Rachel Burmeister; Andrij Holian. 2019. "The role of sex in particle‐induced inflammation and injury." WIREs Nanomedicine and Nanobiotechnology 12, no. 2: e1589.

Original research article
Published: 20 September 2019 in Frontiers in Immunology
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Occupational exposure to respirable crystalline silica (cSiO2) has been etiologically linked to human autoimmunity. Intranasal instillation with cSiO2 triggers profuse inflammation in the lung and onset of autoimmunity in lupus-prone mice; however, dietary supplementation with the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) abrogates these responses. Inflammasome activation, IL-1 cytokine release, and death in alveolar macrophages following cSiO2 exposure are early and critical events that likely contribute to triggering premature autoimmune pathogenesis by this particle. Here we tested the hypothesis that DHA suppresses cSiO2-induced NLRP3 inflammasome activation, IL-1 cytokine release, and cell death in the macrophage. The model used was the murine macrophage RAW 264.7 cell line stably transfected with the inflammasome adapter protein ASC (RAW-ASC). Following priming with LPS, both the canonical activator nigericin and cSiO2 elicited robust inflammasome activation in RAW-ASC cells, as reflected by IL-1β release and caspase-1 activation. These responses were greatly diminished or absent in wild-type RAW cells. In contrast to IL-1β, cSiO2 induced IL-1α release in both RAW-ASC and to a lesser extent in RAW-WT cells after LPS priming. cSiO2-driven effects in RAW-ASC cells were confirmed in bone-marrow derived macrophages. Pre-incubating RAW-ASC cells with 10 and 25 μM DHA for 24 h enriched this fatty acid in the phospholipids by 15- and 25-fold, respectively, at the expense of oleic acid. DHA pre-incubation suppressed inflammasome activation and release of IL-1β and IL-1α by nigericin, cSiO2, and two other crystals – monosodium urate and alum. DHA's suppressive effects were linked to inhibition of LPS-induced Nlrp3, Il1b, and Il1a transcription, potentially through the activation of PPARγ. Finally, nigericin-induced death was inflammasome-dependent, indicative of pyroptosis, and could be inhibited by DHA pretreatment. In contrast, cSiO2-induced death was inflammasome-independent and not inhibited by DHA. Taken together, these findings indicate that DHA suppresses cSiO2-induced inflammasome activation and IL-1 cytokine release in macrophages by acting at the level of priming, but was not protective against cSiO2-induced cell death.

ACS Style

Kathryn Wierenga; Josephine Wee; Kristen N. Gilley; Lichchavi Rajasinghe; Melissa A. Bates; Mikhail A. Gavrilin; Andrij Holian; James J. Pestka. Docosahexaenoic Acid Suppresses Silica-Induced Inflammasome Activation and IL-1 Cytokine Release by Interfering With Priming Signal. Frontiers in Immunology 2019, 10, 2130 .

AMA Style

Kathryn Wierenga, Josephine Wee, Kristen N. Gilley, Lichchavi Rajasinghe, Melissa A. Bates, Mikhail A. Gavrilin, Andrij Holian, James J. Pestka. Docosahexaenoic Acid Suppresses Silica-Induced Inflammasome Activation and IL-1 Cytokine Release by Interfering With Priming Signal. Frontiers in Immunology. 2019; 10 ():2130.

Chicago/Turabian Style

Kathryn Wierenga; Josephine Wee; Kristen N. Gilley; Lichchavi Rajasinghe; Melissa A. Bates; Mikhail A. Gavrilin; Andrij Holian; James J. Pestka. 2019. "Docosahexaenoic Acid Suppresses Silica-Induced Inflammasome Activation and IL-1 Cytokine Release by Interfering With Priming Signal." Frontiers in Immunology 10, no. : 2130.