2022
Murray, Alexa; Banota, Tanvi; Guo, Grace L; Smith, Ley Cody; Meshanni, Jaclynn A; Lee, Jordan; Kong, Bo; Abramova, Elena V; Goedken, Michael; Gow, Andrew J; Laskin, Jeffrey D; Laskin, Debra L
Farnesoid X receptor regulates lung macrophage activation and injury following nitrogen mustard exposure Journal Article
In: Toxicol Appl Pharmacol, vol. 454, pp. 116208, 2022, ISSN: 1096-0333.
@article{pmid35998709,
title = {Farnesoid X receptor regulates lung macrophage activation and injury following nitrogen mustard exposure},
author = {Alexa Murray and Tanvi Banota and Grace L Guo and Ley Cody Smith and Jaclynn A Meshanni and Jordan Lee and Bo Kong and Elena V Abramova and Michael Goedken and Andrew J Gow and Jeffrey D Laskin and Debra L Laskin},
url = {https://pubmed.ncbi.nlm.nih.gov/35998709/},
doi = {10.1016/j.taap.2022.116208},
issn = {1096-0333},
year = {2022},
date = {2022-11-01},
urldate = {2022-11-01},
journal = {Toxicol Appl Pharmacol},
volume = {454},
pages = {116208},
abstract = {Nitrogen mustard (NM) is a cytotoxic vesicant known to cause acute lung injury which progresses to fibrosis; this is associated with a sequential accumulation of pro- and anti-inflammatory macrophages in the lung which have been implicated in NM toxicity. Farnesoid X receptor (FXR) is a nuclear receptor involved in regulating lipid homeostasis and inflammation. In these studies, we analyzed the role of FXR in inflammatory macrophage activation, lung injury and oxidative stress following NM exposure. Wild-type (WT) and FXR mice were treated intratracheally with PBS (control) or NM (0.08 mg/kg). Bronchoalveolar lavage fluid (BAL) and lung tissue were collected 3, 14 and 28 d later. NM caused progressive histopathologic alterations in the lung including inflammatory cell infiltration and alveolar wall thickening and increases in protein and cells in BAL; oxidative stress was also noted, as reflected by upregulation of heme oxygenase-1. These changes were more prominent in male FXR mice. Flow cytometric analysis revealed that loss of FXR resulted in increases in proinflammatory macrophages at 3 d post NM; this correlated with upregulation of COX-2 and ARL11, markers of macrophage activation. Markers of anti-inflammatory macrophage activation, CD163 and STAT6, were also upregulated after NM; this response was exacerbated in FXR mice at 14 d post-NM. These findings demonstrate that FXR plays a role in limiting macrophage inflammatory responses important in lung injury and oxidative stress. Maintaining or enhancing FXR function may represent a useful strategy in the development of countermeasures to treat mustard lung toxicity.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Joseph, Laurie B; Gordon, Marion K; Zhou, Peihong; Hahn, Rita A; Lababidi, Hamdi; Croutch, Claire R; Sinko, Patrick J; Heck, Diane E; Laskin, Debra L; Laskin, Jeffrey D
Sulfur mustard corneal injury is associated with alterations in the epithelial basement membrane and stromal extracellular matrix Journal Article
In: Exp Mol Pathol, vol. 128, pp. 104807, 2022, ISSN: 1096-0945.
@article{pmid35798063,
title = {Sulfur mustard corneal injury is associated with alterations in the epithelial basement membrane and stromal extracellular matrix},
author = {Laurie B Joseph and Marion K Gordon and Peihong Zhou and Rita A Hahn and Hamdi Lababidi and Claire R Croutch and Patrick J Sinko and Diane E Heck and Debra L Laskin and Jeffrey D Laskin},
url = {https://pubmed.ncbi.nlm.nih.gov/35798063/},
doi = {10.1016/j.yexmp.2022.104807},
issn = {1096-0945},
year = {2022},
date = {2022-10-01},
urldate = {2022-10-01},
journal = {Exp Mol Pathol},
volume = {128},
pages = {104807},
abstract = {Sulfur mustard (SM; bis(2-chloroethyl) sulfide) is a highly reactive bifunctional alkylating agent synthesized for chemical warfare. The eyes are particularly sensitive to SM where it causes irritation, pain, photophobia, and blepharitis, depending on the dose and duration of exposure. In these studies, we examined the effects of SM vapor on the corneas of New Zealand white male rabbits. Edema and hazing of the cornea, signs of acute injury, were observed within one day of exposure to SM, followed by neovascularization, a sign of chronic or late phase pathology, which persisted for at least 28 days. Significant epithelial-stromal separation ranging from ~8-17% of the epithelial surface was observed. In the stroma, there was a marked increase in CD45 leukocytes and a decrease of keratocytes, along with areas of disorganization of collagen fibers. SM also disrupted the corneal basement membrane and altered the expression of perlecan, a heparan sulfate proteoglycan, and cellular fibronectin, an extracellular matrix glycoprotein. This was associated with an increase in basement membrane matrix metalloproteinases including ADAM17, which is important in remodeling of the basement membrane during wound healing. Tenascin-C, an extracellular matrix glycoprotein, was also upregulated in the stroma 14-28 d post SM, a finding consistent with its role in organizing structural components of the stroma necessary for corneal transparency. These data demonstrate that SM vapor causes persistent alterations in structural components of the cornea. Further characterization of SM-induced injury in rabbit cornea will be useful for the identification of targets for the development of ocular countermeasures.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Jan, Yi-Hua; Heck, Diane E; An, Yunqi; Laskin, Debra L; Laskin, Jeffrey D
Nitrogen Mustard Alkylates and Cross-Links p53 in Human Keratinocytes Journal Article
In: Chem Res Toxicol, vol. 35, no. 4, pp. 636–650, 2022, ISSN: 1520-5010.
@article{pmid35312310,
title = {Nitrogen Mustard Alkylates and Cross-Links p53 in Human Keratinocytes},
author = {Yi-Hua Jan and Diane E Heck and Yunqi An and Debra L Laskin and Jeffrey D Laskin},
url = {https://pubmed.ncbi.nlm.nih.gov/35312310/},
doi = {10.1021/acs.chemrestox.1c00420},
issn = {1520-5010},
year = {2022},
date = {2022-01-01},
urldate = {2022-01-01},
journal = {Chem Res Toxicol},
volume = {35},
number = {4},
pages = {636--650},
abstract = {Cytotoxic blistering agents such as sulfur mustard and nitrogen mustard (HN2) were synthesized for chemical warfare. Toxicity is due to reactive chloroethyl side chains that modify and damage cellular macromolecules including DNA and proteins. In response to DNA damage, cells initiate a DNA damage response directed at the recruitment and activation of repair-related proteins. A central mediator of the DNA damage response is p53, a protein that plays a critical role in regulating DNA repair. We found that HN2 causes cytosolic and nuclear accumulation of p53 in HaCaT keratinocytes; HN2 also induced post-translational modifications on p53 including S15 phosphorylation and K382 acetylation, which enhance p53 stability, promote DNA repair, and mediate cellular metabolic responses to stress. HN2 also cross-linked p53, forming dimers and high-molecular-weight protein complexes in the cells. Cross-linked multimers were also modified by K48-linked ubiquitination indicating that they are targets for proteasome degradation. HN2-induced modifications transiently suppressed the transcriptional activity of p53. Using recombinant human p53, HN2 alkylation was found to be concentration- and redox status-dependent. Dithiothreitol-reduced protein was more efficiently cross-linked indicating that p53 cysteine residues play a key role in protein modification. LC-MS/MS analysis revealed that HN2 directly alkylated p53 at C124, C135, C141, C176, C182, C275, C277, H115, H178, K132, and K139, forming both monoadducts and cross-links. The formation of intermolecular complexes was a consequence of HN2 cross-linked cysteine residues between two molecules of p53. Together, these data demonstrate that p53 is a molecular target for mustard vesicants. Modification of p53 likely mediates cellular responses to HN2 including DNA repair and cell survival contributing to vesicant-induced cytotoxicity.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2021
Sandhu, Simarjot Kaur; Kumar, Suneel; Raut, Jayant; Singh, Mandeep; Kaur, Sandeep; Sharma, Garima; Roldan, Tomas L; Trehan, Sonia; Holloway, Jennifer; Wahler, Gabriella; Laskin, Jeffrey D; Sinko, Patrick J; Berthiaume, Francois; Michniak-Kohn, Bozena; Rishi, Praveen; Ganesh, Narayanan; Kaur, Indu Pal
In: Antioxidants (Basel), vol. 10, no. 5, 2021, ISSN: 2076-3921.
@article{pmid34063003,
title = {Systematic Development and Characterization of Novel, High Drug-Loaded, Photostable, Curcumin Solid Lipid Nanoparticle Hydrogel for Wound Healing},
author = {Simarjot Kaur Sandhu and Suneel Kumar and Jayant Raut and Mandeep Singh and Sandeep Kaur and Garima Sharma and Tomas L Roldan and Sonia Trehan and Jennifer Holloway and Gabriella Wahler and Jeffrey D Laskin and Patrick J Sinko and Francois Berthiaume and Bozena Michniak-Kohn and Praveen Rishi and Narayanan Ganesh and Indu Pal Kaur},
url = {https://pubmed.ncbi.nlm.nih.gov/34063003/},
doi = {10.3390/antiox10050725},
issn = {2076-3921},
year = {2021},
date = {2021-05-01},
urldate = {2021-05-01},
journal = {Antioxidants (Basel)},
volume = {10},
number = {5},
abstract = {The study aims to develop high drug-loaded (about 15% lipid matrix) curcumin solid lipid nanoparticles (CSLNs) for wound healing. CSLNs prepared by hot, high-pressure homogenization, without using organic solvents, were optimized using the Taguchi design followed by the central composite design. The optimized CSLNs exhibited a high assay/drug content (0.6% /), solubility (6 × 10 times), and EE (75%) with a particle size < 200 nm (PDI-0.143). The CSLNs were safe (in vitro and in vivo), photostable, autoclavable, stable up to one year at 30 °C and under refrigeration and exhibited a controlled release (zero-order; 5 days). XRD, FTIR, and DSC confirmed solubilization and entrapment of the curcumin within the SLNs. TEM and FESEM revealed a smooth and spherical shape. The CSLNs showed a significant antimicrobial effect (MIC of 64 µg/mL for planktonic cells; 512 µg/mL for biofilm formation; and 2 mg/mL for mature biofilm) against 9144, while free curcumin dispersion did not exhibit any effect. This is the first report on the disruption of mature biofilms by curcumin solid lipid nanoparticles (CSLNs). The cell proliferation potential of CSLNs was also evaluated in vitro while the wound healing potential of CSLNs (incorporated in a hydrogel) was assessed in vivo. In (i) nitrogen mustard gas and (ii) a full-thickness excision wound model, CSLNs exhibited (a) significantly faster wound closure, (b) histologically and immunohistochemically better healing, (c) lower oxidative stress (LPO) and (d) inflammation (TNFα), and (e) increased angiogenesis (VEGF) and antioxidant enzymes, i.e., catalase and GSH levels. CSLNs thus offer a promising modern wound therapy especially for infected wounds, considering their effects in mature biofilm disruption.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Joseph, Laurie B; Gordon, Marion K; Kang, Jieun; Croutch, Claire R; Zhou, Peihong; Heck, Diane E; Laskin, Debra L; Laskin, Jeffrey D
Characterization of the rabbit conjunctiva: Effects of sulfur mustard Journal Article
In: Exp Mol Pathol, vol. 121, pp. 104656, 2021, ISSN: 1096-0945.
@article{pmid34081961,
title = {Characterization of the rabbit conjunctiva: Effects of sulfur mustard},
author = {Laurie B Joseph and Marion K Gordon and Jieun Kang and Claire R Croutch and Peihong Zhou and Diane E Heck and Debra L Laskin and Jeffrey D Laskin},
url = {https://pubmed.ncbi.nlm.nih.gov/34081961/},
doi = {10.1016/j.yexmp.2021.104656},
issn = {1096-0945},
year = {2021},
date = {2021-01-01},
urldate = {2021-01-01},
journal = {Exp Mol Pathol},
volume = {121},
pages = {104656},
abstract = {Sulfur mustard (SM; bis (2-chloroethyl) sulfide) is a potent vesicant which causes irritation of the conjunctiva and damage to the cornea. In the present studies, we characterized the ocular effects of SM in New Zealand white rabbits. Within one day of exposure to SM, edema and hazing of the cornea were observed, followed by neovascularization which persisted for at least 28 days. This was associated with upper and lower eyelid edema and conjunctival inflammation. The conjunctiva is composed of a proliferating epithelium largely consisting of stratified columnar epithelial cells overlying a well-defined dermis. Superficial layers of the conjunctival epithelium were found to express keratin 1, a marker of differentiating squamous epithelium, while in cells overlying the basement membrane expressed keratin 17, a marker of stratified squamous epithelium. SM exposure upregulated keratin 17 expression. Mucin 5 ac producing goblet cells were interspersed within the conjunctiva. These cells generated both acidic and neutral mucins. Increased numbers of goblet cells producing neutral mucins were evident after SM exposure; upregulation of expression of membrane-associated mucin 1 and mucin 4 in the superficial layers of the conjunctival epithelium were also noted. These data demonstrate that ocular exposure of rabbits to SM causes significant damage not only to the cornea, but to the eyelid and conjunctiva, suggesting multiple targets within the eye that should be assessed when evaluating the efficacy of potential countermeasures.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Venosa, Alessandro; Smith, L Cody; Gow, Andrew J; Zarbl, Helmut; Laskin, Jeffrey D; Laskin, Debra L
In: Toxicol Appl Pharmacol, vol. 423, pp. 115569, 2021, ISSN: 1096-0333.
@article{pmid33971176,
title = {Macrophage activation in the lung during the progression of nitrogen mustard induced injury is associated with histone modifications and altered miRNA expression},
author = {Alessandro Venosa and L Cody Smith and Andrew J Gow and Helmut Zarbl and Jeffrey D Laskin and Debra L Laskin},
url = {https://pubmed.ncbi.nlm.nih.gov/33971176/},
doi = {10.1016/j.taap.2021.115569},
issn = {1096-0333},
year = {2021},
date = {2021-01-01},
urldate = {2021-01-01},
journal = {Toxicol Appl Pharmacol},
volume = {423},
pages = {115569},
abstract = {Activated macrophages have been implicated in lung injury and fibrosis induced by the cytotoxic alkylating agent, nitrogen mustard (NM). Herein, we determined if macrophage activation is associated with histone modifications and altered miRNA expression. Treatment of rats with NM (0.125 mg/kg, i.t.) resulted in increases in phosphorylation of H2A.X in lung macrophages at 1 d and 3 d post-exposure. This DNA damage response was accompanied by methylation of histone (H) 3 lysine (K) 4 and acetylation of H3K9, marks of transcriptional activation, and methylation of H3K36 and H3K9, marks associated with transcriptional repression. Increases in histone acetyl transferase and histone deacetylase were also observed in macrophages 1 d and 28 d post-NM exposure. PCR array analysis of miRNAs (miR)s involved in inflammation and fibrosis revealed unique and overlapping expression profiles in macrophages isolated 1, 3, 7, and 28 d post-NM. An IPA Core Analysis of predicted mRNA targets of differentially expressed miRNAs identified significant enrichment of Diseases and Functions related to cell cycle arrest, apoptosis, cell movement, cell adhesion, lipid metabolism, and inflammation 1 d and 28 d post NM. miRNA-mRNA interaction network analysis revealed highly connected miRNAs representing key upstream regulators of mRNAs involved in significantly enriched pathways including miR-34c-5p and miR-27a-3p at 1 d post NM and miR-125b-5p, miR-16-5p, miR-30c-5p, miR-19b-3p and miR-148b-3p at 28 d post NM. Collectively, these data show that NM promotes histone remodeling and alterations in miRNA expression linked to lung macrophage responses during inflammatory injury and fibrosis.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
DeSantis-Rodrigues, Andrea; Hahn, Rita A; Zhou, Peihong; Babin, Michael; Svoboda, Kathy K H; Chang, Yoke-Chen; Gerecke, Donald R; Gordon, Marion K
SM1997 downregulates mustard-induced enzymes that disrupt corneal epithelial attachment Journal Article
In: Anat Rec (Hoboken), vol. 304, no. 9, pp. 1974–1983, 2021, ISSN: 1932-8494.
@article{pmid33554453,
title = {SM1997 downregulates mustard-induced enzymes that disrupt corneal epithelial attachment},
author = {Andrea DeSantis-Rodrigues and Rita A Hahn and Peihong Zhou and Michael Babin and Kathy K H Svoboda and Yoke-Chen Chang and Donald R Gerecke and Marion K Gordon},
url = {https://pubmed.ncbi.nlm.nih.gov/33554453},
doi = {10.1002/ar.24597},
issn = {1932-8494},
year = {2021},
date = {2021-01-01},
urldate = {2021-01-01},
journal = {Anat Rec (Hoboken)},
volume = {304},
number = {9},
pages = {1974--1983},
abstract = {Amino-Plex (SM1997) is a spray or liquid cosmeceutical that has been used for skin dryness, aging, or sun exposure. Its formulation includes electrolytes, trace minerals, amino acids, peptides, nucleosides and nucleotides, all substances that are <10 kDa. It is designed to increase oxygen levels in cells, improve glucose transport, stimulate ATP synthesis, and stimulate collagen formation, actions that can help facilitate repair of damaged cells. It also supports collagen synthesis and formation of healthy granulation tissue, accelerating reepithelization of damaged skin. Here, SM1997 has been tested as an agent to improve the healing of mustard injury to the cornea. The results indicate that SM1997 facilitates the retention of corneal epithelial attachment when applied to corneal organ cultures after nitrogen mustard exposure. In addition, it reduces the activation of enzymes that lead to epithelial-stromal separation, namely, ADAM17 and MMP-9. Therefore, SM1997 should be further investigated as a potential therapy sulfur mustard and nitrogen mustard exposure.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Malaviya, Rama; Bellomo, Alyssa; Abramova, Elena; Croutch, Claire R; Roseman, Julie; Tuttle, Rick; Peters, Eric; Casillas, Robert P; Sunil, Vasanthi R; Laskin, Jeffrey D; Laskin, Debra L
Pulmonary injury and oxidative stress in rats induced by inhaled sulfur mustard is ameliorated by anti-tumor necrosis factor-α antibody Journal Article
In: Toxicol Appl Pharmacol, vol. 428, pp. 115677, 2021, ISSN: 1096-0333.
@article{pmid34390737,
title = {Pulmonary injury and oxidative stress in rats induced by inhaled sulfur mustard is ameliorated by anti-tumor necrosis factor-α antibody},
author = {Rama Malaviya and Alyssa Bellomo and Elena Abramova and Claire R Croutch and Julie Roseman and Rick Tuttle and Eric Peters and Robert P Casillas and Vasanthi R Sunil and Jeffrey D Laskin and Debra L Laskin},
url = {https://pubmed.ncbi.nlm.nih.gov/34390737},
doi = {10.1016/j.taap.2021.115677},
issn = {1096-0333},
year = {2021},
date = {2021-01-01},
urldate = {2021-01-01},
journal = {Toxicol Appl Pharmacol},
volume = {428},
pages = {115677},
abstract = {Sulfur mustard (SM) is a bifunctional alkylating agent that causes severe injury to the respiratory tract. This is accompanied by an accumulation of macrophages in the lung and the release of the proinflammatory cytokine, tumor necrosis factor (TNF)α. In these studies, we analyzed the effects of blocking TNFα on lung injury, inflammation and oxidative stress induced by inhaled SM. Rats were treated with SM vapor (0.4 mg/kg) or air control by intratracheal inhalation. This was followed 15-30 min later by anti-TNFα antibody (15mg/kg, i.v.) or PBS control. Animals were euthanized 3 days later. Anti-TNFα antibody was found to blunt SM-induced peribronchial edema, perivascular inflammation and alveolar plasma protein and inflammatory cell accumulation in the lung; this was associated with reduced expression of PCNA in histologic sections and decreases in BAL levels of fibrinogen. SM-induced increases in inflammatory proteins including soluble receptor for glycation end products, its ligand, high mobility group box-1, and matrix metalloproteinase-9 were also reduced by anti-TNFα antibody administration, along with increases in numbers of lung macrophages expressing TNFα, cyclooxygenase-2 and inducible nitric oxide synthase. This was correlated with reduced oxidative stress as measured by expression of heme oxygenase-1 and Ym-1. Together, these data suggest that inhibiting TNFα may represent an efficacious approach to mitigating acute lung injury, inflammatory macrophage activation, and oxidative stress induced by inhaled sulfur mustard.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}