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Recent Publications of Rutgers University CounterACT Research Center of Excellence Members

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NCBI: db=pubmed; Term=Laskin JD OR Laskin DL OR Marion MK OR Gerecke DR OR Heindel ND OR Heck DE OR Sinko PJ
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Macrophages and inflammatory mediators in pulmonary injury induced by mustard vesicants.

Tue, 08/01/2017 - 20:47
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Macrophages and inflammatory mediators in pulmonary injury induced by mustard vesicants.

Ann N Y Acad Sci. 2016 Jun;1374(1):168-75

Authors: Malaviya R, Sunil VR, Venosa A, Vayas KN, Businaro R, Heck DE, Laskin JD, Laskin DL

Abstract
Sulfur mustard (SM) and nitrogen mustard (NM) are cytotoxic alkylating agents that cause severe and progressive injury to the respiratory tract, resulting in significant morbidity and mortality. Evidence suggests that macrophages and the inflammatory mediators they release play roles in both acute and long-term pulmonary injuries caused by mustards. In this article, we review the pathogenic effects of SM and NM on the respiratory tract and potential inflammatory mechanisms contributing to this activity.

PMID: 27351588 [PubMed - indexed for MEDLINE]

The molecules in the corneal basement membrane zone affected by mustard exposure suggest potential therapies.

Thu, 07/20/2017 - 10:34
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The molecules in the corneal basement membrane zone affected by mustard exposure suggest potential therapies.

Ann N Y Acad Sci. 2016 Aug;1378(1):158-165

Authors: Gordon MK, DeSantis-Rodrigues A, Hahn R, Zhou P, Chang Y, Svoboda KK, Gerecke DR

Abstract
Mustard exposures result in epithelial-stromal separations in the cornea and epidermal-dermal separations in the skin. Large blisters often manifest in skin, while the cornea develops microblisters, and, when enough form, the epithelium sloughs. If the exposure is severe, healing can be imperfect and can result in long-term adverse consequences. For the cornea, this could manifest as recurrent corneal erosions. Since the corneal epithelial-stromal separations are in the region identified by electron microscopy as the lamina lucida, the same region affected by the blistering disease junctional epidermolysis bullosa (JEB), we postulated that the molecules that are defective in JEB would be the same ones cleaved by mustard compounds. These molecules are α6β4 integrin and collagen XVII, which can be cleaved by matrix metalloproteinase-9 (MMP-9) and ADAM17, respectively. Therefore, our laboratory has tested MMP-9 and ADAM17 inhibitors as potential therapies to attenuate corneal mustard injury. Our results demonstrated that inhibiting MMP-9 and ADAM17 resulted in less epithelial-stromal separation in the corneas at 24 h postexposure, as compared with using only medium as a therapy.

PMID: 27737494 [PubMed - indexed for MEDLINE]

Multi-inhibitor prodrug constructs for simultaneous delivery of anti-inflammatory agents to mustard-induced skin injury.

Thu, 07/20/2017 - 10:34
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Multi-inhibitor prodrug constructs for simultaneous delivery of anti-inflammatory agents to mustard-induced skin injury.

Ann N Y Acad Sci. 2016 Aug;1378(1):174-179

Authors: Lacey CJ, Wohlman I, Guillon C, Saxena J, Fianu-Velgus C, Aponte E, Young SC, Heck DE, Joseph LB, Laskin JD, Heindel ND

Abstract
The molecular pathology of sulfur mustard injury is complex, with at least nine inflammation-related enzymes and receptors upregulated in the zone of the insult. A new approach wherein inhibitors of these targets have been linked by hydrolyzable bonds, either one to one or via separate preattachment to a carrier molecule, has been shown to significantly enhance the therapeutic response compared with the individual agents. This article reviews the published work of the authors in this drug development domain over the last 8 years.

PMID: 27505078 [PubMed - indexed for MEDLINE]

Preparedness and response to chemical and biological threats: the role of exposure science.

Thu, 07/20/2017 - 10:34
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Preparedness and response to chemical and biological threats: the role of exposure science.

Ann N Y Acad Sci. 2016 Aug;1378(1):108-117

Authors: Lioy PJ, Laskin JD, Georgopoulos PG

Abstract
There are multiple components to emergency preparedness and the response to chemical and biological threat agents. The 5Rs framework (rescue, reentry, recovery, restoration, and rehabitation) outlines opportunities to apply exposure science in emergency events. Exposure science provides guidance and refined tools for characterizing, assessing, and reducing risks from catastrophic events, such as the release of hazardous airborne chemicals or biological agents. Important challenges to be met include deployment of assets, including medications, before and after an emergency response situation. Assessment of past studies demonstrates the value of integrating exposure science methods into risk analysis and the management of catastrophic events.

PMID: 27479653 [PubMed - indexed for MEDLINE]

Novel approaches to mitigating parathion toxicity: targeting cytochrome P450-mediated metabolism with menadione.

Thu, 07/20/2017 - 10:34
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Novel approaches to mitigating parathion toxicity: targeting cytochrome P450-mediated metabolism with menadione.

Ann N Y Acad Sci. 2016 Aug;1378(1):80-86

Authors: Jan YH, Richardson JR, Baker AA, Mishin V, Heck DE, Laskin DL, Laskin JD

Abstract
Accidental or intentional exposures to parathion, an organophosphorus (OP) pesticide, can cause severe poisoning in humans. Parathion toxicity is dependent on its metabolism by the cytochrome P450 (CYP) system to paraoxon (diethyl 4-nitrophenyl phosphate), a highly poisonous nerve agent and potent inhibitor of acetylcholinesterase. We have been investigating inhibitors of CYP-mediated bioactivation of OPs as a method of preventing or reversing progressive parathion toxicity. It is well recognized that NADPH-cytochrome P450 reductase, an enzyme required for the transfer of electrons to CYPs, mediates chemical redox cycling. In this process, the enzyme diverts electrons from CYPs to support chemical redox cycling, which results in inhibition of CYP-mediated biotransformation. Using menadione as the redox-cycling chemical, we discovered that this enzymatic reaction blocks metabolic activation of parathion in rat and human liver microsomes and in recombinant CYPs important to parathion metabolism, including CYP1A2, CYP2B6, and CYP3A4. Administration of menadione to rats reduces metabolism of parathion, as well as parathion-induced inhibition of brain cholinesterase activity. This resulted in inhibition of parathion neurotoxicity. Menadione has relatively low toxicity and is approved by the Food and Drug Administration for other indications. Its ability to block parathion metabolism makes it an attractive therapeutic candidate to mitigate parathion-induced neurotoxicity.

PMID: 27441453 [PubMed - indexed for MEDLINE]

Multidisciplinary approaches to stimulate wound healing.

Thu, 07/20/2017 - 10:34
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Multidisciplinary approaches to stimulate wound healing.

Ann N Y Acad Sci. 2016 Aug;1378(1):137-142

Authors: Businaro R, Corsi M, Di Raimo T, Marasco S, Laskin DL, Salvati B, Capoano R, Ricci S, Siciliano C, Frati G, De Falco E

Abstract
New civil wars and waves of terrorism are causing crucial social changes, with consequences in all fields, including health care. In particular, skin injuries are evolving as an epidemic issue. From a physiological standpoint, although wound repair takes place more rapidly in the skin than in other tissues, it is still a complex organ to reconstruct. Genetic and clinical variables, such as diabetes, smoking, and inflammatory/immunological pathologies, are also important risk factors limiting the regenerative potential of many therapeutic applications. Therefore, optimization of current clinical strategies is critical. Here, we summarize the current state of the field by focusing on stem cell therapy applications in wound healing, with an emphasis on current clinical approaches being developed. These involve protocols for the ex vivo expansion of adipose tissue-derived mesenchymal stem cells by means of a patented Good Manufacturing Practice-compliant platelet lysate. Combinations of multiple strategies, including genetic modifications and stem cells, biomimetic scaffolds, and novel vehicles, such as nanoparticles, are also discussed as future approaches.

PMID: 27434638 [PubMed - indexed for MEDLINE]

Tetramethylenedisulfotetramine: pest control gone awry.

Thu, 07/20/2017 - 10:34
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Tetramethylenedisulfotetramine: pest control gone awry.

Ann N Y Acad Sci. 2016 Aug;1378(1):68-79

Authors: Shakarjian MP, Laukova M, Velíšková J, Stanton PK, Heck DE, Velíšek L

Abstract
Incidences of pesticide poisonings are a significant cause of morbidity and mortality worldwide. The seizure-inducing rodenticide tetramethylenedisulfotetramine is one of the most toxic of these agents. Although banned, it has been responsible for thousands of accidental, intentional, and mass poisonings in mainland China and elsewhere. An optimal regimen for treatment of poisoning has not been established. Its facile synthesis from easily obtained starting materials, extreme potency, and lack of odor, color, or taste make it a potential chemical threat agent. This review describes the toxicologic properties of this agent, more recent advances in our understanding of its properties, and recommendations for future research.

PMID: 27384716 [PubMed - indexed for MEDLINE]

Tissue injury and repair following cutaneous exposure of mice to sulfur mustard.

Thu, 07/20/2017 - 10:34
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Tissue injury and repair following cutaneous exposure of mice to sulfur mustard.

Ann N Y Acad Sci. 2016 Aug;1378(1):118-123

Authors: Joseph LB, Composto GM, Heck DE

Abstract
In mouse skin, sulfur mustard (SM) is a potent vesicant, damaging both the epidermis and the dermis. The extent of wounding is dependent on the dose of SM and the duration of exposure. Initial responses include erythema, pruritus, edema, and xerosis; this is followed by an accumulation of inflammatory leukocytes in the tissue, activation of mast cells, and the release of mediators, including proinflammatory cytokines and bioactive lipids. These proinflammatory mediators contribute to damaging the epidermis, hair follicles, and sebaceous glands and to disruption of the epidermal basement membrane. This can lead to separation of the epidermis from the dermis, resulting in a blister, which ruptures, leading to the formation of an eschar. The eschar stimulates the formation of a neoepidermis and wound repair and may result in persistent epidermal hyperplasia. Epidermal damage and repair is associated with upregulation of enzymes generating proinflammatory and pro-growth/pro-wound healing mediators, including cyclooxygenase-2, which generates prostanoids, inducible nitric oxide synthase, which generates nitric oxide, fibroblast growth factor receptor 2, and galectin-3. Characterization of the mediators regulating structural changes in the skin during SM-induced tissue damage and wound healing will aid in the development of therapeutic modalities to mitigate toxicity and stimulate tissue repair processes.

PMID: 27371823 [PubMed - indexed for MEDLINE]

The effect of fibroblast growth factor 15 deficiency on the development of high fat diet induced non-alcoholic steatohepatitis.

Wed, 07/05/2017 - 10:06

The effect of fibroblast growth factor 15 deficiency on the development of high fat diet induced non-alcoholic steatohepatitis.

Toxicol Appl Pharmacol. 2017 Jun 30;:

Authors: Schumacher JD, Kong B, Pan Y, Zhan L, Sun R, Aa J, Rizzolo D, Richardson JR, Chen A, Goedken M, Aleksunes LM, Laskin DL, Guo GL

Abstract
Non-alcoholic steatohepatitis (NASH) is a form of non-alcoholic fatty liver disease (NAFLD) characterized by steatosis, inflammation, and fibrosis often associated with metabolic syndrome. Fibroblast growth factor 15 (FGF15), an endocrine factor mainly produced in the distal part of small intestine, has emerged to be a critical factor in regulating bile acid homeostasis, energy metabolism, and liver regeneration. We hypothesized that FGF15 alters the development of each of the listed features of NASH. To test this hypothesis, four-week old male Fgf15(-/-) and their corresponding wild-type (WT) mice were fed either a high fat diet (HFD) or a control chow diet for six months. The results confirmed that HFD feeding for six months in WT mice recapitulated human NASH phenotype, including macrovesicular steatosis, inflammation, and fibrosis. Whereas FGF15 deficiency had no effect on the severity of liver steatosis or inflammation, it was associated with decreased liver fibrosis. Furthermore, FGF15 deficiency resulted in abnormal bile acid homeostasis, increased insulin resistance, increased HFD-induced serum triglycerides, decreased inductions of hepatic cholesterol content by HFD, and altered gene expression of lipid metabolic enzymes. These data suggest that FGF15 improves lipid homeostasis and reduces bile acid synthesis, but promotes fibrosis during the development of NASH.

PMID: 28673684 [PubMed - as supplied by publisher]

Anti-TNFα Therapy in Inflammatory Lung Diseases bn.

Sat, 06/24/2017 - 10:26
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Anti-TNFα Therapy in Inflammatory Lung Diseases bn.

Pharmacol Ther. 2017 Jun 19;:

Authors: Malaviya R, Laskin JD, Laskin DL

Abstract
Increased levels of tumor necrosis factor (TNF) α have been linked to a number of pulmonary inflammatory diseases including asthma, chronic obstructive pulmonary disease (COPD), acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), sarcoidosis, and interstitial pulmonary fibrosis (IPF). TNFα plays multiple roles in disease pathology by inducing an accumulation of inflammatory cells, stimulating the generation of inflammatory mediators, and causing oxidative and nitrosative stress, airway hyperresponsiveness and tissue remodeling. TNF-targeting biologics, therefore, present a potentially highly efficacious treatment option. This review summarizes current knowledge on the role of TNFα in pulmonary disease pathologies, with a focus on the therapeutic potential of TNFα-targeting agents in treating inflammatory lung diseases.

PMID: 28642115 [PubMed - as supplied by publisher]

Localization of the placental BCRP/ABCG2 transporter to lipid rafts: Role for cholesterol in mediating efflux activity.

Mon, 06/19/2017 - 10:33

Localization of the placental BCRP/ABCG2 transporter to lipid rafts: Role for cholesterol in mediating efflux activity.

Placenta. 2017 Jul;55:29-36

Authors: Szilagyi JT, Vetrano AM, Laskin JD, Aleksunes LM

Abstract
INTRODUCTION: The breast cancer resistance protein (BCRP/ABCG2) is an efflux transporter in the placental barrier. By transporting chemicals from the fetal to the maternal circulation, BCRP limits fetal exposure to a range of drugs, toxicants, and endobiotics such as bile acids and hormones. The purpose of the present studies was to 1) determine whether BCRP localizes to highly-ordered, cholesterol-rich lipid raft microdomains in placenta microvillous membranes, and 2) determine the impact of cholesterol on BCRP-mediated placental transport in vitro.
METHODS: BCRP expression was analyzed in lipid rafts isolated from placentas from healthy, term pregnancies and BeWo trophoblasts by density gradient ultracentrifugation. BeWo cells were also tested for their ability to efflux BCRP substrates after treatment with the cholesterol sequestrant methyl-β-cyclodextrin (MβCD, 5 mM, 1 h) or the cholesterol synthesis inhibitor pravastatin (200 μM, 48 h).
RESULTS AND DISCUSSION: BCRP was found to co-localize with lipid raft proteins in detergent-resistant, lipid raft-containing fractions from placental microvillous membranes and BeWo cells. Treatment of BeWo cells with MβCD redistributed BCRP protein into higher density non-lipid raft fractions. Repletion of the cells with cholesterol restored BCRP localization to lipid raft-containing fractions. Treatment of BeWo cells with MβCD or pravastatin increased cellular retention of two BCRP substrates, the fluorescent dye Hoechst 33342 and the mycotoxin zearalenone. Repletion with cholesterol restored BCRP transporter activity. Taken together, these data demonstrate that cholesterol may play a critical role in the post-translational regulation of BCRP in placental lipid rafts.

PMID: 28623970 [PubMed - in process]

Mitigation of nitrogen mustard mediated skin injury by a novel indomethacin bifunctional prodrug.

Wed, 06/14/2017 - 10:12
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Mitigation of nitrogen mustard mediated skin injury by a novel indomethacin bifunctional prodrug.

Exp Mol Pathol. 2016 Jun;100(3):522-31

Authors: Composto GM, Laskin JD, Laskin DL, Gerecke DR, Casillas RP, Heindel ND, Joseph LB, Heck DE

Abstract
Nitrogen mustard (NM) is a bifunctional alkylating agent that is highly reactive in the skin causing extensive tissue damage and blistering. In the present studies, a modified cutaneous murine patch model was developed to characterize NM-induced injury and to evaluate the efficacy of an indomethacin pro-drug in mitigating toxicity. NM (20μmol) or vehicle control was applied onto 6mm glass microfiber filters affixed to the shaved dorsal skin of CD-1 mice for 6min. This resulted in absorption of approximately 4μmol of NM. NM caused localized skin damage within 1 d, progressing to an eschar within 2-3 d, followed by wound healing after 4-5 d. NM-induced injury was associated with increases in skin thickness, inflammatory cell infiltration, reduced numbers of sebocytes, basal keratinocyte double stranded DNA breaks, as measured by phospho-histone 2A.X expression, mast cell degranulation and increases in inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Wound healing was characterized by epidermal hyperplasia and marked increases in basal cells expressing proliferating cell nuclear antigen. A novel indomethacin-anticholinergic prodrug (4338) designed to target cyclooxygenases and acetylcholinesterase (AChE), was found to markedly suppress NM toxicity, decreasing wound thickness and eschar formation. The prodrug also inhibited mast cell degranulation, suppressed keratinocyte expression of iNOS and COX-2, as well as markers of epidermal proliferation. These findings indicate that a novel bifunctional pro-drug is effective in limiting NM mediated dermal injury. Moreover, our newly developed cutaneous patch model is a sensitive and reproducible method to assess the mechanism of action of countermeasures.

PMID: 27189522 [PubMed - indexed for MEDLINE]

Diacetyl/L-xylulose reductase mediates chemical redox cycling in lung epithelial cells.

Fri, 06/09/2017 - 10:45

Diacetyl/L-xylulose reductase mediates chemical redox cycling in lung epithelial cells.

Chem Res Toxicol. 2017 Jun 08;:

Authors: Yang S, Jan YH, Mishin V, Heck DE, Laskin DL, Laskin JD

Abstract
Reactive carbonyls such as diacetyl (2,3-butanedione) and 2,3-pentanedione in tobacco and many food and consumer products are known to cause severe respiratory diseases. Many of these chemicals are detoxified by carbonyl reductases in the lung, in particular, dicarbonyl/L-xylulose reductase (DCXR), a multifunctional enzyme important in glucose metabolism. DCXR is a member of the short-chain dehydrogenase/reductase (SDR) superfamily. Using recombinant human enzyme, we discovered that DCXR mediates redox cycling of a variety of quinones generating superoxide anion, hydrogen peroxide and, in the presence of transition metals, hydroxyl radicals. Redox cycling activity preferentially utilized NADH as a co-substrate and was greatest for 9,10-phenanthrenequinone and 1,2-naphthoquinone, followed by 1,4-naphthoquinone and 2-methyl-1,4-naphthoquinone (menadione). Using 9,10-phenanthrenequinone as the substrate, quinone redox cycling was found to inhibit DCXR reduction of L-xylulose and diacetyl. Competitive inhibition of enzyme activity by the quinone was observed with respect to diacetyl (Ki = 190 µM) and L-xylulose (Ki = 940 µM). Abundant DCXR activity was identified in A549 lung epithelial cells when diacetyl was used as a substrate. Quinones inhibited reduction of this dicarbonyl, causing an accumulation of diacetyl in the cells and culture medium and a decrease in acetoin, the reduced product of diacetyl. The identification of DCXR as an enzyme activity mediating chemical redox cycling suggests that it may be important in generating cytotoxic reactive oxygen species in the lung. These activities, together with inhibition dicarbonyl/L-xylulose metabolism by redox-active chemicals, as well as consequent deficiencies in pentose metabolism, are likely to contribute to lung injury following exposure to dicarbonyls and quinones.

PMID: 28595002 [PubMed - as supplied by publisher]

World Trade Center (WTC) dust exposure in mice is associated with inflammation, oxidative stress and epigenetic changes in the lung.

Fri, 06/02/2017 - 10:32
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World Trade Center (WTC) dust exposure in mice is associated with inflammation, oxidative stress and epigenetic changes in the lung.

Exp Mol Pathol. 2017 Feb;102(1):50-58

Authors: Sunil VR, Vayas KN, Fang M, Zarbl H, Massa C, Gow AJ, Cervelli JA, Kipen H, Laumbach RJ, Lioy PJ, Laskin JD, Laskin DL

Abstract
Exposure to World Trade Center (WTC) dust has been linked to respiratory disease in humans. In the present studies we developed a rodent model of WTC dust exposure to analyze lung oxidative stress and inflammation, with the goal of elucidating potential epigenetic mechanisms underlying these responses. Exposure of mice to WTC dust (20μg, i.t.) was associated with upregulation of heme oxygenase-1 and cyclooxygenase-2 within 3days, a response which persisted for at least 21days. Whereas matrix metalloproteinase was upregulated 7days post-WTC dust exposure, IL-6RA1 was increased at 21days; conversely, expression of mannose receptor, a scavenger receptor important in particle clearance, decreased. After WTC dust exposure, increases in methylation of histone H3 lysine K4 at 3days, lysine K27 at 7days and lysine K36, were observed in the lung, along with hypermethylation of Line-1 element at 21days. Alterations in pulmonary mechanics were also observed following WTC dust exposure. Thus, 3days post-exposure, lung resistance and tissue damping were decreased. In contrast at 21days, lung resistance, central airway resistance, tissue damping and tissue elastance were increased. These data demonstrate that WTC dust-induced inflammation and oxidative stress are associated with epigenetic modifications in the lung and altered pulmonary mechanics. These changes may contribute to the development of WTC dust pathologies.

PMID: 27986442 [PubMed - indexed for MEDLINE]

The spleen as an extramedullary source of inflammatory cells responding to acetaminophen-induced liver injury.

Wed, 05/31/2017 - 10:32
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The spleen as an extramedullary source of inflammatory cells responding to acetaminophen-induced liver injury.

Toxicol Appl Pharmacol. 2016 Aug 01;304:110-20

Authors: Mandal M, Gardner CR, Sun R, Choi H, Lad S, Mishin V, Laskin JD, Laskin DL

Abstract
Macrophages have been shown to play a role in acetaminophen (APAP)-induced hepatotoxicity, contributing to both pro- and anti-inflammatory processes. In these studies, we analyzed the role of the spleen as an extramedullary source of hepatic macrophages. APAP administration (300mg/kg, i.p.) to control mice resulted in an increase in CD11b(+) infiltrating Ly6G(+) granulocytic and Ly6G(-) monocytic cells in the spleen and the liver. The majority of the Ly6G(+) cells were also positive for the monocyte/macrophage activation marker, Ly6C, suggesting a myeloid derived suppressor cell (MDSC) phenotype. By comparison, Ly6G(-) cells consisted of 3 subpopulations expressing high, intermediate, and low levels of Ly6C. Splenectomy was associated with increases in mature (F4/80(+)) and immature (F4/80(-)) pro-inflammatory Ly6C(hi) macrophages and mature anti-inflammatory (Ly6C(lo)) macrophages in the liver after APAP; increases in MDSCs were also noted in the livers of splenectomized (SPX) mice after APAP. This was associated with increases in APAP-induced expression of chemokine receptors regulating pro-inflammatory (CCR2) and anti-inflammatory (CX3CR1) macrophage trafficking. In contrast, APAP-induced increases in pro-inflammatory galectin-3(+) macrophages were blunted in livers of SPX mice relative to control mice, along with hepatic expression of TNF-α, as well as the anti-inflammatory macrophage markers, FIZZ-1 and YM-1. These data demonstrate that multiple subpopulations of pro- and anti-inflammatory cells respond to APAP-induced injury, and that these cells originate from distinct hematopoietic reservoirs.

PMID: 27163765 [PubMed - indexed for MEDLINE]

Mustard vesicant-induced lung injury: Advances in therapy.

Tue, 05/30/2017 - 10:15
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Mustard vesicant-induced lung injury: Advances in therapy.

Toxicol Appl Pharmacol. 2016 Aug 15;305:1-11

Authors: Weinberger B, Malaviya R, Sunil VR, Venosa A, Heck DE, Laskin JD, Laskin DL

Abstract
Most mortality and morbidity following exposure to vesicants such as sulfur mustard is due to pulmonary toxicity. Acute injury is characterized by epithelial detachment and necrosis in the pharynx, trachea and bronchioles, while long-term consequences include fibrosis and, in some instances, cancer. Current therapies to treat mustard poisoning are primarily palliative and do not target underlying pathophysiologic mechanisms. New knowledge about vesicant-induced pulmonary disease pathogenesis has led to the identification of potentially efficacious strategies to reduce injury by targeting inflammatory cells and mediators including reactive oxygen and nitrogen species, proteases and proinflammatory/cytotoxic cytokines. Therapeutics under investigation include corticosteroids, N-acetyl cysteine, which has both mucolytic and antioxidant properties, inducible nitric oxide synthase inhibitors, liposomes containing superoxide dismutase, catalase, and/or tocopherols, protease inhibitors, and cytokine antagonists such as anti-tumor necrosis factor (TNF)-α antibody and pentoxifylline. Antifibrotic and fibrinolytic treatments may also prove beneficial in ameliorating airway obstruction and lung remodeling. More speculative approaches include inhibitors of transient receptor potential channels, which regulate pulmonary epithelial cell membrane permeability, non-coding RNAs and mesenchymal stem cells. As mustards represent high priority chemical threat agents, identification of effective therapeutics for mitigating toxicity is highly significant.

PMID: 27212445 [PubMed - indexed for MEDLINE]

Mustard vesicants alter expression of the endocannabinoid system in mouse skin.

Wed, 05/24/2017 - 10:58
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Mustard vesicants alter expression of the endocannabinoid system in mouse skin.

Toxicol Appl Pharmacol. 2016 Jul 15;303:30-44

Authors: Wohlman IM, Composto GM, Heck DE, Heindel ND, Lacey CJ, Guillon CD, Casillas RP, Croutch CR, Gerecke DR, Laskin DL, Joseph LB, Laskin JD

Abstract
Vesicants including sulfur mustard (SM) and nitrogen mustard (NM) are bifunctional alkylating agents that cause skin inflammation, edema and blistering. This is associated with alterations in keratinocyte growth and differentiation. Endogenous cannabinoids, including N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoyl glycerol (2-AG), are important in regulating inflammation, keratinocyte proliferation and wound healing. Their activity is mediated by binding to cannabinoid receptors 1 and 2 (CB1 and CB2), as well as peroxisome proliferator-activated receptor alpha (PPARα). Levels of endocannabinoids are regulated by fatty acid amide hydrolase (FAAH). We found that CB1, CB2, PPARα and FAAH were all constitutively expressed in mouse epidermis and dermal appendages. Topical administration of NM or SM, at concentrations that induce tissue injury, resulted in upregulation of FAAH, CB1, CB2 and PPARα, a response that persisted throughout the wound healing process. Inhibitors of FAAH including a novel class of vanillyl alcohol carbamates were found to be highly effective in suppressing vesicant-induced inflammation in mouse skin. Taken together, these data indicate that the endocannabinoid system is important in regulating skin homeostasis and that inhibitors of FAAH may be useful as medical countermeasures against vesicants.

PMID: 27125198 [PubMed - indexed for MEDLINE]

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