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Sarcoid-Like Granulomatous Disease: Pathologic Case Series in World Trade Center Dust Exposed Rescue and Recovery Workers.

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Sarcoid-Like Granulomatous Disease: Pathologic Case Series in World Trade Center Dust Exposed Rescue and Recovery Workers.

Int J Environ Res Public Health. 2019 03 06;16(5):

Authors: Sunil VR, Radbel J, Hussain S, Vayas KN, Cervelli J, Deen M, Kipen H, Udasin I, Laumbach R, Sunderram J, Laskin JD, Laskin DL

Abstract
Sarcoid-like granulomatous diseases (SGD) have been previously identified in cohorts of World Trade Center (WTC) dust-exposed individuals. In the present studies, we analyzed lung and/or lymph node biopsies from patients referred to our clinic with suspected WTC dust-induced lung disease to evaluate potential pathophysiologic mechanisms. Histologic sections of lung and/or lymph node samples were analyzed for markers of injury, oxidative stress, inflammation, fibrosis, and epigenetic modifications. Out of seven patients examined, we diagnosed four with SGD and two with pulmonary fibrosis; one was diagnosed later with SGD at another medical facility. Patients with SGD were predominantly white, obese men, who were less than 50 years old and never smoked. Cytochrome b5, cytokeratin 17, heme oxygenase-1, lipocalin-2, inducible nitric oxide synthase, cyclooxygenase 2, tumor necrosis factor α, ADP-ribosylation factor-like GTPase 11, mannose receptor-1, galectin-3, transforming growth factor β, histone-3 and methylated histone-3 were identified in lung and lymph nodes at varying levels in all samples examined. Three of the biopsy samples with granulomas displayed peri-granulomatous fibrosis. These findings are important and suggest the potential of WTC dust-induced fibrotic sarcoid. It is likely that patient demographics and/or genetic factors influence the response to WTC dust injury and that these contribute to different pathological outcomes.

PMID: 30845693 [PubMed - indexed for MEDLINE]

Functional Evidence of Pulmonary Extracellular Vesicles in Infectious and Noninfectious Lung Inflammation.

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Functional Evidence of Pulmonary Extracellular Vesicles in Infectious and Noninfectious Lung Inflammation.

J Immunol. 2018 09 01;201(5):1500-1509

Authors: Lee H, Zhang D, Laskin DL, Jin Y

Abstract
Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a highly complex process that can be triggered by both noninfectious (sterile) and infectious stimuli. Inflammatory lung responses are one of the key features in the pathogenesis of this devastating syndrome. How ALI/ARDS-associated inflammation develops remains incompletely understood, particularly after exposure to sterile stimuli. Emerging evidence suggests that extracellular vesicles (EVs) regulate intercellular communication and inflammatory responses in various diseases. In this study, we characterized the generation and function of pulmonary EVs in the setting of ALI/ARDS, induced by sterile stimuli (oxidative stress or acid aspiration) and infection (LPS/Gram-negative bacteria) in mice. EVs detected in bronchoalveolar lavage fluid (BALF) were markedly increased after exposure of animals to both types of stimuli. After sterile stimuli, alveolar type-І epithelial cells were the main source of the BALF EVs. In contrast, infectious stimuli-induced BALF EVs were mainly derived from alveolar macrophages (AMs). Functionally, BALF EVs generated in both the noninfectious and infectious ALI models promoted the recruitment of macrophages in in vivo mouse models. Furthermore, BALF EVs differentially regulated AM production of cytokines and inflammatory mediators, as well as TLR expression in AMs in vivo. Regardless of their origin, BALF EVs contributed significantly to the development of lung inflammation in both the sterile and infectious ALI. Collectively, our results provide novel insights into the mechanisms by which EVs regulate the development of lung inflammation in response to diverse stimuli, potentially providing novel therapeutic and diagnostic targets for ALI/ARDS.

PMID: 29997122 [PubMed - indexed for MEDLINE]

Phototoxicity of 7-oxycoumarins with keratinocytes in culture.

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Phototoxicity of 7-oxycoumarins with keratinocytes in culture.

Bioorg Chem. 2019 May 25;89:103014

Authors: Guillon C, Jan YH, Heck DE, Mariano TM, Rapp RD, Jetter M, Kardos K, Whittemore M, Akyea E, Jabin I, Laskin JD, Heindel ND

Abstract
Seventy-one 7-oxycoumarins, 66 synthesized and 5 commercially sourced, were tested for their ability to inhibit growth in murine PAM212 keratinocytes. Forty-nine compounds from the library demonstrated light-induced lethality. None was toxic in the absence of UVA light. Structure-activity correlations indicate that the ability of the compounds to inhibit cell growth was dependent not only on their physiochemical characteristics, but also on their ability to absorb UVA light. Relative lipophilicity was an important factor as was electron density in the pyrone ring. Coumarins with electron withdrawing moieties - cyano and fluoro at C3 - were considerably less active while those with bromines or iodine at that location displayed enhanced activity. Coumarins that were found to inhibit keratinocyte growth were also tested for photo-induced DNA plasmid nicking. A concentration-dependent alteration in migration on neutral gels caused by nicking was observed.

PMID: 31170642 [PubMed - as supplied by publisher]

Identification of a Pyranocoumarin Photosensitizer that is a Potent Inhibitor of Keratinocyte Growth.

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Identification of a Pyranocoumarin Photosensitizer that is a Potent Inhibitor of Keratinocyte Growth.

Photochem Photobiol. 2018 05;94(3):577-582

Authors: Laskin JD, Jan YH, Jetter MM, Guillon CD, Mariano TM, Heck DE, Heindel ND

Abstract
Photosensitizers are used in the treatment of epidermal proliferation and differentiation disorders such as psoriasis and vitiligo. In these studies, a ring-expanded carbon homolog of the linear psoralen (furo[3,2-g]benzopyran-7-one) class of photosensitizers, 4,10-dimethyl-2H,8H-benzo[1,2-b:5,4-b']dipyran-2-one (NDH2476), was synthesized and analyzed for biological activity. Following activation by ultraviolet light (UVA, 320-400 nm), NDH2476 was found to be a potent inhibitor of keratinocyte growth (IC50  = 9 nm). Similar derivatives methylated in the pyran ring, or containing a saturated pyran ring structure, were markedly less active or inactive as photosensitizers. NDH2476 was found to intercalate and damage DNA following UVA light treatment as determined by plasmid DNA unwinding and nicking experiments. Taken together, these data demonstrate that an intact furan ring in psoralen photosensitizers is not required for keratinocyte growth inhibition or DNA damage. Our findings that low nanomolar concentrations of a benzopyranone derivative were active as a photosensitizer indicates that this or a structurally related compound may be useful in the treatment of skin diseases involving aberrant epidermal cell growth and differentiation.

PMID: 29315592 [PubMed - indexed for MEDLINE]

Hydroxyl Radicals in E-cigarette Vapor and E-vapor Oxidative Potentials under Different Vaping Patterns.

Hydroxyl Radicals in E-cigarette Vapor and E-vapor Oxidative Potentials under Different Vaping Patterns.

Chem Res Toxicol. 2019 Apr 12;:

Authors: Son Y, Mishin V, Laskin JD, Mainelis G, Wackowski OA, Delnevo C, Schwander S, Khlystov A, Samburova V, Meng Q

Abstract
Available studies, while limited in number, suggest that e-cigarette vaping induces oxidative stress, with one potential mechanism being the direct formation of reactive oxygen species (ROS) in e-vapor. In the present studies, we measured the formation of hydroxyl radical (•OH), the most destructive ROS, in e-vapor under a range of relevant vaping patterns (i.e., power settings, solvent concentrations, flavorings). Study results show that increased power output and puff volume correspond with the formation of significantly higher amounts of •OH in e-vapor due to elevated coil temperature and oxygen supply. Vegetable glycerin (VG) e-liquids generated higher •OH levels than propylene glycol (PG) e-liquids, as did flavored e-liquids relative to non-flavored e-liquids. E-vapor in combination with ascorbic acid, which is an abundant biological molecule in human epithelial lining fluid, can also induce •OH formation. The dose of radical per puff associated with e-cigarette vaping was 10-1000 times lower than the reported dose generated by cigarette smoking. However, the daily average •OH dose can be comparable to that from cigarette smoking depending on vaping patterns. Overall, e-cigarette users who use VG-based flavored e-cigarettes at higher power output settings may be at increased risk for •OH exposures and related health consequences such as asthma and chronic obstructive pulmonary disease.

PMID: 30977360 [PubMed - as supplied by publisher]

The sulfur mustard analog mechlorethamine (bis(2-chloroethyl)methylamine) modulates cell cycle progression via the DNA damage response in human lung epithelial A549 cells.

The sulfur mustard analog mechlorethamine (bis(2-chloroethyl)methylamine) modulates cell cycle progression via the DNA damage response in human lung epithelial A549 cells.

Chem Res Toxicol. 2019 Apr 09;:

Authors: Jan YH, Heck DE, Laskin DL, Laskin JD

Abstract
Nitrogen mustard, mechlorethamine (bis(2-chloroethyl)methylamine; HN2) and sulfur mustard, are potent vesicants that modify and disrupt cellular macromolecules, including DNA leading to cytotoxicity and tissue injury. In many cell types, HN2 upregulates DNA damage signaling pathways including ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3-related (ATR), as well as DNA-dependent protein kinase (DNA-PK). In the present studies, we investigated crosstalk between HN2-induced DNA damage response and cell cycle progression using human A549 lung epithelial cells. HN2 (1-20 µM; 24 h) caused a concentration-dependent arrest of cells in the S and G2/M phases of the cell cycle. This was associated with inhibition of DNA synthesis, as measured by incorporation of 5-ethynyl-2'-deoxyuridine (EdU) into S phase cells. Cell cycle arrest was correlated with activation of DNA damage and cell cycle checkpoint signaling. Thus, HN2 treatment resulted in time- and concentration-dependent increases in expression of phosphorylated ATM (S1981), Chk2 (T68), H2AX (Ser139), and p53 (ser15). Activation of DNA damage signaling was most pronounced in S-phase cells followed by G2/M-phase cells. HN2-induced cell cycle arrest was suppressed by the ATM and DNA-PK inhibitors, KU55933 and NU7441, respectively, and to a lesser extent by VE-821, an ATR inhibitor. This was correlated with abrogation of DNA damage checkpoints signaling. These data indicate that activation of ATM, ATR, and DNA-PK signaling pathways by HN2 are important in the mechanism of vesicant-induced cell cycle arrest and cytotoxicity. Drugs that inhibit activation of DNA damage signaling may be effective countermeasures for vesicant-induced tissue injury.

PMID: 30964658 [PubMed - as supplied by publisher]

Quinone and nitrofurantoin redox cycling by recombinant cytochrome b5 reductase.

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Quinone and nitrofurantoin redox cycling by recombinant cytochrome b5 reductase.

Toxicol Appl Pharmacol. 2018 11 15;359:102-107

Authors: Szilagyi JT, Fussell KC, Wang Y, Jan YH, Mishin V, Richardson JR, Heck DE, Yang S, Aleksunes LM, Laskin DL, Laskin JD

Abstract
NADH cytochrome b5 reductase mediates electron transfer from NADH to cytochrome b5 utilizing flavin adenine dinucleotide as a redox cofactor. Reduced cytochrome b5 is an important cofactor in many metabolic reactions including cytochrome P450-mediated xenobiotic metabolism, steroid biosynthesis and fatty acid metabolism, hemoglobin reduction, and methionine and plasmalogen synthesis. Using recombinant human enzyme, we discovered that cytochrome b5 reductase 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 was oxygen-dependent and preferentially utilized NADH as a co-substrate; NADH was 5-10 times more active than NADPH in supporting redox cycling. Redox cycling activity was greatest for 9,10-phenanthrenequinone and 1,2-naphthoquinone, followed by 1,4-naphthoquinone and 2-methyl-1,4-naphthoquinone (menadione), nitrofurantoin and 2-hydroxyestradiol. Using menadione as the substrate, quinone redox cycling was found to inhibit reduction of cytochrome b5 by cytochrome b5 reductase, as measured by heme spectral changes in cytochrome b5. Under anaerobic conditions where redox cycling is inhibited, menadione had no effect on the reduction of cytochrome b5. Chemical redox cycling by cytochrome b5 reductase may be important in generating cytotoxic reactive oxygen species in target tissues. This activity, together with the inhibition of cytochrome b5 reduction by redox-active chemicals and consequent deficiencies in available cellular cytochrome b5, are likely to contribute to tissue injury following exposure to quinones and related redox active chemicals.

PMID: 30222979 [PubMed - indexed for MEDLINE]

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