Evaluation of protease inhibitors and an antioxidant for treatment of sulfur mustard-induced toxic lung injury

Anderson, Dana R.; Taylor, Stephanie L.; Fetterer, David P.; Holmes, Wesley W.

doi:10.1016/j.tox.2008.08.025

Cited by 48 publications

(37 citation statements)

References 25 publications

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“…Oxidative and nitrosative stress have also been shown to contribute to toxicity (Laskin et al, 2010). This is supported by findings that antioxidants ameliorate vesicant-induced lung injury (Anderson et al, 2009; Hoesel et al, 2008; McClintock et al, 2006; McClintock et al, 2002). …”

Section: Introductionmentioning

confidence: 55%

“…Oxidative stress has been proposed to play an important role in vesicant-induced pulmonary toxicity (Anderson et al, 2009; Hoesel et al, 2008; Malaviya et al, 2012; Mukhopadhyay et al, 2006; Sunil et al, 2012). In response to oxidative stress, cells upregulate HO-1, a phase II stress response enzyme with antioxidant and anti-inflammatory activity (Otterbein et al, 1999; Rahman et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

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Pentoxifylline attenuates nitrogen mustard-induced acute lung injury, oxidative stress and inflammation

Sunil

Vayas

Cervelli

et al. 2014

Experimental and Molecular Pathology

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Nitrogen mustard (NM) is a toxic alkylating agent that causes damage to the respiratory tract. Evidence suggests that macrophages and inflammatory mediators including tumor necrosis factor (TNF)α contribute to pulmonary injury. Pentoxifylline is a TNFα inhibitor known to suppress inflammation. In these studies, we analyzed the ability of pentoxifylline to mitigate NM-induced lung injury and inflammation. Exposure of male Wistar rats (250 g; 8–10 weeks) to NM (0.125 mg/kg, i.t.) resulted in severe histolopathological changes in the lung within 3 d of exposure, along with increases in bronchoalveolar lavage (BAL) cell number and protein, indicating inflammation and alveolar-epithelial barrier dysfunction. This was associated with increases in oxidative stress proteins including lipocalin (Lcn)2 and heme oxygenase (HO)-1 in the lung, along with pro-inflammatory/cytotoxic (COX-2+ and MMP-9+), and anti-inflammatory/wound repair (CD163+ and Gal-3+) macrophages. Treatment of rats with pentoxifylline (46.7 mg/kg, i.p.) daily for 3 d beginning 15 min after NM significantly reduced NM-induced lung injury, inflammation, and oxidative stress, as measured histologically and by decreases in BAL cell and protein content, and levels of HO-1 and Lcn2. Macrophages expressing COX-2 and MMP-9 also decreased after pentoxifylline, while CD163+ and Gal-3+ macrophages increased. This was correlated with persistent upregulation of markers of wound repair including pro-surfactant protein-C and proliferating nuclear cell antigen by Type II cells. NM-induced lung injury and inflammation were associated with alterations in the elastic properties of the lung, however these were largely unaltered by pentoxifylline. These data suggest that pentoxifylline may be useful in treating acute lung injury, inflammation and oxidative stress induced by vesicants.

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Section: Introductionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Pentoxifylline attenuates nitrogen mustard-induced acute lung injury, oxidative stress and inflammation

Sunil

Vayas

Cervelli

et al. 2014

Experimental and Molecular Pathology

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“…Adult male Sprague Dawley rats (200-300 g) from Charles River Laboratories (Wilmington, Massachusetts) were used. Animals were exposed to SM or vehicle (ethanol, EtOH) at the USAMRICD Aberdeen Proving Ground using a vapor generator based model as previously reported (Anderson et al, 1996(Anderson et al, , 2000(Anderson et al, , 2009;Gao et al, 2011;Malaviya et al, 2010;Veress et al, 2015). Rats were anesthetized with a combination of ketamine (80 mg/ kg, IM) and xylazine (10 mg/kg, IM).…”

Section: Methodsmentioning

confidence: 99%

From the Cover: Catalytic Antioxidant Rescue of Inhaled Sulfur Mustard Toxicity

et al. 2016

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Sulfur mustard (bis 2-chloroethyl ethyl sulfide, SM) is a powerful bi-functional vesicating chemical warfare agent. SM tissue injury is partially mediated by the overproduction of reactive oxygen species resulting in oxidative stress. We hypothesized that using a catalytic antioxidant (AEOL 10150) to alleviate oxidative stress and secondary inflammation following exposure to SM would attenuate the toxic effects of SM inhalation. Adult male rats were intubated and exposed to SM (1.4 mg/kg), a dose that produces an LD 50 at approximately 24 h. Rats were randomized and treated via subcutaneous injection with either sterile PBS or AEOL 10150 (5 mg/kg, sc, every 4 h) beginning 1 h post-SM exposure. Rats were euthanized between 6 and 48 h after exposure to SM and survival and markers of injury were determined. Catalytic antioxidant treatment improved survival after SM inhalation in a dose-dependent manner, up to 52% over SM PBS at 48 h post-exposure. This improvement was sustained for at least 72 h after SM exposure when treatments were stopped after 48 h. Non-invasive monitoring throughout the duration of the studies also revealed blood oxygen saturations were improved by 10% and clinical scores were reduced by 57% after SM exposure in the catalytic antioxidant treatment group. Tissue analysis showed catalytic antioxidant therapy was able to decrease airway cast formation by 69% at 48 h post-exposure. To investigate antioxidant induced changes at the peak of injury, several biomarkers of oxidative stress and inflammation were evaluated at 24 h post-exposure. AEOL 10150 attenuated SM-mediated lung lipid oxidation, nitrosative stress and many proinflammatory cytokines. The findings indicate that catalytic antioxidants may be useful medical countermeasure against inhaled SM exposure.Key words: sulfur mustard; chemical weapons; antioxidant.Sulfur mustard (SM) is a chemical warfare agent possessing strong alkylating properties that induces inflammation and tissue necrosis. SM exposure produces delayed and highly incapacitating injuries that can be lethal (Anderson, 2015). SM was used during World War I and is still maintained in the chemical weapons arsenals of several countries (Kehe and Szinicz, 2005). A specific and effective antidote is not available for use after SM exposure despite research conducted for nearly 100 years (Kehe and Szinicz, 2005). The population most at risk for exposure to SM is comprised of soldiers and individuals working or living near storage depots, but SM is also considered to be a potential terrorist threat due to its low cost of production and simple synthesis.Sulfur mustard (SM) vapor adversely affects the skin, eyes, and the respiratory tract. The respiratory tract is highly

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“…Evidence suggests that oxidative stress contributes to mustard induced pulmonary toxicity (Anderson et al, 2009; Gould et al, 2009; Hoesel et al, 2008; Mukhopadhyay et al, 2006b; Shohrati et al, 2010; Weinberger et al, 2011). Thus, following exposure to vesicants, a decrease in glutathione is observed in the respiratory tract, along with increases in markers of oxidative stress, such as malondialdehyde, 8-hydroxyguanosine and 4-hydroxynonenal (Kumar et al, 2001; Mukherjee et al, 2009; O'Neill et al, 2010).…”

Section: Antioxidant Expression In Rat Lung Following Mustard Exposurementioning

confidence: 99%

Inflammatory mechanisms of pulmonary injury induced by mustards

et al. 2016

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Exposure of humans and animals to vesicants, including sulfur mustard (SM) and nitrogen mustard (NM), causes severe and debilitating damage to the respiratory tract. Both acute and long term pathological consequences are observed in the lung following a single exposure to these vesicants. Evidence from our laboratories and others suggest that macrophages and inflammatory mediators they release play an important role in mustard-induced lung injury. In this paper, the pathogenic effects of SM and NM on the lung are reviewed, along with the potential role of inflammatory macrophages and mediators they release in mustard-induced pulmonary toxicity.

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Evaluation of protease inhibitors and an antioxidant for treatment of sulfur mustard-induced toxic lung injury

Cited by 48 publications

References 25 publications

Pentoxifylline attenuates nitrogen mustard-induced acute lung injury, oxidative stress and inflammation

Pentoxifylline attenuates nitrogen mustard-induced acute lung injury, oxidative stress and inflammation

From the Cover: Catalytic Antioxidant Rescue of Inhaled Sulfur Mustard Toxicity

Inflammatory mechanisms of pulmonary injury induced by mustards

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