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

Abstract

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

Antioxidant drug therapy as a neuroprotective countermeasure of nerve agent toxicity

“…The utility of Mn III TDE-2-ImP 5+ extends beyond OP exposures with the ability to limit toxicity resulting from other chemical agents in post-exposure treatment paradigms. Mn III TDE-2-ImP 5+ has been demonstrated to improve mortality and inhibit lung, skin and nasal damage resulting from exposure to the vesicating and alkylating agent, sulfur mustard and its analog, 2-chloroethyl ethyl sulfide (CEES) ( McElroy et al, 2016 ; O’Neill et al, 2011 ; O’Neill et al, 2010 ; Tewari-Singh et al, 2014 ). The compound was also found to protect the lung from exposure to chlorine gas ( McGovern et al, 2011 ).…”

“…It may be used at the site, ambulance or in the hospital setting as it targets late effects; however, earlier intervention with daily injectable dosing would be optimal. In animals, Mn III TDE-2-ImP 5+ was effective at protecting the lung and skin when given at 5 mg/kg up to one hour after exposure to sulfur mustard or CEES ( McElroy et al, 2016 ; O’Neill et al, 2011 ; O’Neill et al, 2010 ; Tewari-Singh et al, 2014 ). Doses ranging from 5 to 7 mg/kg were sufficient to protect the brain from nerve agents and their surrogates when given 15 min to one hour following exposure ( Liang et al, 2018a ; Liang et al, 2018b ; Pearson et al, 2015 ).…”

An Official American Thoracic Society Workshop Report: Chemical Inhalational Disasters. Biology of Lung Injury, Development of Novel Therapeutics, and Medical Preparedness

“…Direct administration of tissue plasminogen factor into airways can eliminate or reverse airways obstruction by fibrin, and prevent gas exchange abnormalities and respiratory failure (135,136). These therapies for the acute process might be complemented by catalytic antioxidants (141), flavonones (142), and/or cell-based therapies (143).…”

Immunomodulatory Effect of Curcumin in the Upregulation of Inflammasome Pathway Genes Induced by Sulfur Mustard Analog: An In-vitro Study

“…Moreover, during the recent decades, it was applied against some nations such as Iran and Syria, too. [1][2][3] Cellular and molecular biology-based studies have indicated that SM can alkylate DNA and proteins, destroy enzymes, induce free radicals, and finally can cause necrosis and apoptosis in cells. In addition to death and acute complications, SM can cause long-term side effects on the lungs, skin, and eyes of its victims.…”