Airway Tissue Plasminogen Activator Prevents Acute Mortality Due to Lethal Sulfur Mustard Inhalation

Veress, Livia A.; Anderson, Dana R.; Hendry‐Hofer, Tara B.; Houin, Paul R.; Rioux, Jacqueline S.; Garlick, Rhonda B.; Loader, Joan E.; Paradiso, Danielle; Smith, R. H.; Rancourt, Raymond C.; Holmes, Wesley W.; White, Carl W.

doi:10.1093/toxsci/kfu225

Cited by 37 publications

(52 citation statements)

References 17 publications

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“…Direct intratracheal administration of tissue plasminogen activator (tPA) has been previously shown to improve survival of animals after exposure to CEES and SM through the reduction of obstructive airway casts. Stoichiometric antioxidants including the water soluble vitamin E analog trolox, and the bioflavonoid quercetin have been shown to improve median survival times in mice exposed to SM (Kumar et al, 2001;Veress et al, 2013Veress et al, , 2015. This is the first published study to report significant improvements in survival using a catalytic antioxidant in a rat model of SM inhalation.…”

Section: Discussionmentioning

confidence: 82%

“…SM-mediated airway occlusions were scored for percent occlusion as previously described (Veress et al 2015). Airway casts were clearly visible in animals exposed to SM compared with sham treatment group and were diminished in the catalytic antioxidant treatment group (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Under this rule it is important to not only show that the countermeasure can improve a significant outcome such as survival, but also improve function and quality of life (Jett, 2016). Diminished arterial oxygen saturations following SM exposure have previously been reported in this model system (Rancourt et al, 2013;Veress et al, 2015). In addition to the pulse oximetry for liveanimal surveillance, each animal was assigned a clinical score at each time point.…”

Section: Discussionmentioning

confidence: 99%

“…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%

“…Lungs were stored in specimen containers filled with 4% paraformaldehyde until microdissection. Lungs were microdissected under a light microscope and major airways were assigned cast scores as previously described (Veress et al, 2015).…”

Section: Methodsmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 82%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

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Fibrin airway cast obstruction: Experience, classification, and treatment guideline from Denver

Liptzin

McGraw

Houin

et al. 2021

Pediatric Pulmonology

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Background and Objectives Plastic bronchitis (PB) is a condition characterized by the formation of thick airway casts leading to acute and often life‐threatening airway obstruction. PB occurs mainly in pediatric patients with congenital heart disease (CHO) who have undergone staged surgical palliation (Glenn, Fontan), but can also occur after chemical inhalation, H1N1, severe COVID‐19, sickle cell disease, severe asthma, and other diseases. Mortality risk from PB can be up to 40%–60%, and no treatment guideline exist. The objectives herein are to develop a standardized evaluation, classification, and treatment guideline for PB patients presenting with tracheobronchial casts, based on our experience with PB at the Children's Hospital of Colorado in Denver. Methods We describe 11 patients with CHO‐associated PB (post‐Fontan [n = 9], pre‐Fontan [n = 2]) who presented with their initial episodes. We utilized histopathological analysis of tracheobronchial casts to guide treatment in these patients, utilizing our hospital‐wide guideline document and classification system. Results We found that 100% of post‐Fontan PB patients had fibrinous airway casts, while pre‐Fontan PB casts were fibrinous only in one of two patients (50%). Utilizing histopathology as a guide to therapy, PB patients with fibrin airway casts were treated with airway‐delivered fibrinolytics and anticoagulants, as well as aggressive airway clearance and other supportive care measures. These therapies resulted in successful cast resolution and improved survival in post‐Fontan PB patients. Conclusion We have shown an improved outcome in PB patients whose treatment plan was based on Denver's PB classification schema and standardized treatment guideline based on tracheobronchial cast histopathology.

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