From the Cover: Catalytic Antioxidant Rescue of Inhaled Sulfur Mustard Toxicity.
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 LD50at 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.
Department of Pharmaceutical Sciences, University of Colorado, Aurora, Colorado 80045.|Department of Medicine, National Jewish Health, Denver, Colorado 80206.
Cameron S
CS
McElroy
Department of Medicine, National Jewish Health, Denver, Colorado 80206.
Elysia
E
Min
Department of Medicine, National Jewish Health, Denver, Colorado 80206.
Jie
J
Huang
Department of Pediatrics, University of Colorado, Aurora, Colorado 80045.
Joan E
JE
Loader
Department of Pediatrics, University of Colorado, Aurora, Colorado 80045.
Tara B
TB
Hendry-Hofer
Department of Pediatrics, University of Colorado, Aurora, Colorado 80045.
Rhonda B
RB
Garlick
Department of Pediatrics, University of Colorado, Aurora, Colorado 80045.
Jackie S
JS
Rioux
Department of Pediatrics, University of Colorado, Aurora, Colorado 80045.
Livia A
LA
Veress
Department of Pediatrics, University of Colorado, Aurora, Colorado 80045.
Russell
R
Smith
Department of Pediatrics, University of Colorado, Aurora, Colorado 80045.
Chris
C
Osborne
Analytical Toxicology Division, Proving Grounds United States Army Medical Research Institute of Chemical Defense (USAMRICD), Aberdeen, Maryland 21010.
Dana R
DR
Anderson
Analytical Toxicology Division, Proving Grounds United States Army Medical Research Institute of Chemical Defense (USAMRICD), Aberdeen, Maryland 21010.
Wesley W
WW
Holmes
Analytical Toxicology Division, Proving Grounds United States Army Medical Research Institute of Chemical Defense (USAMRICD), Aberdeen, Maryland 21010.
Danielle C
DC
Paradiso
Department of Pharmaceutical Sciences, University of Colorado, Aurora, Colorado 80045.|Department of Pediatrics, University of Colorado, Aurora, Colorado 80045.
Carl W
CW
White
Department of Pharmaceutical Sciences, University of Colorado, Aurora, Colorado 80045 DayB@NJHealth.org.|Department of Medicine, National Jewish Health, Denver, Colorado 80206.
Brian J
BJ
Day
D000818:Animals; D000931:Antidotes / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D002619:Chemical Warfare Agents / Q000633:toxicity*; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018836:Inflammation Mediators / Q000378:metabolism; D019570:Inhalation Exposure; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D055370:Lung Injury / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology*; D009151:Mustard Gas / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects*; D011014:Pneumonia / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors
C472668:AEOL 10150; D000931:Antidotes; D000975:Antioxidants; D002619:Chemical Warfare Agents; D016207:Cytokines; D018836:Inflammation Mediators; D008665:Metalloporphyrins; D017382:Reactive Oxygen Species; D009151:Mustard Gas
antioxidant.; chemical weapons; sulfur mustard