Original Contribution
Treatment with the catalytic metalloporphyrin AEOL 10150 reduces inflammation and oxidative stress due to inhalation of the sulfur mustard analog 2-chloroethyl ethyl sulfide

https://doi.org/10.1016/j.freeradbiomed.2010.01.039Get rights and content

Abstract

Sulfur mustard (bis-2-(chloroethyl) sulfide; SM) is a highly reactive vesicating and alkylating chemical warfare agent. A SM analog, 2-chloroethyl ethyl sulfide (CEES), has been utilized to elucidate mechanisms of toxicity and as a screen for therapeutics. Previous studies with SM and CEES have demonstrated a role for oxidative stress as well as decreased injury with antioxidant treatment. We tested whether posttreatment with the metalloporphyrin catalytic antioxidant AEOL 10150 would improve outcome in CEES-induced lung injury. Anesthetized rats inhaled 5% CEES for 15 min via a nose-only inhalation system. At 1 and 9 h after CEES exposure, rats were given AEOL 10150 (5 mg/kg, sc). At 18 h post-CEES exposure BALF lactate dehydrogenase activity, protein, IgM, red blood cells, and neutrophils were elevated but were decreased by AEOL 10150 treatment. Lung myeloperoxidase activity was increased after CEES inhalation and was ameliorated by AEOL 10150. The lung oxidative stress markers 8-OHdG and 4-HNE were elevated after CEES exposure and significantly decreased by AEOL 10150 treatment. These findings demonstrate that CEES inhalation increased lung injury, inflammation, and oxidative stress, and AEOL 10150 was an effective rescue agent. Further investigation utilizing catalytic antioxidants as treatment for SM inhalation injury is warranted.

Section snippets

Reagents

2-Chloroethyl ethyl sulfide was obtained from TCI America (Portland, OR, USA). AEOL 10150 was generously supplied by Aeolus Pharmaceuticals (Laguna Niguel, CA, USA). All other chemicals, of the highest grade available, were obtained from Sigma (St. Louis, MO, USA) unless otherwise specified.

Animals

Male Sprague–Dawley rats (Harlan, Indianapolis, IN, USA) weighing 275–350 g were used. Animals were provided with food and water ad libitum. All procedures employed were approved by the Animal Care and Use

General observations, pulse oximetry, and survival

Eighteen hours after CEES exposure, rats were noted to be mildly lethargic with variable tachypnea. Arterial hemoglobin oxygen saturation (SpO2) was used as an estimation of the oxygen saturation levels. Using each animal as its own control, there was no significant change in SpO2 comparing baseline (mean 93.2 ± 0.8 SEM, n = 6) readings to those 18 h after CEES exposure (mean 92.8 ± 0.7 SEM, n = 6), indicating a lack of hypoxemia. These numbers were comparable to those of adult male rats at Denver

Discussion

This report demonstrates that lung injury, inflammation, and oxidative damage related to inhalation of CEES were ameliorated by AEOL 10150 treatment. Specifically, increased BALF LDH after CEES inhalation demonstrated increased cellular injury. Protein and IgM levels in BALF were increased after CEES exposure. All of these indicators of lung injury were diminished by AEOL 10150 treatment. CEES inhalation increased PMNs in the BALF and lung tissue. Treatment with AEOL 10150 decreased PMN

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