Original ContributionTreatment with the catalytic metalloporphyrin AEOL 10150 reduces inflammation and oxidative stress due to inhalation of the sulfur mustard analog 2-chloroethyl ethyl sulfide
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
References (47)
- et al.
Medical aspects of sulphur mustard poisoning
Toxicology
(2005) - et al.
Molecular basis for mustard-induced vesication
Fundam. Appl. Toxicol.
(1985) - et al.
Free radical-mediated lung response to the monofunctional sulfur mustard butyl 2-chloroethyl sulfide after subcutaneous injection
Toxicology
(1992) - et al.
Biochemical changes in mouse lung after subcutaneous injection of the sulfur mustard 2-chloroethyl 4-chlorobutyl sulfide
Toxicology
(2004) - et al.
Flavin-dependent antioxidant properties of a new series of meso-N,N′-dialkyl-imidazolium substituted manganese(III) porphyrins
Biochem. Pharmacol.
(2004) Catalytic antioxidants: a radical approach to new therapeutics
Drug Discov. Today
(2004)- et al.
Manganic porphyrins possess catalase activity and protect endothelial cells against hydrogen peroxide-mediated injury
Arch. Biochem. Biophys.
(1997) - et al.
Evaluation of the relative contribution of nitric oxide and peroxynitrite to the suppression of mitochondrial respiration in immunostimulated macrophages using a manganese mesoporphyrin superoxide dismutase mimetic and peroxynitrite scavenger
FEBS Lett.
(1996) - et al.
Metalloporphyrins are potent inhibitors of lipid peroxidation
Free Radic. Biol. Med.
(1999) - et al.
Reactions of manganese porphyrins with peroxynitrite and carbonate radical anion
J. Biol. Chem.
(2003)
Long-term administration of a small molecular weight catalytic metalloporphyrin antioxidant, AEOL 10150, protects lungs from radiation-induced injury
Int. J. Radiat. Oncol. Biol. Phys.
Gas chromatography–mass spectrometry of 4-hydroxynonenal in tissues
Methods Enzymol
Identification of 4-hydroxynonenal as a cytotoxic product originating from the peroxidation of liver microsomal lipids
Biochim. Biophys. Acta
Role of MAPK/AP-1 signaling pathway in the protection of CEES-induced lung injury by antioxidant liposome
Toxicology
Microcirculation-derived factors in airway epithelial repair in vivo
Microvasc. Res.
A metalloporphyrin superoxide dismutase mimetic protects against paraquat-induced lung injury in vivo
Toxicol. Appl. Pharmacol.
Inhibition of airway inflammation and hyperreactivity by an antioxidant mimetic
Free Radic. Biol. Med.
Role of mitogen-activated protein kinases in 4-hydroxy-2-nonenal-induced actin remodeling and barrier function in endothelial cells
J. Biol. Chem.
Redox regulation of 4-hydroxy-2-nonenal-mediated endothelial barrier dysfunction by focal adhesion, adherens, and tight junction proteins
J. Biol. Chem.
Free radical production from the interaction of 2-chloroethyl vesicants (mustard gas) with pyridine nucleotide-driven flavoprotein electron transport systems
Toxicol. Appl. Pharmacol.
Toxicology and pharmacology of the chemical warfare agent sulfur mustard
Pharmacol. Rev.
Protection from half-mustard-gas-induced acute lung injury in the rat
J. Appl. Toxicol.
Attenuation of half sulfur mustard gas-induced acute lung injury in rats
J. Appl. Toxicol.
Cited by (66)
Toxic blister agents: Chemistry, mode of their action and effective treatment strategies
2021, Chemico-Biological InteractionsPulmonary protective efficacy of S-2[2-aminoethylamino] ethyl phenyl sulphide (DRDE-07) and its analogues against sulfur mustard induced toxicity in mice
2020, Environmental Toxicology and PharmacologyCitation Excerpt :These changes suggest that oxidative stress and inflammation occurs in the lungs. A similar alteration in the BALF protein level and the influx of inflammatory cells have been described in various studies (Anderson et al., 1993; Allon et al., 2009; Neill et al., 2010; Sunil et al., 2011). Furthermore, our data demonstrate a notable depletion of GSH level in BALF and lung tissue accompanied increased lipid peroxidation.
Antioxidant drug therapy as a neuroprotective countermeasure of nerve agent toxicity
2020, Neurobiology of DiseaseCitation Excerpt :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, MnIIITDE-2-ImP5+ 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).
Time course study of oxidative stress in sulfur mustard analog 2‑chloroethyl ethyl sulfide-induced toxicity
2019, International ImmunopharmacologyTRPA1 and CGRP antagonists counteract vesicant-induced skin injury and inflammation
2018, Toxicology Letters