Pulmonary injury and oxidative stress in rats induced by inhaled sulfur mustard is ameliorated by anti-tumor necrosis factor-α antibody.

Abstract

Sulfur mustard (SM) is a bifunctional alkylating agent that causes severe injury to the respiratory tract. This is accompanied by an accumulation of macrophages in the lung and the release of the proinflammatory cytokine, tumor necrosis factor (TNF)α. In these studies, we analyzed the effects of blocking TNFα on lung injury, inflammation and oxidative stress induced by inhaled SM. Rats were treated with SM vapor (0.4 mg/kg) or air control by intratracheal inhalation. This was followed 15-30 min later by anti-TNFα antibody (15mg/kg, i.v.) or PBS control. Animals were euthanized 3 days later. Anti-TNFα antibody was found to blunt SM-induced peribronchial edema, perivascular inflammation and alveolar plasma protein and inflammatory cell accumulation in the lung; this was associated with reduced expression of PCNA in histologic sections and decreases in BAL levels of fibrinogen. SM-induced increases in inflammatory proteins including soluble receptor for glycation end products, its ligand, high mobility group box-1, and matrix metalloproteinase-9 were also reduced by anti-TNFα antibody administration, along with increases in numbers of lung macrophages expressing TNFα, cyclooxygenase-2 and inducible nitric oxide synthase. This was correlated with reduced oxidative stress as measured by expression of heme oxygenase-1 and Ym-1. Together, these data suggest that inhibiting TNFα may represent an efficacious approach to mitigating acute lung injury, inflammatory macrophage activation, and oxidative stress induced by inhaled sulfur mustard.

• Authors: Rama Malaviya, Alyssa Bellomo, Elena Abramova, Claire R Croutch, Julie Roseman, Rick Tuttle, Eric Peters, Robert P Casillas, Vasanthi R Sunil, Jeffrey D Laskin, Debra L Laskin
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 428 Pg. 115677 (10 01 2021) ISSN: 1096-0333 [Electronic] United States
• PMID: 34390737 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Antibodies, Monoclonal
• Chemical Warfare Agents
• Tumor Necrosis Factor-alpha
• Mustard Gas

Topics

• Acute Lung Injury (chemically induced, drug therapy, metabolism)
• Animals
• Antibodies, Monoclonal (pharmacology, therapeutic use)
• Chemical Warfare Agents (toxicity)
• Inhalation Exposure (adverse effects)
• Male
• Mustard Gas (administration & dosage, toxicity)
• Oxidative Stress (drug effects, physiology)
• Rats
• Rats, Wistar
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, metabolism)