Inflammatory effects of inhaled sulfur mustard in rat lung

Abstract

Inhalation of sulfur mustard (SM), a bifunctional alkylating agent that causes severe lung damage, is a significant threat to both military and civilian populations. The mechanisms mediating its cytotoxic effects are unknown and were investigated in the present studies. Male rats Crl:CD(SD) were anesthetized, and then intratracheally intubated and exposed to 0.7–1.4 mg/kg SM by vapor inhalation. Animals were euthanized 6, 24, 48 h or 7 days post-exposure and bronchoalveolar lavage fluid (BAL) and lung tissue collected. Exposure of rats to SM resulted in rapid pulmonary toxicity, including focal ulceration and detachment of the trachea and bronchial epithelia from underlying mucosa, thickening of alveolar septal walls and increased numbers of inflammatory cells in the tissue. There was also evidence of autophagy and apoptosis in the tissue. This was correlated with increased BAL protein content, a marker of injury to the alveolar epithelial lining. SM exposure also resulted in increased expression of markers of inflammation including cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNFα), inducible nitric oxide synthase (iNOS), and matrix metalloproteinase-9 (MMP-9), each of which has been implicated in pulmonary toxicity. Whereas COX-2, TNFα and iNOS were mainly localized in alveolar regions, MMP-9 was prominent in bronchial epithelium. In contrast, expression of the anti-oxidant hemeoxygenase, and the anti-inflammatory collectin, surfactant protein-D, decreased in the lung after SM exposure. These data demonstrate that SM-induced oxidative stress and injury are associated with the generation of cytotoxic inflammatory proteins which may contribute to the pathogenic response to this vesicant.

The Role of Oxidative Stress in Severity of Obstructive Pulmonary Complications in Sputum of Sulfur Mustard-Injured Patients

“…SM-induced oxidative stress is thought to be a primary event triggering inflammation [16,32]. In our study, oxidant-antioxidant imbalance due to changes in GSH and MDA levels in moderate and severe groups may lead to progressive inflammation.…”

“…MDA levels in the sputum and exhaled breath condensate and plasma of patients with different pulmonary diseases have been reported to be in the range of controls [31] or elevated compared to healthy controls [6]. Similarly, the MDA level was increased in BAL of patients with SM-induced pulmonary injury [8,32].…”

Effect of recombinant human IFNγ in the treatment of chronic pulmonary complications due to sulfur mustard intoxication

“…MMP9 is the most important type of MMP involved in SM toxicity. Previous studies have indicated that MMP9 status rises following SM injury (Calvet et al 1999;Malaviya et al 2010). In the current research, immunotherapy with IFNg was associated with a remarkable decline in serum MMP9; this effect may prevent deleterious consequences of protease activation by SM.…”

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

“…were selected to determine if antioxidant treatments would affect their presence in bronchoalveolar lavage fluid (BALF) (Emmler et al, 2007;Malaviya et al, 2010;Ricketts et al, 2000;Seagrave et al, 2010;Zhu et al, 2014). The cytokines were analyzed using a proinflammatory multiplex panel that included cytokines previously reported to be elevated by SM exposure.…”

“…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).…”