Mustard vesicant-induced lung injury: Advances in therapy

Abstract

Most mortality and morbidity following exposure to vesicants such as sulfur mustard is due to pulmonary toxicity. Acute injury is characterized by epithelial detachment and necrosis in the pharynx, trachea and bronchioles, while long-term consequences include fibrosis and in some instances, cancer. Current therapies to treat mustard poisoning are primarily palliative and do not target underlying pathophysiologic mechanisms. New knowledge about vesicant-induced pulmonary disease pathogenesis has led to the identification of potentially efficacious strategies to reduce injury by targeting inflammatory cells and mediators including reactive oxygen and nitrogen species, proteases and proinflammatory/cytotoxic cytokines. Therapeutics under investigation include corticosteroids, N-acetyl cysteine, which has both mucolytic and antioxidant properties, inducible nitric oxide synthase inhibitors, liposomes containing superoxide dismutase, catalase, and/or tocopherols, protease inhibitors, and cytokine antagonists such as anti-tumor necrosis factor (TNF)-α antibody and pentoxifylline. Antifibrotic and fibrinolytic treatments may also prove beneficial in ameliorating airway obstruction and lung remodeling. More speculative approaches include inhibitors of transient receptor potential channels, which regulate pulmonary epithelial cell membrane permeability, non-coding RNAs and mesenchymal stem cells. As mustards represent high priority chemical threat agents, identification of effective therapeutics for mitigating toxicity is highly significant.

Regulation of Nitrogen Mustard-Induced Lung Macrophage Activation by Valproic Acid, a Histone Deacetylase Inhibitor

“…By comparison, VPA had no effect on NM-induced alveolar epithelial barrier dysfunction, as measured by BAL protein levels, or on structural alterations in the respiratory tract. These findings suggest that there are multiple mechanisms underlying the pathologic and cytotoxic effects of NM in the lung (Weinberger et al, 2016). Previous studies demonstrated that VPA was effective in reducing acute lung injury induced by LPS, ischemia-perfusion and sepsis (Ji et al, 2013;Kim et al, 2012;Shang, et al, 2010;Wu et al, 2015).…”

Macrophages and inflammatory mediators in pulmonary injury induced by mustard vesicants

“…Oxidative stress has been shown to contribute to vesicant-induced lung injury, in part by triggering the inflammatory cascade. 3,41,42 Thus, following exposure to vesicants, antioxidant levels decrease, and markers of oxidative stress, such as malondialdehyde, 8-hydroxyguanosine, and 4-hydroxynonenal, increase. [43][44][45] Additionally, treatment of animals with antioxidants reduces vesicant-induced lung injury and inflammation.…”

Evaluation of mRNA Expression Levels of TNFα, TNFR1 and IL1β in Lung Tissue 20 Years after Sulfur-mustard Exposure

“…Hence, findings of this study may elucidate ineffectiveness of the current practice in management of the COPD and IPF which did not take in to account this undeylying immunopathological mechanism. Currently, there is no the Food and Drug Administration (FDA) approved protocol for treatment of the SM induced pulomonary complications 16 and this novel finding may help to establish a desired treatment protocol.…”

“…For they, a curative treatment is not available up to now. 15,16 In addition, some studies have demonstrated that the levels of local and systemic proinflammatory cytokine may be different, which causes different regulation mechanisms in the local and circulating cytokines. 17 Hence, we evaluated mRNA expression of proinflammatory cytokines, IL-1β, TNFα and TNFR1, at the local position in the lung formalin-fixed, paraffinembedded (FFPE) section of SM-exposed subjects and non-exposed patients.…”