Inflammatory mechanisms of pulmonary injury induced by mustards

Abstract

Exposure of humans and animals to vesicants, including sulfur mustard (SM) and nitrogen mustard (NM), causes severe and debilitating damage to the respiratory tract. Both acute and long term pathological consequences are observed in the lung following a single exposure to these vesicants. Evidence from our laboratories and others suggest that macrophages and inflammatory mediators they release play an important role in mustard-induced lung injury. In this paper, the pathogenic effects of SM and NM on the lung are reviewed, along with the potential role of inflammatory macrophages and mediators they release in mustard-induced pulmonary toxicity.

Macrophages and inflammatory mediators in pulmonary injury induced by mustard vesicants

“…At this dose, all animals survive and appear clinically normal for at least 4 weeks. Importantly, histopathological alterations induced by NM in the rat trachea, bronchi, and lung are generally similar to those observed with SM . In the trachea and bronchi, acute changes, including focal attenuation of the epithelium, detachment of the epithelium from the mucosa, loss of cilia, and an accumulation of fibrin entrapping necrotic epithelial cells and debris in the lumen, are observed 1–3 days postexposure .…”

“…Importantly, histopathological alterations induced by NM in the rat trachea, bronchi, and lung are generally similar to those observed with SM. [12][13][14][15][16][17][18] In the trachea and bronchi, acute changes, including focal attenuation of the epithelium, detachment of the epithelium from the mucosa, loss of cilia, and an accumulation of fibrin entrapping necrotic epithelial cells and debris in the lumen, are observed 1-3 days postexposure. 14 At this time, multifocal hyperplasia, bronchiolized alveoli, perivascular and peribronchial edema, hyperplasia and hypertrophy of goblet cells, blood vessel hemorrhage, fibrin deposits, and inflammatory cell infiltrates, along with patchy, mild thickening of alveolar septa, are also noted in the lower respiratory tract and the lung.…”

Mustard vesicant-induced lung injury: Advances in therapy

“…Lung injury induced by mustards is associated with a rapid and persistent inflammatory response (Malaviya et al, 2015a; Tang and Loke, 2012). Cytotoxic/proinflammatory proteins including TNF-α, IL-1, and COX-2, as well as reactive oxygen and nitrogen species are also elevated in the lung after pulmonary exposure to mustards (Malaviya et al, 2010, 2012; Sunil et al, 2012; Tang and Loke, 2012; Venosa et al, 2015; Xiaoji et al, 2014).…”

“…This is associated with decreased expression of inflammatory proteins and markers of oxidative stress, as well as improved pulmonary mechanics. Similarly, monoclonal anti-TNFα antibody is highly effective in mitigating NM-induced histopathologic alterations in the lung, including edema, interstitial thickening, and leukocytic infiltration (Malaviya et al, 2015a, b). Of particular interest are findings that anti-TNFα antibody treatment of rats downregulates NM-induced TGFβ expression, a response associated with decreases in collagen deposition and the development of fibrosis (Malaviya et al, 2015b).…”

“…Fibrin and collagen deposition also increase in the lung leading to a collapse of alveolar structures, and the appearance of honeycombing (Malaviya et al, 2012; Mukherjee et al, 2009; Veress et al, 2010). The symptoms of chemical burn in the lung (edema, congestion, hemorrhage, and inflammation) also increase progressively over 28 days (Das et al, 2003; Malaviya et al, 2012, 2015a; Venosa et al, 2015). …”