Functional and inflammatory alterations in the lung following exposure of rats to nitrogen mustard

Abstract

Nitrogen mustard is a vesicant that causes damage to the respiratory tract. In these studies, we characterized the acute effects of nitrogen mustard on lung structure, inflammatory mediator expression, and pulmonary function, with the goal of identifying mediators potentially involved in toxicity. Treatment of rats (male Wistar, 200–225 g) with nitrogen mustard (mechlorethamine hydrochloride, i.t., 0.25 mg/kg) resulted in marked histological changes in the respiratory tract, including necrotizing bronchiolitis, thickening of alveolar septa, and inflammation which was evident within 24 h. This was associated with increases in bronchoalveolar lavage protein and cells, confirming injury to alveolar epithelial regions of the lung. Nitrogen mustard administration also resulted in increased expression of inducible nitric oxide synthase and cyclooxygenase-2, pro-inflammatory proteins implicated in lung injury, in alveolar macrophages and alveolar and bronchial epithelial cells. Expression of connective tissue growth factor and matrix metalloproteinase-9, mediators regulating extracellular matrix turnover was also increased, suggesting that pathways leading to chronic lung disease are initiated early in the pathogenic process. Following nitrogen mustard exposure, alterations in lung mechanics and function were also observed. These included decreases in baseline static compliance, end-tidal volume and airway resistance, and a pronounced loss of methacholine responsiveness in resistance, tissue damping and elastance. Taken together, these data demonstrate that nitrogen mustard induces rapid structural and inflammatory changes in the lung which are associated with altered lung functioning. Understanding the nature of the injury induced by nitrogen mustard and related analogs may aid in the development of efficacious therapies for treatment of pulmonary injury resulting from exposure to vesicants.

Pentoxifylline attenuates nitrogen mustard-induced acute lung injury, oxidative stress and inflammation

“…NM-induced pulmonary toxicity is characterized by prominent histopathologic alterations in the lung including inflammatory cell accumulation, edema, fibrin deposition, bronchiolar and alveolar epithelial hyperplasia, bronchiectasis, fibroplasia and emphysema, along with increases in BAL protein and cells, which is in accord with previous studies (Malaviya et al, 2012; Sunil et al, 2011b). Pentoxifylline post-treatment significantly attenuated histologic evidence of pulmonary inflammation and injury, as well as increases in BAL protein and cell content.…”

“…Of particular interest is tumor necrosis factor (TNF)α, a macrophage-derived pro-inflammatory cytokine rapidly generated in the lung in response to injury induced by vesicants (Malaviya et al, 2010; Sunil et al, 2011b; Sunil et al, 2012). The major receptor mediating the pro-inflammatory activity of TNFα is TNFR1 (Parameswaran and Patial, 2010).…”

Characterization of Distinct Macrophage Subpopulations during Nitrogen Mustard–Induced Lung Injury and Fibrosis

“…Our findings that M1 and M2 macrophages sequentially accumulate in the lung following NM exposure, and that their appearance correlates with acute injury and fibrosis, suggest that they may contribute to these pathogenic responses. (13). In earlier studies, we found that this dose of NM is effective in inducing acute lung injury, which progresses to fibrosis without significant mortality (6).…”

Protective Effects of Melatonin and S-Methylisothiourea on Mechlorethamine Induced Nephrotoxicity

“…NO and peroxynitrite oxidize and covalently modify membrane lipids, thiols, proteins, and DNA, inducing cytotoxicity and perpetuating inflammation. In another study, it has been demonstrated that the expression of iNOS was rapidly up-regulated in alveolar macrophages following MEC exposure [31]. iNOS is predominantly expressed in inflammatory cells such as macrophages in affected tissues.…”