Citation

Malaviya R, Sunil VR, Venosa A, Verissimo VL, Cervelli JA, Vayas KN, Hall L, Laskin JD, Laskin DL. Toxicol. Sci. 2015; 148(1): 71-88.

Affiliation

Departments of *Pharmacology and Toxicology, Ernest Mario School of Pharmacy and laskin@eohsi.rutgers.edu.

Copyright

(Copyright © 2015, Oxford University Press)

DOI

10.1093/toxsci/kfv161

PMID

26243812

Abstract

Nitrogen mustard (NM) is a bifunctional alkylating agent that causes acute injury to the lung that progresses to fibrosis. This is accompanied by a prominent infiltration of macrophages into the lung and upregulation of proinflammatory/profibrotic cytokines including tumor necrosis factor (TNF)α. In these studies, we analyzed the ability of anti-TNFα antibody to mitigate NM-induced lung injury, inflammation and fibrosis. Treatment of rats with anti-TNFα antibody (15 mg/kg, i.v., every 9 d) beginning 30 min after intratracheal administration of NM (0.125 mg/kg) reduced progressive histopathologic alterations in the lung including perivascular and peribronchial edema, macrophage/monocyte infiltration, interstitial thickening, bronchiolization of alveolar walls, fibrin deposition, emphysema and fibrosis. NM-induced damage to the alveolar-epithelial barrier, measured by bronchoalveolar lavage (BAL) protein and cell content, was also reduced by anti-TNFα antibody, along with expression of the oxidative stress marker, heme oxygenase (HO)-1. Whereas the accumulation of proinflammatory/cytotoxic M1 macrophages in the lung in response to NM was suppressed by anti-TNFα antibody, anti-inflammatory/ profibrotic M2 macrophages were increased or unchanged. Treatment of rats with anti-TNFα antibody also reduced NM-induced increases in expression of the profibrotic mediator, transforming growth factor (TGF)-β. This was associated with a reduction in NM-induced collagen deposition in the lung. These data suggest that inhibiting TNFα may represent an efficacious approach to mitigating lung injury induced by mustards.

Language: en