Attenuation of Nitrogen Mustard-Induced Pulmonary Injury and Fibrosis by Anti-Tumor Necrosis Factor-α Antibody

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)alpha. In these studies, we analyzed the ability of anti-TNF alpha antibody to mitigate NM-induced lung injury, inflammation, and fibrosis. Treatment of rats with anti-TNF alpha antibody (15 mg/kg, iv, every 9 days) 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-TNF alpha antibody, along with expression of the oxidative stress marker, heme oxygenase-1. Whereas the accumulation of proinflammatory/cytotoxic M1 macrophages in the lung in response to NM was suppressed by anti-TNF alpha antibody, antiinflammatory/profibrotic M2 macrophages were increased or unchanged. Treatment of rats with anti-TNF alpha antibody also reduced NM-induced increases in expression of the profibrotic mediator, transforming growth factor-beta. This was associated with a reduction in NM-induced collagen deposition in the lung. These data suggest that inhibiting TNF alpha may represent an efficacious approach to mitigating lung injury induced by mustards.