TY  - JOUR
PY  - 2015//
TI  - Attenuation of nitrogen mustard-induced pulmonary injury and fibrosis by anti-tumor necrosis factor-α antibody
JO  - Toxicological sciences
A1  - Malaviya, Rama
A1  - Sunil, Vasanthi R.
A1  - Venosa, Alessandro
A1  - Verissimo, Vivianne L.
A1  - Cervelli, Jessica A.
A1  - Vayas, Kinal N.
A1  - Hall, LeRoy
A1  - Laskin, Jeffrey D.
A1  - Laskin, Debra L.
SP  - 71
EP  - 88
VL  - 148
IS  - 1
N2  - 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.<p />  <p>Language: en</p>
LA  - en
SN  - 1096-6080
UR  - http://dx.doi.org/10.1093/toxsci/kfv161
ID  - ref1
ER  -