title: Attenuation of Nitrogen Mustard-Induced Pulmonary Injury and Fibrosis by Anti-Tumor Necrosis Factor-α Antibody.
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, 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-TNFα 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-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-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.
authors.affiliation: *Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy.
authors.forename: Rama
authors.initials: R
authors.lastname: Malaviya
authors.affiliation: *Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy.
authors.forename: Vasanthi R
authors.initials: VR
authors.lastname: Sunil
authors.affiliation: *Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Venosa
authors.affiliation: *Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy.
authors.forename: Vivianne L
authors.initials: VL
authors.lastname: Verissimo
authors.affiliation: *Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Cervelli
authors.affiliation: *Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy.
authors.forename: Kinal N
authors.initials: KN
authors.lastname: Vayas
authors.affiliation: Department of Drug Safety Sciences, Janssen Research & Development, Raritan, New Jersey 08869.
authors.forename: LeRoy
authors.initials: L
authors.lastname: Hall
authors.affiliation: Department of Environmental and Occupational Medicine, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey 08854; and.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Laskin
authors.affiliation: *Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, laskin@eohsi.rutgers.edu.
authors.forename: Debra L
authors.initials: DL
authors.lastname: Laskin
mesh_terms: D000477:Alkylating Agents / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D002619:Chemical Warfare Agents / Q000737:chemistry / Q000633:toxicity; D018450:Disease Progression; D007074:Immunoglobulin G / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008466:Mechlorethamine / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051379:Mice; D058990:Molecular Targeted Therapy; D018384:Oxidative Stress / Q000187:drug effects; D011656:Pulmonary Emphysema / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000378:metabolism / Q000627:therapeutic use; D020545:Respiratory Mucosa / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000477:Alkylating Agents; D000911:Antibodies, Monoclonal; D015415:Biomarkers; D002619:Chemical Warfare Agents; D007074:Immunoglobulin G; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D008466:Mechlorethamine
keywords: alveolar macrophages; fibrosis; lung injury; vesicant