Attenuation of acute nitrogen mustard-induced lung injury, inflammation and fibrogenesis by a nitric oxide synthase inhibitor

Rama Malaviya, Alessandro Venosa, Le Roy Hall, Andrew J. Gow, Patrick J. Sinko, Jeffrey D. Laskin, Debra L. Laskin

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30 Citations (Scopus)

Abstract

Nitrogen mustard (NM) is a toxic vesicant known to cause damage to the respiratory tract. Injury is associated with increased expression of inducible nitric oxide synthase (iNOS). In these studies we analyzed the effects of transient inhibition of iNOS using aminoguanidine (AG) on NM-induced pulmonary toxicity. Rats were treated intratracheally with 0.125mg/kg NM or control. Bronchoalveolar lavage fluid (BAL) and lung tissue were collected 1d-28d later and lung injury, oxidative stress and fibrosis assessed. NM exposure resulted in progressive histopathological changes in the lung including multifocal lesions, perivascular and peribronchial edema, inflammatory cell accumulation, alveolar fibrin deposition, bronchiolization of alveolar septal walls, and fibrosis. This was correlated with trichrome staining and expression of proliferating cell nuclear antigen (PCNA). Expression of heme oxygenase (HO)-1 and manganese superoxide dismutase (Mn-SOD) was also increased in the lung following NM exposure, along with levels of protein and inflammatory cells in BAL, consistent with oxidative stress and alveolar-epithelial injury. Both classically activated proinflammatory (iNOS+ and cyclooxygenase-2+) and alternatively activated profibrotic (YM-1+ and galectin-3+) macrophages appeared in the lung following NM administration; this was evident within 1d, and persisted for 28d. AG administration (50mg/kg, 2×/day, 1d-3d) abrogated NM-induced injury, oxidative stress and inflammation at 1d and 3d post exposure, with no effects at 7d or 28d. These findings indicate that nitric oxide generated via iNOS contributes to acute NM-induced lung toxicity, however, transient inhibition of iNOS is not sufficient to protect against pulmonary fibrosis.

Original languageEnglish
Pages (from-to)279-291
Number of pages13
JournalToxicology and Applied Pharmacology
Volume265
Issue number3
DOIs
Publication statusPublished - 15 Dec 2012
Externally publishedYes

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Keywords

  • INOS
  • Macrophages
  • Nitric oxide
  • Oxidative stress
  • Pulmonary toxicity
  • Vesicants

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

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