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

Toxicol Appl Pharmacol. 2012 Dec 15;265(3):279-91. doi: 10.1016/j.taap.2012.08.027. Epub 2012 Sep 6.

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 0.125 mg/kg NM or control. Bronchoalveolar lavage fluid (BAL) and lung tissue were collected 1 d-28 d 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 28 d. AG administration (50 mg/kg, 2×/day, 1d-3 d) abrogated NM-induced injury, oxidative stress and inflammation at 1d and 3d post exposure, with no effects at 7 d or 28 d. 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bronchoalveolar Lavage Fluid / chemistry
  • Bronchoalveolar Lavage Fluid / cytology
  • Drug Interactions
  • Enzyme Inhibitors / pharmacology
  • Fibrosis / chemically induced*
  • Fibrosis / drug therapy*
  • Fibrosis / metabolism
  • Fibrosis / pathology
  • Guanidines / pharmacology*
  • Heme Oxygenase-1 / metabolism
  • Immunohistochemistry
  • Lung Injury / chemically induced*
  • Lung Injury / drug therapy*
  • Lung Injury / metabolism
  • Lung Injury / pathology
  • Male
  • Mechlorethamine / toxicity*
  • Nitric Oxide Synthase Type II / antagonists & inhibitors*
  • Proliferating Cell Nuclear Antigen / metabolism
  • Rats
  • Rats, Wistar
  • Superoxide Dismutase / metabolism

Substances

  • Enzyme Inhibitors
  • Guanidines
  • Proliferating Cell Nuclear Antigen
  • Mechlorethamine
  • Nitric Oxide Synthase Type II
  • Heme Oxygenase-1
  • Superoxide Dismutase
  • pimagedine