Lung injury, oxidative stress and fibrosis in mice following exposure to nitrogen mustard

Toxicol Appl Pharmacol. 2020 Jan 15;387:114798. doi: 10.1016/j.taap.2019.114798. Epub 2019 Oct 31.

Abstract

Nitrogen mustard (NM) is a cytotoxic vesicant known to cause acute lung injury which progresses to fibrosis. Herein, we developed a murine model of NM-induced pulmonary toxicity with the goal of assessing inflammatory mechanisms of injury. C57BL/6J mice were euthanized 1-28 d following intratracheal exposure to NM (0.08 mg/kg) or PBS control. NM caused progressive alveolar epithelial thickening, perivascular inflammation, bronchiolar epithelial hyperplasia, interstitial fibroplasia and fibrosis, peaking 14 d post exposure. Enlarged foamy macrophages were also observed in the lung 14 d post NM, along with increased numbers of microparticles in bronchoalveolar lavage fluid (BAL). Following NM exposure, rapid and prolonged increases in BAL cells, protein, total phospholipids and surfactant protein (SP)-D were also detected. Flow cytometric analysis showed that CD11b+Ly6G-F4/80+Ly6Chi proinflammatory macrophages accumulated in the lung after NM, peaking at 3 d. This was associated with macrophage expression of HMGB1 and TNFα in histologic sections. CD11b+Ly6G-F4/80+Ly6Clo anti-inflammatory/pro-fibrotic macrophages also increased in the lung after NM peaking at 14 d, a time coordinate with increases in TGFβ expression and fibrosis. NM exposure also resulted in alterations in pulmonary mechanics including increases in tissue elastance and decreases in compliance and static compliance, most prominently at 14 d. These findings demonstrate that NM induces structural and inflammatory changes in the lung that correlate with aberrations in pulmonary function. This mouse model will be useful for mechanistic studies of mustard lung injury and for assessing potential countermeasures.

Keywords: Fibrosis; Lung injury; Macrophages; Mustard vesicants; Pulmonary function.

Publication types

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

MeSH terms

  • Acute Lung Injury / chemically induced*
  • Acute Lung Injury / immunology
  • Acute Lung Injury / pathology
  • Animals
  • Chemical Warfare Agents / toxicity*
  • Disease Models, Animal
  • Feasibility Studies
  • Female
  • Fibrosis
  • Humans
  • Lung / drug effects
  • Lung / pathology*
  • Macrophages / drug effects
  • Macrophages / immunology
  • Male
  • Mechlorethamine / toxicity*
  • Mice
  • Oxidative Stress / drug effects

Substances

  • Chemical Warfare Agents
  • Mechlorethamine