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Lung injury, oxidative stress and fibrosis in mice following exposure to nitrogen mustard.
- Source :
-
Toxicology and applied pharmacology [Toxicol Appl Pharmacol] 2020 Jan 15; Vol. 387, pp. 114798. Date of Electronic Publication: 2019 Oct 31. - Publication Year :
- 2020
-
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 <superscript>+</superscript> Ly6G <superscript>-</superscript> F4/80 <superscript>+</superscript> Ly6C <superscript>hi</superscript> 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 <superscript>+</superscript> Ly6G <superscript>-</superscript> F4/80 <superscript>+</superscript> Ly6C <superscript>lo</superscript> 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.<br />Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Published by Elsevier Inc.)
- Subjects :
- Acute Lung Injury immunology
Acute Lung Injury pathology
Animals
Disease Models, Animal
Feasibility Studies
Female
Fibrosis
Humans
Lung drug effects
Macrophages drug effects
Macrophages immunology
Male
Mice
Oxidative Stress drug effects
Acute Lung Injury chemically induced
Chemical Warfare Agents toxicity
Lung pathology
Mechlorethamine toxicity
Subjects
Details
- Language :
- English
- ISSN :
- 1096-0333
- Volume :
- 387
- Database :
- MEDLINE
- Journal :
- Toxicology and applied pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 31678244
- Full Text :
- https://doi.org/10.1016/j.taap.2019.114798