Ammonia exposure by intratracheal instillation causes severe and deteriorating lung injury and vascular effects in mice

Abstract

Objective

Ammonia (NH₃) is a corrosive alkaline gas that can cause life-threatening injuries by inhalation. The aim was to establish a disease model for NH₃-induced injuries similar to acute lung injury (ALI) described in exposed humans and investigate the progression of lung damage, respiratory dysfunction and evaluate biomarkers for ALI and inflammation over time.

Methods

Female BALB/c mice were exposed to an NH₃ dose of 91.0 mg/kg·bw using intratracheal instillation and the pathological changes were followed for up to 7 days.

Results

NH₃ instillation resulted in the loss of body weight along with a significant increase in pro-inflammatory mediators in both bronchoalveolar lavage fluid (e.g. IL-1β, IL-6, KC, MMP-9, SP-D) and blood (e.g. IL-6, Fibrinogen, PAI-1, PF4/CXCL4, SP-D), neutrophilic lung inflammation, alveolar damage, increased peripheral airway resistance and methacholine-induced airway hyperresponsiveness compared to controls at 20 h. On day 7 after exposure, deteriorating pathological changes such as increased macrophage lung infiltration, heart weights, lung hemorrhages and coagulation abnormalities (elevated plasma levels of PAI-1, fibrinogen, endothelin and thrombomodulin) were observed but no increase in lung collagen. Some of the analyzed blood biomarkers (e.g. RAGE, IL-1β) were unaffected despite severe ALI and may not be significant for NH₃-induced damages.

Conclusions

NH₃ induces severe acute lung injuries that deteriorate over time and biomarkers in lungs and blood that are similar to those found in humans. Therefore, this model has potential use for developing diagnostic tools for NH₃-induced ALI and for finding new therapeutic treatments, since no specific antidote has been identified yet.

Keywords:

• Ammonia
• chemical-induced acute lung injury
• ARDS
• animal models
• inflammation
• coagulation
• fibrinolysis
• respiratory mechanics

Acknowledgements

Barbro Ekstrand-Hammarström, Åsa Gustafsson, Elisabeth Wigenstam and Karin Wallgren are gratefully acknowledged for invaluable help with the animal experiments and while writing the manuscript.

Disclosure statement

The authors report no declarations of interest.

Additional information

Funding

This work was supported by grants from the Swedish Center for Disaster Toxicology at the National Board of Health and Welfare and the Swedish Ministry of Defence.