Elfsmark_2022_Inhal.Toxicol_34_145

OBJECTIVE: Ammonia (NH(3)) is a corrosive alkaline gas that can cause life-threatening injuries by inhalation. The aim was to establish a disease model for NH(3)-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 NH(3) dose of 91.0 mg/kg.bw using intratracheal instillation and the pathological changes were followed for up to 7 days. RESULTS: NH(3) 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-1beta, 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-1beta) were unaffected despite severe ALI and may not be significant for NH(3)-induced damages. CONCLUSIONS: NH(3) 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 NH(3)-induced ALI and for finding new therapeutic treatments, since no specific antidote has been identified yet.