Challenges and complexities in treating ammonia-induced lung injuries: ammonia disrupts cellular membranes and induces severe damage

Ammonia (NH₃) inhalation is a common occupational exposure, causing injuries similar to acute lung injury (ALI). Medical management is limited to supportive care, as no specific antidotes are currently available. This study aimed to evaluate the efficacy of potential therapeutic interventions to mitigate NH₃-induced damage using both <i>in vivo</i> (mouse) and <i>in vitro</i> (A549 alveolar epithelial cells) models. BALB/c mice received 91.0 mg/kg NH₃ <i>via</i> intratracheal instillation, followed by intraperitoneal dexamethasone (100 mg/kg) at 1, 5, and 23 h post-exposure to assess therapeutic effects. Analyses were performed on days 1 and 7. The complementary studies in A549 cells examined whether therapeutic interventions could counteract NH₃-induced toxicity affecting cell viability and function. Dexamethasone-treatment did not counteract the lethal damage in mice or significantly reduce the severity of ALI that intensified over time, including increased lung inflammatory cell infiltration, lung hemorrhages, and coagulation abnormalities. However, treatment reduced methacholine-induced AHR, and MMP-9 and SP-D levels at 20h post-exposure. Most treatments in A549 cells failed to prevent apoptotic and necrotic cell death, oxidative stress, mitochondrial dysfunction, and membrane damage caused by NH₃exposure however, the membrane stabilizer Poloxamer 188 (P188) highlighted the importance of stabilizing the cellular membrane damage to prevent further damages. While standard treatment with corticosteroids offered limited protection in NH₃-exposed mice, the study’s complementary <i>in vitro</i> investigations on new medical counter measures highlighted the complexity and severity of NH₃-induced lung injury. Together, the <i>in vivo</i> and <i>in vitro</i> findings emphasize the urgent need for effective medical countermeasures.