Fentanyl is a highly potent synthetic opioid and a major contributor to opioid-related mortality due to central respiratory depression. Inhalational exposure occurs during recreational misuse, polysubstance abuse, occupational handling, and potential chemical threat scenarios. However, whether inhaled fentanyl is associated with pulmonary toxicity independent of central effects remains unclear. Adult male C57BL/6 mice were exposed to aerosolized fentanyl (0.1, 1, or 5 mg/kg; nebulized dose, 5 min) or saline and evaluated 1 and 14 days post-exposure. Within 24 hours, fentanyl exposure was associated with acute lung injury characterized by alveolar hemorrhage, increased bronchoalveolar lavage protein and inflammatory cells, high lactate dehydrogenase levels, elevated lung wet-to-dry ratio, and reduced arterial oxygenation. Systemic hyperglycemia and increased plasma IL-1β and IL-12p70 were observed, with significant upregulation of caspase-1 activity and IL-1β in lung tissue. Similar IL-1β induction occurred in ex vivo human lung tissue and in vitro human macrophages. At 14 days, delayed dose-dependent remodeling was evident. Low-dose exposure (0.1 mg/kg) produced emphysematous changes, airspace enlargement, and increased mean linear intercept, consistent with emphysema-like changes. Higher doses (1 and 5 mg/kg) were associated with fibrotic remodeling, increased collagen deposition, and fibrotic remodeling. High-dose exposure (5 mg/kg) reduced 14-day survival to 65%. In conclusion, these findings demonstrate that aerosolized fentanyl exposure is associated with acute lung injury and subsequent delayed structural remodeling, accompanied by IL-1β-associated inflammatory signaling. These findings highlight potential pulmonary risks of inhaled fentanyl relevant to substance abuse, occupational safety, emergency response preparedness, and regulatory toxicology risk assessment.
