A Single Early-Life Acetaminophen Exposure Causes Persistent Abnormalities in the Murine Lung

Area of Science:

• Pulmonary toxicology
• Developmental biology
• Pharmacology

Background:

• Acetaminophen (APAP) is widely used, but its effects on developing lungs are debated.
• Pulmonary expression of cytochrome P450 2E1 (Cyp2e1) during development may influence susceptibility.
• Interleukin-6 (IL6) plays a role in APAP-induced tissue injury.

Purpose of the Study:

• To investigate the correlation between pulmonary Cyp2e1 expression and lung injury following early-life APAP exposure in mice.
• To assess the role of IL6 in APAP-induced pulmonary damage and long-term effects.

Main Methods:

• P14 mice (C57BL/6 and IL6-/-) were exposed to APAP.
• Histologic, metabolic, functional, and transcriptional pulmonary responses were evaluated.
• Fluorescent lifetime imaging microscopy (FLIM) assessed mitochondrial load.
• Gene and protein expression (Cyp2e1, IL6, Nrf2, STAT3) and signaling pathways were analyzed.

Main Results:

• APAP exposure in P14 mice caused pulmonary histologic and functional injury with increased mitochondrial load, but no hepatic injury.
• Pulmonary gene expression showed increased Cyp2e1, Nrf2 targets, and pro-inflammatory genes, including IL6.
• IL6-/- mice exhibited attenuated STAT3 signaling and injury.
• A single APAP dose at P14 led to persistent lung enlargement and alveolar simplification at P28 in both WT and IL6-/- mice.

Conclusions:

• Developmentally regulated pulmonary Cyp2e1 expression correlates with susceptibility to APAP-induced lung injury.
• Early-life APAP exposure can cause persistent pulmonary dysfunction without causing liver injury.
• Further research is needed on the link between Cyp2e1, APAP, and long-term lung problems.