Abstract
Whether early-life acetaminophen (APAP) exposures injure the developing lung is controversial. We sought to correlate murine pulmonary developmental expression profiles of Cyp2e1 to susceptibility to APAP exposure. Postnatal day 14 (P14) C57BL/6 mice were exposed to APAP (140 mg/kg × 1 i.p.) and assessed for evidence of a histologic, metabolic, functional, and/or transcriptional pulmonary response. Similar experiments were performed in P14 IL6(-/-) mice, given the controversial role of IL-6 in APAP-induced tissue injury. No evidence of hepatic injury was noted in APAP-exposed P14 mice. In contrast, within 6 hours of exposure, pulmonary tissue demonstrated histologic and functional evidence of injury and increased mitochondrial load by fluorescence lifetime imaging microscopy. The pulmonary transcriptional response was marked by increased expression of Cyp2e1, Nrf2 targets, and proinflammatory genes. Specifically, APAP exposure increased pulmonary IL-6 mRNA, protein, and associated STAT3 signaling. In contrast, IL6(-/-) mice demonstrated attenuated STAT3 signaling and injury at 6 hours of exposure. At P28, functional and stereologic assessment of both wild-type and IL6(-/-) mice exposed to a single dose of APAP at P14 revealed persistent abnormalities consistent with lung enlargement and alveolar simplification. Developmentally regulated surges in pulmonary Cyp2e1 expression correlate with sensitivity to APAP exposures that do not cause recognizable hepatic injury. A single exposure during this developmental window is enough to cause persistent functional and stereological abnormalities. These results highlight the need to further study the relationship between developmentally regulated pulmonary Cyp2e1 expression, APAP exposures, and long-term pulmonary dysfunction.