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Acetaminophen has been shown to reduce postoperative opiate burden, and may provide similar efficacy for closure of the patent ductus arteriosus (PDA) as nonsteroidal anti-inflammatory drugs (NSAIDs). Despite these potential benefits, APAP exposures have spread to increasingly less mature infants, a highly vulnerable population for whom robust pharmacokinetic and pharmacodynamic data for APAP are lacking. Concerningly, preclinical studies suggest that perinatal APAP exposures may result in unanticipated adverse effects that are unique to the developing lung. In this review, we discuss the clinical observations linking APAP exposures to adverse respiratory outcomes and the preclinical data demonstrating a developmental susceptibility to APAP-induced lung injury. We show how clinical observations linking perinatal APAP exposures to pulmonary injury have been taken to the bench to produce important insights into the potential mechanisms underlying these findings. We argue that the available data support a more cautious approach to APAP use in the NICU until large randomized controlled trials provide appropriate safety and efficacy data. <\/jats:p>","DOI":"10.1152\/ajplung.00080.2022","type":"journal-article","created":{"date-parts":[[2022,5,3]],"date-time":"2022-05-03T15:46:15Z","timestamp":1651592775000},"page":"L1-L13","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Racing against time: leveraging preclinical models to understand pulmonary susceptibility to perinatal acetaminophen exposures"],"prefix":"10.1152","volume":"323","author":[{"given":"David J.","family":"McCulley","sequence":"first","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, University of California, San Diego, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik A.","family":"Jensen","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, The Children\u2019s Hospital of Philadelphia, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6613-1439","authenticated-orcid":true,"given":"Jennifer M. 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