PMID- 30328361 OWN - NLM STAT- MEDLINE DCOM- 20191212 LR - 20200901 IS - 1366-5928 (Electronic) IS - 0049-8254 (Print) IS - 0049-8254 (Linking) VI - 49 IP - 9 DP - 2019 Sep TI - Acetaminophen is both bronchodilatory and bronchoprotective in human precision cut lung slice airways. PG - 1106-1115 LID - 10.1080/00498254.2018.1536814 [doi] AB - Epidemiologic studies have demonstrated an association between acetaminophen (APAP) use and the development of asthma symptoms. However, few studies have examined relationships between APAP-induced signaling pathways associated with the development of asthma symptoms. We tested the hypothesis that acute APAP exposure causes airway hyper-responsiveness (AHR) in human airways. Precision cut lung slice (PCLS) airways from humans and mice were used to determine the effects of APAP on airway bronchoconstriction and bronchodilation and to assess APAP metabolism in lungs. APAP did not promote AHR in normal or asthmatic human airways ex vivo. Rather, high concentrations mildly bronchodilated airways pre-constricted with carbachol (CCh), histamine (His), or immunoglobulin E (IgE) cross-linking. Further, the addition of APAP prior to bronchoconstrictors protected the airways from constriction. Similarly, in vivo treatment of mice with APAP (200 mg/kg IP) resulted in reduced bronchoconstrictor responses in PCLS airways ex vivo. Finally, in both mouse and human PCLS airways, exposure to APAP generated only low amounts of APAP-protein adducts, indicating minimal drug metabolic activity in the tissues. These findings indicate that acute exposure to APAP does not initiate AHR, that high-dose APAP is protective against bronchoconstriction, and that APAP is a mild bronchodilator. FAU - Kennedy, Joshua L AU - Kennedy JL AD - a Division of Allergy and Immunology, Department of Pediatrics , University of Arkansas for Medical Sciences , Little Rock , AR , USA. AD - b Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine , University of Arkansas for Medical Sciences , Little Rock , AR , USA. AD - c Arkansas Children's Hospital Research Institute , Little Rock , AR , USA. FAU - Kurten, Richard C AU - Kurten RC AD - a Division of Allergy and Immunology, Department of Pediatrics , University of Arkansas for Medical Sciences , Little Rock , AR , USA. AD - c Arkansas Children's Hospital Research Institute , Little Rock , AR , USA. AD - d Department of Physiology and Biophysics , University of Arkansas for Medical Sciences , Little Rock , AR , USA. FAU - McCullough, Sandra AU - McCullough S AD - e Division of Clinical Pharmacology and Toxicology, Department of Pediatrics , University of Arkansas for Medical Sciences , Little Rock , AR , USA. FAU - Panettieri, Reynold A AU - Panettieri RA AD - f Department of Medicine , Rutgers, the State University of New Jersey , New Brunswick , NJ , USA. FAU - Koziol-White, Cynthia AU - Koziol-White C AD - f Department of Medicine , Rutgers, the State University of New Jersey , New Brunswick , NJ , USA. FAU - Jones, Stacie M AU - Jones SM AD - a Division of Allergy and Immunology, Department of Pediatrics , University of Arkansas for Medical Sciences , Little Rock , AR , USA. AD - c Arkansas Children's Hospital Research Institute , Little Rock , AR , USA. AD - d Department of Physiology and Biophysics , University of Arkansas for Medical Sciences , Little Rock , AR , USA. FAU - Caid, Katherine AU - Caid K AD - g Department of Pediatrics , University of Arkansas for Medical Sciences , Little Rock , AR , USA. FAU - Gill, Pritmohinder S AU - Gill PS AD - c Arkansas Children's Hospital Research Institute , Little Rock , AR , USA. AD - g Department of Pediatrics , University of Arkansas for Medical Sciences , Little Rock , AR , USA. FAU - Roberts, Dean AU - Roberts D AD - e Division of Clinical Pharmacology and Toxicology, Department of Pediatrics , University of Arkansas for Medical Sciences , Little Rock , AR , USA. FAU - Jaeschke, Hartmut AU - Jaeschke H AD - h Department of Pharmacology, Toxicology, and Therapeutics , University of Kansas Medical Center , Kansas City , KS , USA. FAU - McGill, Mitchell R AU - McGill MR AD - i Department of Environmental and Occupational Health, Fay W. Boozman College of Public Health , University of Arkansas for Medical Sciences , Little Rock , AR , USA. FAU - James, Laura AU - James L AD - e Division of Clinical Pharmacology and Toxicology, Department of Pediatrics , University of Arkansas for Medical Sciences , Little Rock , AR , USA. LA - eng GR - UL1 TR000039/TR/NCATS NIH HHS/United States GR - P01 HL114471/HL/NHLBI NIH HHS/United States GR - L40 AI107898/AI/NIAID NIH HHS/United States GR - KL2 TR000063/TR/NCATS NIH HHS/United States GR - UL1 TR003107/TR/NCATS NIH HHS/United States GR - P30 GM118247/GM/NIGMS NIH HHS/United States GR - K08 AI121345/AI/NIAID NIH HHS/United States PT - Journal Article PT - Video-Audio Media DEP - 20190130 PL - England TA - Xenobiotica JT - Xenobiotica; the fate of foreign compounds in biological systems JID - 1306665 RN - 0 (Bronchodilator Agents) RN - 362O9ITL9D (Acetaminophen) RN - 8Y164V895Y (Carbachol) RN - QF8SVZ843E (Albuterol) SB - IM MH - Acetaminophen/administration & dosage/adverse effects/*pharmacology MH - Albuterol/pharmacology MH - Animals MH - Asthma/physiopathology MH - Bronchoconstriction/*drug effects MH - Bronchodilator Agents/adverse effects/*pharmacology MH - Carbachol/pharmacology MH - Chemical and Drug Induced Liver Injury/etiology MH - Dose-Response Relationship, Drug MH - Humans MH - Lung/*drug effects/physiology MH - Male MH - Mice, Inbred C57BL MH - Mice, Inbred Strains MH - Middle Aged MH - Organ Culture Techniques MH - Oxidative Stress/drug effects MH - Respiratory Hypersensitivity/chemically induced PMC - PMC6570570 MID - NIHMS1520297 OTO - NOTNLM OT - Acetaminophen OT - acetaminophen metabolism OT - airway hyper-responsiveness OT - asthma OT - precision cut lung slice COIS- Disclosure Statement: The authors have no relevant conflicts of interest. EDAT- 2018/10/18 06:00 MHDA- 2019/12/18 06:00 PMCR- 2020/09/01 CRDT- 2018/10/18 06:00 PHST- 2018/10/18 06:00 [pubmed] PHST- 2019/12/18 06:00 [medline] PHST- 2018/10/18 06:00 [entrez] PHST- 2020/09/01 00:00 [pmc-release] AID - 10.1080/00498254.2018.1536814 [doi] PST - ppublish SO - Xenobiotica. 2019 Sep;49(9):1106-1115. doi: 10.1080/00498254.2018.1536814. Epub 2019 Jan 30.