1. Acetaminophen is both bronchodilatory and bronchoprotective in human precision cut lung slice airways.
- Author
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Kennedy JL, Kurten RC, McCullough S, Panettieri RA, Koziol-White C, Jones SM, Caid K, Gill PS, Roberts D, Jaeschke H, McGill MR, and James L
- Subjects
- Acetaminophen administration & dosage, Acetaminophen adverse effects, Albuterol pharmacology, Animals, Asthma physiopathology, Bronchodilator Agents adverse effects, Carbachol pharmacology, Chemical and Drug Induced Liver Injury etiology, Dose-Response Relationship, Drug, Humans, Lung physiology, Male, Mice, Inbred C57BL, Mice, Inbred Strains, Middle Aged, Organ Culture Techniques, Oxidative Stress drug effects, Respiratory Hypersensitivity chemically induced, Acetaminophen pharmacology, Bronchoconstriction drug effects, Bronchodilator Agents pharmacology, Lung drug effects
- Abstract
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.
- Published
- 2019
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