Acetaminophen is both bronchodilatory and bronchoprotective in human precision cut lung slice airways

Joshua L. Kennedy, Richard C. Kurten, Sandra McCullough, Reynold Panettieri, Cynthia Koziol-White, Stacie M. Jones, Katherine Caid, Pritmohinder S. Gill, Dean Roberts, Hartmut Jaeschke, Mitchell R. McGill, Laura James

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1106-1115
Number of pages10
JournalXenobiotica
Volume49
Issue number9
DOIs
StatePublished - Sep 2 2019

Fingerprint

Acetaminophen
Lung
Respiratory Hypersensitivity
Bronchoconstrictor Agents
Bronchoconstriction
Asthma
Bronchodilator Agents
Carbachol
Metabolism
Constriction
Immunoglobulin E
Histamine
Epidemiologic Studies

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Toxicology
  • Pharmacology
  • Health, Toxicology and Mutagenesis

Keywords

  • Acetaminophen
  • acetaminophen metabolism
  • airway hyper-responsiveness
  • asthma
  • precision cut lung slice

Cite this

Kennedy, Joshua L. ; Kurten, Richard C. ; McCullough, Sandra ; Panettieri, Reynold ; Koziol-White, Cynthia ; Jones, Stacie M. ; Caid, Katherine ; Gill, Pritmohinder S. ; Roberts, Dean ; Jaeschke, Hartmut ; McGill, Mitchell R. ; James, Laura. / Acetaminophen is both bronchodilatory and bronchoprotective in human precision cut lung slice airways. In: Xenobiotica. 2019 ; Vol. 49, No. 9. pp. 1106-1115.
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Kennedy, JL, Kurten, RC, McCullough, S, Panettieri, R, Koziol-White, C, Jones, SM, Caid, K, Gill, PS, Roberts, D, Jaeschke, H, McGill, MR & James, L 2019, 'Acetaminophen is both bronchodilatory and bronchoprotective in human precision cut lung slice airways', Xenobiotica, vol. 49, no. 9, pp. 1106-1115. https://doi.org/10.1080/00498254.2018.1536814

Acetaminophen is both bronchodilatory and bronchoprotective in human precision cut lung slice airways. / Kennedy, Joshua L.; Kurten, Richard C.; McCullough, Sandra; Panettieri, Reynold; Koziol-White, Cynthia; Jones, Stacie M.; Caid, Katherine; Gill, Pritmohinder S.; Roberts, Dean; Jaeschke, Hartmut; McGill, Mitchell R.; James, Laura.

In: Xenobiotica, Vol. 49, No. 9, 02.09.2019, p. 1106-1115.

Research output: Contribution to journalArticle

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T1 - Acetaminophen is both bronchodilatory and bronchoprotective in human precision cut lung slice airways

AU - Kennedy, Joshua L.

AU - Kurten, Richard C.

AU - McCullough, Sandra

AU - Panettieri, Reynold

AU - Koziol-White, Cynthia

AU - Jones, Stacie M.

AU - Caid, Katherine

AU - Gill, Pritmohinder S.

AU - Roberts, Dean

AU - Jaeschke, Hartmut

AU - McGill, Mitchell R.

AU - James, Laura

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N2 - 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.

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.

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