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Research ArticleInflammation, Immunopharmacology, and Asthma

Acetaminophen Attenuates House Dust Mite–Induced Allergic Airway Disease in Mice

Gregory J. Smith, Roger S. Thrall, Michelle M. Cloutier, Jose E. Manautou and John B. Morris
Journal of Pharmacology and Experimental Therapeutics September 2016, 358 (3) 569-579; DOI: https://doi.org/10.1124/jpet.116.233684
Gregory J. Smith
Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (G.J.S., J.E.M., J.B.M); Department of Immunology, University of Connecticut Health Center, Farmington, Connecticut (R.S.T.); Connecticut Children’s Medical Center, Hartford, Connecticut (M.M.C.)
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Roger S. Thrall
Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (G.J.S., J.E.M., J.B.M); Department of Immunology, University of Connecticut Health Center, Farmington, Connecticut (R.S.T.); Connecticut Children’s Medical Center, Hartford, Connecticut (M.M.C.)
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Michelle M. Cloutier
Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (G.J.S., J.E.M., J.B.M); Department of Immunology, University of Connecticut Health Center, Farmington, Connecticut (R.S.T.); Connecticut Children’s Medical Center, Hartford, Connecticut (M.M.C.)
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Jose E. Manautou
Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (G.J.S., J.E.M., J.B.M); Department of Immunology, University of Connecticut Health Center, Farmington, Connecticut (R.S.T.); Connecticut Children’s Medical Center, Hartford, Connecticut (M.M.C.)
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John B. Morris
Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (G.J.S., J.E.M., J.B.M); Department of Immunology, University of Connecticut Health Center, Farmington, Connecticut (R.S.T.); Connecticut Children’s Medical Center, Hartford, Connecticut (M.M.C.)
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  • Fig. 1.
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    Fig. 1.

    APAP attenuates the inflammatory response to HDM. (A) HDM model timeline with APAP administration either for 5 days during week 1 or 4 days during week 2. Mice were administered either a 1.25 or 10 µg dose of HDM in either of the weeks of the 2-week protocol. Mice were euthanized and BAL was performed on day 12. Black arrows above the timeline represent days mice received doses of HDM and or APAP. (B) BAL cells of mice administered either vehicle control (HDM control), APAP during week 1 (HDM + APAP Wk1), or APAP during week 2 (HDM+APAP Wk2), and a 1.25 or 10 µg dose of HDM (intranasal). Differential cell count data are presented as mean cells/ml ± S.E.M. (n = 5 mice/group, except for HDM+APAP Wk2 1.25 µg, where n = 4). (C) Protein levels represented as mean percent of control ± S.E.M. in BAL fluid supernatants (n = 5 mice/group). The black line at y = 100% represents the mean of the pooled control values (n = 10 mice/group) and the dotted lines represent ± the S.E.M. Controls averaged 116.6 ± 4.0 µg/ml total protein. Data were analyzed by analysis of variance followed by Newman-Keuls test. Separate analyses were performed for the 1.25 and 10 µg dose groups. Groups with differing superscripts differ from each other at the P < 0.05 level. All data are representative of two independent experiments.

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    Fig. 2.

    Time course of the effect of APAP on the HDM-induced inflammatory response. Mice were administered APAP during week 2 (days 8–11), along with a 1.25 µg dose of HDM following the same dosing regimen as in (A). BAL fluid was collected from separate groups of mice during each day of week 2. (A–D) BAL cell data are presented as mean cells/ml ± S.E.M. (n = 4–6 mice/group) [* P < 0.05 compared with HDM; analysis of variance (ANOVA) with Newman-Keuls test]. No inflammatory cell types were observed in control groups. (E) Protein levels in BAL fluid supernatants represented as mean percent of control ± S.E.M. (n = 5 mice/group). The vehicle control and APAP alone groups were not significantly different; therefore, they were pooled to form the control group (black line at y = 100%, n = 10 mice/group). Controls averaged 113.1 ± 4.2 µg/ml total protein. Dotted lines represent control mean ± S.E.M. Data were analyzed by ANOVA followed by Newman-Keuls test; line and bars with differing superscripts differ from each other at the P < 0.05 level. All data are representative of two independent experiments.

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    Fig. 3.

    Time courses of gene induction in the lung for selected genes modulated by HDM and APAP: (A) Il-4, (B) Il-5, (C) Muc5AC, (D) Mip2, and (E) Cyp2E1. Lung tissue was collected from groups of mice on days 8, 10, and 12 of the time course experiment. For all genes analyzed, the vehicle control and APAP alone groups did not differ significantly; therefore, they were combined to form a pooled control group for statistical analysis. Individual gene names are indicated at the top of each graph, and data are presented as mean fold increase ± S.E.M. over pooled control (black line at y = 1). Dotted line represents control mean ± S.E.M. Lines and bars with differing superscripts differ at the P < 0.05 level (analysis of variance with Newman-Keuls test). Data are representative of two independent experiments (n = 4–6 mice/group).

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    Fig. 4.

    Effect of P450 inhibition on attenuation of HDM response by APAP. Treatment of animals with 5-PP 1 hour prior to APAP treatment began once per day on day 8 and ended on day 9. BAL was performed on day 10. A 1.25 µg dose of HDM was used. (A–D) Differential cell count data are presented as mean cells/ml ± S.E.M. (n = 4–6 mice/group). Bars with differing superscripts differ at the P < 0.05 level (analysis of variance with Newman-Keuls test). No inflammatory cell types were observed in control groups and data are representative of two independent experiments.

  • Fig. 5.
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    Fig. 5.

    HDM-exposed mice demonstrate moderate perivascular/peribronchiolar inflammation, which is largely absent in APAP-treated mice. Lungs were fixed in formalin, sectioned, and stained with hematoxylin and eosin (H&E) or PAS. (A–D) Arrows indicate examples of perivascular/peribronchiolar inflammation (H&E × 200). (E–H) Arrows indicate examples of mucus production by airway goblet cells (PAS × 200). Images are representative of lungs from each group indicated above each image column, and two independent experiments (n = 3 mice/group).

Tables

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    TABLE 1

    Mouse gene names and functions for qRT-PCR analysis

    GeneNameFunctionReference
    Il-4Interleukin 4Th2-type cytokine responseLambrecht and Hammad (2015)
    Il-5Interleukin 5Th2-type cytokine responseLambrecht and Hammad (2015)
    Il-13Interleukin 13Th2-type cytokine responseLambrecht and Hammad (2015)
    CaSRCalcium-sensing receptorAirway inflammation, hyper-responsivenessYarova et al. (2015)
    Muc5ACMucin 5ACAirway mucus gel formationEvans et al. (2015)
    Mip2Macrophage inflammatory protein 2Neutrophil chemotactic factorWolpe et al. (1989)
    iNosInducible nitric oxide synthaseMast cell activation, smooth muscle toneColeman (2002)
    Cyp2E1Cytochrome P450, family 2, subfamily EAPAP metabolism to NAPQIHinson et al. (2010)
    Nqo1NAD(P)H dehydrogenase, quinone 1Detoxification of NAPQIMoffit et al. (2007)
    • NAPQI, N-acetyl-p-benzoquinone-imine.

    • View popup
    TABLE 2

    Mouse primer sequences for qRT-PCR (listed 5′-3′)

    GeneForwardReverse
    β-ActinGCAACGAGCGGTTCCGCCCAAGAAGGAAGGCTGGA
    Il-4CGAGCTCACTCTCTGTGGTGTGAACGAGGTCACAGGAGAA
    Il-5CTCTGTTGACAAGCAATGAGACGTCTTCAGTATGTCTAGCCCCTG
    Il-13CCTGGCTCTTGCTTGCCTTGGTCTTGTGTGATGTTGCTCA
    CaSRAGCAGGTGACCTTCGATGAGTACTTCCTTGAACACAATGGAGC
    Muc5ACCTGTGACATTATCCCATAAGCCCAAGGGGTATAGCTGGCCTGA
    Mip2CCAACCACCAGGCTACAGGGCGTCACACTCAAGCTCTG
    iNosTGAAGAAAACCCCTTGTGCTTTCTGTGCTGTCCCAGTGAG
    Cyp2E1GGGACATTCCTGTGTTCCAGCTTAGGGAAAACCTCCGCAC
    Nqo1TTTAGGGTCGTCTTGGCAACGTCTTCTCTGAATGGGCCAG

Additional Files

  • Figures
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  • Data Supplement

    Files in this Data Supplement:

    • Supplemental Figures -

      Supplemental Figure 1 - HDM produces a dose-dependent increase in BAL cellularity

      Supplemental Figure 2 - Time courses of gene induction in the lung for selected genes modulated by HDM and APAP

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Journal of Pharmacology and Experimental Therapeutics: 358 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 358, Issue 3
1 Sep 2016
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Research ArticleInflammation, Immunopharmacology, and Asthma

Acetaminophen Attenuates Allergic Airway Disease

Gregory J. Smith, Roger S. Thrall, Michelle M. Cloutier, Jose E. Manautou and John B. Morris
Journal of Pharmacology and Experimental Therapeutics September 1, 2016, 358 (3) 569-579; DOI: https://doi.org/10.1124/jpet.116.233684

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Research ArticleInflammation, Immunopharmacology, and Asthma

Acetaminophen Attenuates Allergic Airway Disease

Gregory J. Smith, Roger S. Thrall, Michelle M. Cloutier, Jose E. Manautou and John B. Morris
Journal of Pharmacology and Experimental Therapeutics September 1, 2016, 358 (3) 569-579; DOI: https://doi.org/10.1124/jpet.116.233684
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