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Research ArticleInflammation, Immunopharmacology, and Asthma

Prevention of Bleomycin-Induced Lung Inflammation and Fibrosis in Mice by Naproxen and JNJ7777120 Treatment

Arianna Carolina Rosa, Alessandro Pini, Laura Lucarini, Cecilia Lanzi, Eleonora Veglia, Robin L. Thurmond, Holger Stark and Emanuela Masini
Journal of Pharmacology and Experimental Therapeutics November 2014, 351 (2) 308-316; DOI: https://doi.org/10.1124/jpet.114.215152
Arianna Carolina Rosa
Departments of Drug Science and Technology, University of Turin, Turin, Italy (A.C.R., E.V.); Department of Neuroscience, Psychiatry, and Drug Research, Section of Pharmacology (L.L., C.L., E.M.), and Experimental and Clinical Medicine (A.P.), University of Florence, Florence, Italy; Janssen Research & Development, L.L.C., San Diego, California (R.L.T.); and Heinrich-Heine Düsseldorf University, Institute of Medicinal Chemistry, Düsseldorf, Germany (H.S.)
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Alessandro Pini
Departments of Drug Science and Technology, University of Turin, Turin, Italy (A.C.R., E.V.); Department of Neuroscience, Psychiatry, and Drug Research, Section of Pharmacology (L.L., C.L., E.M.), and Experimental and Clinical Medicine (A.P.), University of Florence, Florence, Italy; Janssen Research & Development, L.L.C., San Diego, California (R.L.T.); and Heinrich-Heine Düsseldorf University, Institute of Medicinal Chemistry, Düsseldorf, Germany (H.S.)
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Laura Lucarini
Departments of Drug Science and Technology, University of Turin, Turin, Italy (A.C.R., E.V.); Department of Neuroscience, Psychiatry, and Drug Research, Section of Pharmacology (L.L., C.L., E.M.), and Experimental and Clinical Medicine (A.P.), University of Florence, Florence, Italy; Janssen Research & Development, L.L.C., San Diego, California (R.L.T.); and Heinrich-Heine Düsseldorf University, Institute of Medicinal Chemistry, Düsseldorf, Germany (H.S.)
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Cecilia Lanzi
Departments of Drug Science and Technology, University of Turin, Turin, Italy (A.C.R., E.V.); Department of Neuroscience, Psychiatry, and Drug Research, Section of Pharmacology (L.L., C.L., E.M.), and Experimental and Clinical Medicine (A.P.), University of Florence, Florence, Italy; Janssen Research & Development, L.L.C., San Diego, California (R.L.T.); and Heinrich-Heine Düsseldorf University, Institute of Medicinal Chemistry, Düsseldorf, Germany (H.S.)
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Eleonora Veglia
Departments of Drug Science and Technology, University of Turin, Turin, Italy (A.C.R., E.V.); Department of Neuroscience, Psychiatry, and Drug Research, Section of Pharmacology (L.L., C.L., E.M.), and Experimental and Clinical Medicine (A.P.), University of Florence, Florence, Italy; Janssen Research & Development, L.L.C., San Diego, California (R.L.T.); and Heinrich-Heine Düsseldorf University, Institute of Medicinal Chemistry, Düsseldorf, Germany (H.S.)
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Robin L. Thurmond
Departments of Drug Science and Technology, University of Turin, Turin, Italy (A.C.R., E.V.); Department of Neuroscience, Psychiatry, and Drug Research, Section of Pharmacology (L.L., C.L., E.M.), and Experimental and Clinical Medicine (A.P.), University of Florence, Florence, Italy; Janssen Research & Development, L.L.C., San Diego, California (R.L.T.); and Heinrich-Heine Düsseldorf University, Institute of Medicinal Chemistry, Düsseldorf, Germany (H.S.)
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Holger Stark
Departments of Drug Science and Technology, University of Turin, Turin, Italy (A.C.R., E.V.); Department of Neuroscience, Psychiatry, and Drug Research, Section of Pharmacology (L.L., C.L., E.M.), and Experimental and Clinical Medicine (A.P.), University of Florence, Florence, Italy; Janssen Research & Development, L.L.C., San Diego, California (R.L.T.); and Heinrich-Heine Düsseldorf University, Institute of Medicinal Chemistry, Düsseldorf, Germany (H.S.)
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Emanuela Masini
Departments of Drug Science and Technology, University of Turin, Turin, Italy (A.C.R., E.V.); Department of Neuroscience, Psychiatry, and Drug Research, Section of Pharmacology (L.L., C.L., E.M.), and Experimental and Clinical Medicine (A.P.), University of Florence, Florence, Italy; Janssen Research & Development, L.L.C., San Diego, California (R.L.T.); and Heinrich-Heine Düsseldorf University, Institute of Medicinal Chemistry, Düsseldorf, Germany (H.S.)
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Abstract

Pulmonary fibrosis, a progressive and lethal lung disease characterized by inflammation and accumulation of extracellular matrix components, is a major therapeutic challenge for which new therapeutic strategies are warranted. Cyclooxygenase (COX) inhibitors have been previously utilized to reduce inflammation. Histamine H4 receptor (H4R), largely expressed in hematopoietic cells, has been identified as a novel target for inflammatory and immune disorders. The aim of this study was to evaluate the effect of JNJ7777120 (1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine), a selective H4R antagonist, and naproxen, a well known nonsteroidal anti-inflammatory drug, and their combination in a murine model of bleomycin-induced fibrosis. Bleomycin (0.05 IU) was instilled intratracheally to C57BL/6 mice, which were then treated by micro-osmotic pump with vehicle, JNJ7777120 (40 mg/kg b.wt.), naproxen (21 mg/kg b.wt.), or a combination of both. Airway resistance to inflation, an index of lung stiffness, was assessed, and lung specimens were processed for inflammation, oxidative stress, and fibrosis markers. Both drugs alone were able to reduce the airway resistance to inflation induced by bleomycin and the inflammatory response by decreasing COX-2 and myeloperoxidase expression and activity and thiobarbituric acid–reactive substance and 8-hydroxy-2′-deoxyguanosine production. Lung fibrosis was inhibited, as demonstrated by the reduction of tissue levels of transforming growth factor-β, collagen deposition, relative goblet cell number, and smooth muscle layer thickness. Our results demonstrate that both JNJ7777120 and naproxen exert an anti-inflammatory and antifibrotic effect that is increased by their combination, which could be an effective therapeutic strategy in the treatment of pulmonary fibrosis.

Footnotes

    • Received April 23, 2014.
    • Accepted August 28, 2014.
  • This work was supported by COST Action BM0806 (to A.C.R., A.P., H.S., and E.M.); and by Ente Cassa di Risparmio di Firenze, Florence, Italy (to E.M.).

  • Some of the data in this study were presented previously: Pini A, Somma T, Formicola G, Thurmond RT, Bani D, and Masini E (2011) Prevention of bleomycin-induced pulmonary fibrosis by a selecetive histamine H4R antagonist. 40th European Histamine Research Society Meeting; 2011 May 11–14; Sochi, Russia; and published in abstract form in Inflamm Res 60:S335.

  • dx.doi.org/10.1124/jpet.114.215152.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 351 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 351, Issue 2
1 Nov 2014
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Research ArticleInflammation, Immunopharmacology, and Asthma

Effect of JNJ7777120 and Naproxen on Lung Fibrosis in Mice

Arianna Carolina Rosa, Alessandro Pini, Laura Lucarini, Cecilia Lanzi, Eleonora Veglia, Robin L. Thurmond, Holger Stark and Emanuela Masini
Journal of Pharmacology and Experimental Therapeutics November 1, 2014, 351 (2) 308-316; DOI: https://doi.org/10.1124/jpet.114.215152

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Research ArticleInflammation, Immunopharmacology, and Asthma

Effect of JNJ7777120 and Naproxen on Lung Fibrosis in Mice

Arianna Carolina Rosa, Alessandro Pini, Laura Lucarini, Cecilia Lanzi, Eleonora Veglia, Robin L. Thurmond, Holger Stark and Emanuela Masini
Journal of Pharmacology and Experimental Therapeutics November 1, 2014, 351 (2) 308-316; DOI: https://doi.org/10.1124/jpet.114.215152
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