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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Pharmacological In Vivo Inhibition of S-Nitrosoglutathione Reductase Attenuates Bleomycin-Induced Inflammation and Fibrosis

Irina G. Luzina, Virginia Lockatell, Nevins W. Todd, Pavel Kopach, Helen S. Pentikis and Sergei P. Atamas
Journal of Pharmacology and Experimental Therapeutics October 2015, 355 (1) 13-22; DOI: https://doi.org/10.1124/jpet.115.224675
Irina G. Luzina
Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland (I.G.L., V.L., N.W.T., P.K., S.P.A); and SAJE Pharma, Baltimore, Maryland (H.S.P.)
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Virginia Lockatell
Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland (I.G.L., V.L., N.W.T., P.K., S.P.A); and SAJE Pharma, Baltimore, Maryland (H.S.P.)
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Nevins W. Todd
Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland (I.G.L., V.L., N.W.T., P.K., S.P.A); and SAJE Pharma, Baltimore, Maryland (H.S.P.)
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Pavel Kopach
Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland (I.G.L., V.L., N.W.T., P.K., S.P.A); and SAJE Pharma, Baltimore, Maryland (H.S.P.)
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Helen S. Pentikis
Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland (I.G.L., V.L., N.W.T., P.K., S.P.A); and SAJE Pharma, Baltimore, Maryland (H.S.P.)
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Sergei P. Atamas
Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland (I.G.L., V.L., N.W.T., P.K., S.P.A); and SAJE Pharma, Baltimore, Maryland (H.S.P.)
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Abstract

Interstitial lung disease (ILD) characterized by pulmonary fibrosis and inflammation poses a substantial biomedical challenge due to often negative disease outcomes combined with the need to develop better, more effective therapies. We assessed the in vivo effect of administration of a pharmacological inhibitor of S-nitrosoglutathione reductase, SPL-334 (4-{[2-[(2-cyanobenzyl)thio]-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl]methyl}benzoic acid), in a mouse model of ILD induced by intratracheal instillation of bleomycin (BLM). Daily i.p. administration of SPL-334 alone at 0.3, 1.0, or 3.0 mg/kg had no effect on animal body weight, appearance, behavior, total and differential bronchoalveolar lavage (BAL) cell counts, or collagen accumulation in the lungs, showing no toxicity of our investigational compound. Similar administration of SPL-334 for 7 days before and for an additional 14 days after BLM instillation resulted in a preventive protective effect on the BLM challenge–induced decline in total body weight and changes in total and differential BAL cellularity. In the therapeutic treatment regimen, SPL-334 was administered at days 7–21 after BLM challenge. Such treatment attenuated the BLM challenge–induced decline in total body weight, changes in total and differential BAL cellularity, and magnitudes of histologic changes and collagen accumulation in the lungs. These changes were accompanied by an attenuation of BLM-induced elevations in pulmonary levels of profibrotic cytokines interleukin-6, monocyte chemoattractant protein-1, and transforming growth factor-β (TGF-β). Experiments in cell cultures of primary normal human lung fibroblast have demonstrated attenuation of TGF-β–induced upregulation in collagen by SPL-334. It was concluded that SPL-334 is a potential therapeutic agent for ILD.

Footnotes

    • Received March 25, 2015.
    • Accepted July 23, 2015.
  • This work was supported by Maryland Industrial Partnerships Award 5111.

  • dx.doi.org/10.1124/jpet.115.224675.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 355 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 355, Issue 1
1 Oct 2015
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

SPL-334 Attenuates Inflammation and Fibrosis in the Lungs

Irina G. Luzina, Virginia Lockatell, Nevins W. Todd, Pavel Kopach, Helen S. Pentikis and Sergei P. Atamas
Journal of Pharmacology and Experimental Therapeutics October 1, 2015, 355 (1) 13-22; DOI: https://doi.org/10.1124/jpet.115.224675

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

SPL-334 Attenuates Inflammation and Fibrosis in the Lungs

Irina G. Luzina, Virginia Lockatell, Nevins W. Todd, Pavel Kopach, Helen S. Pentikis and Sergei P. Atamas
Journal of Pharmacology and Experimental Therapeutics October 1, 2015, 355 (1) 13-22; DOI: https://doi.org/10.1124/jpet.115.224675
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