title: Pharmacological In Vivo Inhibition of S-Nitrosoglutathione Reductase Attenuates Bleomycin-Induced Inflammation and Fibrosis.
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.
authors.affiliation: 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.).
authors.forename: Irina G
authors.initials: IG
authors.lastname: Luzina
authors.affiliation: 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.).
authors.forename: Virginia
authors.initials: V
authors.lastname: Lockatell
authors.affiliation: 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.).
authors.forename: Nevins W
authors.initials: NW
authors.lastname: Todd
authors.affiliation: 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.).
authors.forename: Pavel
authors.initials: P
authors.lastname: Kopach
authors.affiliation: 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.).
authors.forename: Helen S
authors.initials: HS
authors.lastname: Pentikis
authors.affiliation: 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.) satamas@medicine.umaryland.edu.
authors.forename: Sergei P
authors.initials: SP
authors.lastname: Atamas
mesh_terms: D000445:Aldehyde Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D019817:Benzoic Acid / Q000494:pharmacology*; D001761:Bleomycin / Q000009:adverse effects*; D003094:Collagen / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D051379:Mice; D011014:Pneumonia / Q000139:chemically induced* / Q000517:prevention & control*; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000517:prevention & control*; D011744:Pyrimidinones / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D001565:Benzoates; D004791:Enzyme Inhibitors; D011744:Pyrimidinones; C000602674:SPL-334; D016212:Transforming Growth Factor beta; D001761:Bleomycin; D019817:Benzoic Acid; D003094:Collagen; D000445:Aldehyde Oxidoreductases; C087006:formaldehyde dehydrogenase, glutathione-independent