AbstractBackgroundBronchopulmonary dysplasia (BPD) with airway hyperreactivity is a long‐term pulmonary complication of prematurity. The endogenous nonadrenergic, noncholinergic signaling molecule, S‐nitrosoglutathione (GSNO) and its catabolism by GSNO reductase (GSNOR) modulate airway reactivity. Tracheomalacia is a major, underinvestigated complication of BPD. We studied trachealis, left main bronchus (LB), and intrapulmonary bronchiolar (IPB) relaxant responses to GSNO in a murine hyperoxic BPD model.MethodsWild‐type (WT) or GSNOR knockout (KO) newborn mice were raised in 60% (BPD) or 21% (control) oxygen during the first 3 weeks of life. After room air recovery, adult trachealis, LB, and IPB smooth muscle relaxant responses to GSNO (after methacholine preconstriction) were studied using wire myographs. Studies were repeated after GSNOR inhibitor (GSNORi) pretreatment and in KO mice.ResultsGSNO relaxed all airway preparations. GSNO relaxed WT BPD trachealis substantially more than WT controls (P < .05). Pharmacologic or genetic ablation of GSNOR abolished the exaggerated BPD tracheal relaxation to GSNO and also augmented BPD IPB relaxation to GSNO. LB ring contractility was not significantly different between groups or conditions. Additionally, GSNORi treatment induced relaxation of WT IPBs but not trachealis or LB.ConclusionGSNO dramatically relaxed the trachealis in our BPD model, an effect paradoxically reversed by loss of GSNOR. Conversely, GSNOR inhibition augmented IBP relaxation. These data suggest that GSNOR inhibition could benefit both the BPD trachealis and distal airways, restoring relaxant responses to those of room air controls. Because therapeutic options are limited in this high‐risk population, future studies of GSNOR inhibition are needed.

01 Oct 2015·Journal of Pharmacology and Experimental TherapeuticsQ3 · MEDICINE

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

Q3 · MEDICINE

Article

Author: Luzina, Irina G ; Lockatell, Virginia ; Pentikis, Helen S ; Atamas, Sergei P ; Todd, Nevins W ; Kopach, Pavel

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.

PLoS ONEQ3 · CROSS-FIELD

S-Nitrosoglutathione Reductase Inhibition Regulates Allergen-Induced Lung Inflammation and Airway Hyperreactivity

Q3 · CROSS-FIELD

ArticleOA

Author: Maria E. Ferrini ; Kevan Roberts ; David J. P. Bassett ; Matthews O. Bradley ; Zeina Jaffar ; Bryan J. Simons

Allergic asthma is characterized by Th2 type inflammation, leading to airway hyperresponsivenes, mucus hypersecretion and tissue remodeling. S-Nitrosoglutathione reductase (GSNOR) is an alcohol dehydrogenase involved in the regulation of intracellular levels of S-nitrosothiols. GSNOR activity has been shown to be elevated in human asthmatic lungs, resulting in diminished S-nitrosothiols and thus contributing to increased airway hyperreactivity. Using a mouse model of allergic airway inflammation, we report that intranasal administration of a new selective inhibitor of GSNOR, SPL-334, caused a marked reduction in airway hyperreactivity, allergen-specific T cells and eosinophil accumulation, and mucus production in the lungs in response to allergen inhalation. Moreover, SPL-334 treatment resulted in a significant decrease in the production of the Th2 cytokines IL-5 and IL-13 and the level of the chemokine CCL11 (eotaxin-1) in the airways. Collectively, these observations reveal that GSNOR inhibitors are effective not only in reducing airway hyperresponsiveness but also in limiting lung inflammatory responses mediated by CD4(+) Th2 cells. These findings suggest that the inhibition of GSNOR may provide a novel therapeutic approach for the treatment of allergic airway inflammation.

100 Deals associated with SPL-334

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Phase 2	-	SAJE Pharma LLC	-
Asthma	Phase 2	-	SAJE Pharma LLC	-
Asthma	Phase 2	-	The Johns Hopkins University	-
Asthma	Phase 2	-	The Johns Hopkins University	-
Idiopathic Pulmonary Fibrosis	Phase 2	US	SAJE Pharma LLC	-
Inflammation	Phase 2	US	SAJE Pharma LLC	-
Parkinson Disease	Phase 2	US	SAJE Pharma LLC	-

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