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.