Therapeutic effect of neuraminidase-1-Selective inhibition in mouse models of bleomycin-induced pulmonary inflammation and fibrosis
JournalJournal of Pharmacology and Experimental Therapeutics
PublisherAmerican Society for Pharmacology and Experimental Therapy
MetadataShow full item record
AbstractPulmonary fibrosis remains a serious biomedical problem with no cure and an urgent need for better therapies. Neuraminidases (NEUs), including NEU1, have been recently implicated in the mechanism of pulmonary fibrosis by us and others. We now have tested the ability of a broad-spectrum neuraminidase inhibitor, 2,3-dehydro-2-deoxy-N-acetylneuraminic acid (DANA), to modulate the in vivo response to acute intratracheal bleomycin challenge as an experimental model of pulmonary fibrosis. A marked alleviation of bleomycin-induced body weight loss and notable declines in accumulation of pulmonary lymphocytes and collagen deposition were observed. Real-time polymerase chain reaction analyses of human and mouse lung tissues and primary human lung fibroblast cultures were also performed. A predominant expression and pronounced elevation in the levels of NEU1 mRNA were observed in patients with idiopathic pulmonary fibrosis and bleomycin-challenged mice compared with their corresponding controls, whereas NEU2, NEU3, and NEU4 were expressed at far lower levels. The levels of mRNA for the NEU1 chaperone, protective protein/cathepsin A (PPCA), were also elevated by bleomycin. Western blotting analyses demonstrated bleomycin-induced elevations in protein expression of both NEU1 and PPCA in mouse lungs. Two known selective NEU1 inhibitors, C9-pentyl-amide-DANA (C9-BA-DANA) and C5-hexanamido-C9-acetamido-DANA, dramatically reduced bleomycin-induced loss of body weight, accumulation of pulmonary lymphocytes, and deposition of collagen. Importantly, C9-BA-DANA was therapeutic in the chronic bleomycin exposure model with no toxic effects observed within the experimental timeframe. Moreover, in the acute bleomycin model, C9-BA-DANA attenuated NEU1-mediated desialylation and shedding of the mucin-1 ectodomain. These data indicate that NEU1-selective inhibition offers a potential therapeutic intervention for pulmonary fibrotic diseases. Copyright 2021 American Society for Pharmacology and Experimental Therapy. All rights reserved.
SponsorsThis work was supported by National Institutes of Health National Heart, Lung, and Blood Institute [Grant R01-HL126897]; Department of Veterans Affairs [Grant I01CX000101] and [Grant I01BX002499]; and GlycoNet [Project CD-2]. We thank T. Guo (University of Alberta) for providing samples of CG33300. A PCT application relating to some of the findings described here has been filed with I.G.L., S.P.A., S.E.G., and C.W.C. as inventors. C.W.C. is a coinventor on patent filings related to CG33300.
Identifier to cite or link to this itemhttp://hdl.handle.net/10713/15275
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