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PLoS One. 2018 Sep 25;13(9):e0204709. doi: 10.1371/journal.pone.0204709. eCollection 2018.

A synthetic glycosaminoglycan reduces sinonasal inflammation in a murine model of chronic rhinosinusitis.

Author information

1
Division of Head and Neck Surgery, Rhinology-Sinus and Skull Base Surgery Program, Department of Surgery, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
2
GlycoMira Therapeutics, Inc., Salt Lake City, Utah, United States of America.
3
Pulmonary Diseases Critical Care and Environmental Medicine, Tulane University School of Medicine, New Orleans, Louisiana, United States of America.
4
Department of Medicinal Chemistry and Center for Therapeutic Biomaterials, University of Utah, Salt Lake City, Utah, United States of America.

Abstract

Chronic rhinosinusitis (CRS) is characterized by sustained mucosal inflammation, impaired mucociliary clearance, loss of cilia and epithelial barrier breakdown, and tissue remodeling. Certain glycosaminoglycans inhibit various inflammatory mediators, suppress bacterial growth, and provide important functions in mucosal tissue repair and mucociliary clearance. Herein, we evaluated the effects of a synthetic glycosaminoglycan, GM-1111, on the clinical signs and inflammatory tissue changes associated with CRS in mice. CRS was generated by repeated intranasal applications of Aspergillus fumigatus (A. fumigatus) extracts over 4 weeks. Mice were then intranasally administered GM-1111 (600 μg per dose, 5 times a week) or vehicle (phosphate buffered saline, PBS) for an additional 4 weeks while still being given A. fumigatus extracts to maintain a chronic inflammatory environment with acute exacerbations. Clinical signs indicative of sinonasal inflammation were recorded throughout the study. After 9 weeks, whole blood and sinonasal tissues were harvested for hematological, histological, and biochemical examination. The clinical signs, white blood cell counts, tissue markers of sinonasal inflammation, and histological changes caused by A. fumigatus extract administration were compared to the healthy (PBS vehicle) and GM-1111-treated groups (n = 12 per treatment group). Compared to vehicle-treated animals, animals treated with GM-1111 demonstrated significant reductions in clinical signs (p<0.05), degenerative tissue changes, goblet cell hyperplasia, inflammatory cell infiltration (p<0.01), innate immunity- (tlr2, tlr4, myd88, il1b, tnfa, il6, and il12) and adaptive immunity-associated (ccl11, ccl24, ccl5, il4, il5, and il13) cytokine gene expression (p<0.05 to p<0.0001) in sinonasal tissues, and serum IgE levels (p<0.01). Our data suggest that GM-1111 significantly reduces local and systemic effects of CRS-associated sinonasal inflammation.

PMID:
30252910
PMCID:
PMC6155557
DOI:
10.1371/journal.pone.0204709
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

WYL, JRS, and AP are employed by and GDP, TPK, and JAA have stock in GlycoMira Therapeutics, Inc. JAA is a paid consultant for Medtronic ENT, Spirox, and OptiNose. These affiliations do not alter the authors’ adherence to PLoS ONE policies on sharing data and materials.

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