Abigail Pulsipher1,2, Xuan Qin1, Andrew J Thomas1, Glenn D Prestwich3,2, Siam Oottamasathien3,4, Jeremiah A Alt1,3. 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, UT. 2. GlycoMira Therapeutics, Inc., Salt Lake City, UT. 3. Department of Medicinal Chemistry and Center for Therapeutic Biomaterials, Salt Lake City, UT. 4. Division of Pediatric Urology, Department of Surgery, University of Utah School of Medicine, Salt Lake City, UT.
Abstract
BACKGROUND: Glycosaminoglycans (GAGs) are polysaccharides that are distributed on respiratory epithelial cells, endothelial cells, and submucosal glands. Uniquely positioned, certain GAGs exhibit anti-inflammatory properties in respiratory diseases and serve important roles in repairing mucosal surfaces and modulating mucociliary clearance. We hypothesized that topical administration of a synthetic GAG (GM-0111) would prevent sinonasal inflammation in a mouse model of rhinosinusitis (RS). METHODS: To test our hypothesis, C57BL/6 mice were intranasally administered fluorescent GM-0111, and sinonasal tissues were examined for coating and penetration ability. To test therapeutic feasibility, mice (n = 6) were given GM-0111 or hyaluronic acid (HA; 800 μg dose) prior to inducing RS with inflammatory molecule LL-37 (115 μg dose). After 24 hours, sinonasal tissues were harvested for histological and biochemical analysis of inflammatory markers (inflammatory cell infiltration, lamina propria [LP] thickening, and neutrophil enzyme myeloperoxidase [MPO]) and cell death. RESULTS: GM-0111 was observed within sinonasal tissues 1 hour and 24 hours after intranasal administration, indicating rapid and effective coating and penetration. GM-0111 prevented sinonasal tissues from developing inflammatory changes, with significant reductions in mast cell infiltration (p < 0.05), LP thickening (p < 0.001), and MPO levels (p < 0.01) when compared to tissues treated with LL-37 and those pretreated with HA. GM-0111 reduced cell death within sinonasal tissues in contrast to LL-37-treated tissues. CONCLUSION: We report a new synthetic GAG (GM-0111) that uniformly coats and penetrates into the sinonasal mucosa to prevent sinonasal inflammation and cell death in a mouse model of RS.
BACKGROUND: Glycosaminoglycans (GAGs) are polysaccharides that are distributed on respiratory epithelial cells, endothelial cells, and submucosal glands. Uniquely positioned, certain GAGs exhibit anti-inflammatory properties in respiratory diseases and serve important roles in repairing mucosal surfaces and modulating mucociliary clearance. We hypothesized that topical administration of a synthetic GAG (GM-0111) would prevent sinonasal inflammation in a mouse model of rhinosinusitis (RS). METHODS: To test our hypothesis, C57BL/6 mice were intranasally administered fluorescent GM-0111, and sinonasal tissues were examined for coating and penetration ability. To test therapeutic feasibility, mice (n = 6) were given GM-0111 or hyaluronic acid (HA; 800 μg dose) prior to inducing RS with inflammatory molecule LL-37 (115 μg dose). After 24 hours, sinonasal tissues were harvested for histological and biochemical analysis of inflammatory markers (inflammatory cell infiltration, lamina propria [LP] thickening, and neutrophil enzyme myeloperoxidase [MPO]) and cell death. RESULTS: GM-0111 was observed within sinonasal tissues 1 hour and 24 hours after intranasal administration, indicating rapid and effective coating and penetration. GM-0111 prevented sinonasal tissues from developing inflammatory changes, with significant reductions in mast cell infiltration (p < 0.05), LP thickening (p < 0.001), and MPO levels (p < 0.01) when compared to tissues treated with LL-37 and those pretreated with HA. GM-0111 reduced cell death within sinonasal tissues in contrast to LL-37-treated tissues. CONCLUSION: We report a new synthetic GAG (GM-0111) that uniformly coats and penetrates into the sinonasal mucosa to prevent sinonasal inflammation and cell death in a mouse model of RS.
Authors: Y Elaine Lau; Dawn M E Bowdish; Celine Cosseau; Robert E W Hancock; Donald J Davidson Journal: Am J Respir Cell Mol Biol Date: 2005-12-09 Impact factor: 6.914
Authors: Wytske J Fokkens; Valerie J Lund; Joachim Mullol; Claus Bachert; Isam Alobid; Fuad Baroody; Noam Cohen; Anders Cervin; Richard Douglas; Philippe Gevaert; Christos Georgalas; Herman Goossens; Richard Harvey; Peter Hellings; Claire Hopkins; Nick Jones; Guy Joos; Livije Kalogjera; Bob Kern; Marek Kowalski; David Price; Herbert Riechelmann; Rodney Schlosser; Brent Senior; Mike Thomas; Elina Toskala; Richard Voegels; De Yun Wang; Peter John Wormald Journal: Rhinol Suppl Date: 2012-03
Authors: Jianxing Zhang; Xiaoyu Xu; Narayanam V Rao; Brian Argyle; Lindsi McCoard; William J Rusho; Thomas P Kennedy; Glenn D Prestwich; Gerald Krueger Journal: PLoS One Date: 2011-02-09 Impact factor: 3.240
Authors: Apparao B Kummarapurugu; Shuo Zheng; Abigail Pulsipher; Justin R Savage; Jonathan Ma; Bruce K Rubin; Thomas P Kennedy; Judith A Voynow Journal: Am J Respir Cell Mol Biol Date: 2021-02 Impact factor: 6.914
Authors: Jeremiah A Alt; Won Yong Lee; Brock M Davis; Justin R Savage; Thomas P Kennedy; Glenn D Prestwich; Abigail Pulsipher Journal: PLoS One Date: 2018-09-25 Impact factor: 3.240