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.
Highlights
Our data demonstrate that GM-1111 markedly reduces the expression of TLR2 and TLR4 and inflammatory cell migration and invasion into the sinonasal mucosa and epithelium, resulting in the local reduction of cytokine gene expression
We have previously shown that synthetic GAGs strongly block TLR2-induced activation of NFκB and the resulting transcription of proinflammatory mediators in macrophages and human embryonic kidney cells.[32]
Recent investigations have demonstrated that TLR2 and TLR4 are upregulated in patients with Chronic rhinosinusitis (CRS) and that inappropriate regulation of signaling contributes to the increased inflammation observed in CRS.[18]
Summary
Chronic rhinosinusitis (CRS) is a common and debilitating inflammatory condition affecting the nose and paranasal sinuses of up to 15% of the worldwide population.[1,2] The most complete and current evidence-based recommendations for the medical management of CRS include a combination of saline irrigation, topical intranasal corticosteroid sprays, and depending on the phenotype, antibiotics and oral steroids.[2,3] Despite having a myriad of medical treatment options, a large percentage of patients remain unresponsive and experience severe exacerbations that require surgical intervention,[4] underscoring the need for more effective therapeutics.[5,6]The lack of effective medical therapies to treat CRS is due to its complex pathophysiology, as CRS is a multifactorial disease with many possible etiologies. Increasing evidence, supports that multiple endotypes mediated by unique or mixed inflammatory pathways exist in CRSsNP and CRSwNP.[7,8,9,10] Eosinophil-dominated endotypes associated with an underlying mechanism of allergy-mediated hypersensitivity are challenging forms of noninvasive CRS that commonly occur in recalcitrant patients with CRSwNP. These patients usually demonstrate increased blood and tissue eosinophils and CD4-positive T cells, as well as elevated serum levels of immunoglobulin E (IgE) and tissue levels of eosinophil-specific cytokines and chemokines. These patients usually demonstrate increased blood and tissue eosinophils and CD4-positive T cells, as well as elevated serum levels of immunoglobulin E (IgE) and tissue levels of eosinophil-specific cytokines and chemokines. [1,9,11] Experts agree that the elevation of these inflammatory endpoints may be the result of maladaptive immune signaling, triggered by impaired mucociliary function and epithelial cell barrier breakdown.[12,13] The sinonasal epithelium is comprised of ciliated cells and mucus-secreting goblet cells that function as the primary defense against pathogens due to their ability to limit activation of the innate immune response via pattern recognition receptors such as the Toll-like receptors (TLRs).[8,14] Investigations have demonstrated that inappropriate regulation of TLR2 and TLR4 signaling contribute to the increased inflammation seen in CRS.[15,16,17,18,19] The TLRs are potent innate immune receptors involved in the early stages of inflammatory signaling; blocking TLR activation could potentially reduce the downstream production of potent adaptive immunity-associated molecules, leading to decreased inflammatory cell infiltration and inflammatory signaling in the sinonasal mucosa
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