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

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.

Calgranulin C (S100A12) Is Differentially Expressed in Subtypes of Chronic Rhinosinusitis.

Background Calgranulin C (S100A12) is an innate immune peptide at the air-mucosal interface associated with neutrophil involvement, which when overexpressed has been implicated as a biomarker of inflammatory diseases. Decreased epithelial expression of certain innate immune peptides has been reported in chronic rhinosinusitis (CRS). We hypothesized that S100A12 is differentially expressed in the sinonasal mucosa of patients with CRS compared to controls and that S100A12 is a potential biomarker of CRS-specific quality of life (QOL) and disease severity. Methods A prospective observational study was conducted which included 70 patients: 17 controls, 28 having CRS without (CRSsNP), and 25 with (CRSwNP) nasal polyps. The expression of S100A12 and human neutrophil elastase (HNE) was assessed in the anterior ethmoid tissues from all patients using enzyme-linked immunosorbent assay (ELISA) and immunohistochemical (IHC) analyses. Disease-specific QOL (Rhinosinusitis Disability Index) and disease severity (computed tomography [CT] and endoscopy) were evaluated and correlated to the expression levels of S100A12. Results S100A12 and HNE were significantly elevated in patients with CRSsNP compared to normal controls ( P < .05 and P < .001, respectively) and patients with CRSwNP ( P < .05 and P < .001, respectively), as measured by ELISA and IHC analyses. Patients with CRS exhibited worse CRS-specific disease severity compared to normal controls ( P < .05), and the increased protein levels of S100A12 were significantly correlated to disease severity, represented by CT scores ( P < .05). Conclusions S100A12 is differentially expressed in CRS subtypes and is significantly elevated in patients with CRSsNP and associated with CRS-specific disease severity.

LL-37 causes cell death of human nasal epithelial cells, which is inhibited with a synthetic glycosaminoglycan.

LL-37 is an immune peptide that regulates innate and adaptive immune responses in the upper airways. Elevated levels of LL-37 have been linked to cell death and inflammatory diseases, such as chronic rhinosinusitis (CRS). Glycosaminoglycans (GAGs) are polysaccharides that are found on respiratory epithelial cells and serve important roles in mucosal surface repair. Recent findings suggest that a synthetic glycosaminoglycan (GM-0111) can protect against LL-37-induced sinonasal mucosal inflammation and cell death in a murine model of acute RS. Herein, we elucidated the mechanisms by which LL-37 causes sinonasal inflammation and how GM-0111 can prevent these mechanisms. When challenged with LL-37, human nasal epithelial cells (HNEpCs) and mouse macrophages (J774.2) demonstrated increased release of adenosine triphosphate (ATP) and interleukin (IL)-6 and -8, as well as cell death and lysis. These cellular responses were all blocked dose-dependently by pre-treatment with GM-0111. We identified that LL-37-induced cell death is associated with caspase-1 and -8 activation, but not activation of caspase-3/7. These responses were again blocked by GM-0111. Our data suggest that LL-37 causes cellular death of HNEpCs and macrophages through the pro-inflammatory necrotic and/or pyroptotic pathways rather than apoptosis, and that a GM-0111 is capable of inhibiting these pro-inflammatory cellular events.