Expression of the receptor for advanced glycation end products, a target for high mobility group box 1 protein, and its role in chronic recalcitrant rhinosinusitis with nasal polyps

Abstract

A receptor for advanced glycation end products (RAGE) and its ligand high mobility group box 1 (HMGB1) protein has been linked to several chronic diseases, and acts as a trigger for inflammation signaling. Here, we study RAGE and HMGB1 expression in chronic, recalcitrant rhinosinusitis with nasal polyps (CRSwNP) to determine its potential clinical significance, i.e., disease recurrence and severity. RAGE and HMGB1 expression in CRSwNP was evaluated by immunohistochemistry in epithelial cells of fresh sinonasal mucosa samples obtained from the patients diagnosed with recalcitrant CRSwNP (n = 25) and normal control mucosa (NC) (n = 26). RAGE and HMGB1 expression levels in tissues were correlated with disease severity assessed by nasal endoscopy, CT scan, number of previous sinus surgeries, allergy status and nasosinusal microbiology. RAGE and HMGB1 were moderately or strongly expressed in CRSwNP tissue. No or weak RAGE expression was found in NC. HMGB1 was equally strongly expressed in NC. We observed a strong correlation between RAGE and disease severity, recurrence, undergone operations, asthma and aspirin exacerbated respiratory disease (AERD). Elevated RAGE expression is associated with increased disease severity, as well as allergy and AERD in patients with recalcitrant CRSwNP. It is possible that the explanation for recurrent CRSwNP pathogenesis might be related to RAGE overexpression with subsequent sinus mucosa hyperproliferation, necessitating several operations.

Fig. 1

HMGB1 and RAGE expression in NC and in recalcitrant chronic rhinosinusitis with nasal polyps (CRSwNP) tissues. a1 H+E staining of NC mucosa (×100); a2 H+E staining of NC cytology taken under middle turbinate (×400); a3 H+E staining of CRSwNP mucosa (×100); a4 H+E staining of CRSwNP cytology taken under middle turbinate (×400); b1 HMGB1 expression in the intestine (positive control; ×200); b2 HMGB1 expression in NC tissue (×200); b3 HMGB1 expression in CRSwNP tissue (×200); B4 isotype control staining (×200); b5 RAGE expression in the kidney (positive control; ×200); b6 RAGE expression in NC tissue (×200); b7 RAGE expression in CRSwNP tissue (×200); b8 isotype negative control staining in CRSwNP tissue (×200). The sections were scored according to the percentage of rhinosinusitis tissue staining (positivity) (<25 % = 0; 25–75 % = 1; and >75 % = 2). The level of staining intensity was recorded as 0: none, 1: weak, 2: moderate, or 3: strong; as described in “Materials and Methods”). c Intensive HMGB1 immuno reactivity in both the epithelium lining nasal polyps (marked with arrows) and the stroma of nasal polyps (marked with stars). Representative pictures are shown. d Statistical analysis of RAGE expression in tissues. A p value of less than 0.05 was considered to be significant

Fig. 2

RAGE expression in correlation with disease severity. a RAGE ratio vs. CT scoring in both investigated groups; b RAGE ratio vs. polyp size; c RAGE ratio vs. number of previous surgery; p values were used to evaluate differences between CRSwNP patients and NC according to Bonferroni step-down procedure

Fig. 3

RAGE expression in correlation with asthma and AERD. a RAGE ratio vs. AERD; b RAGE ratio vs. asthma history