Rationale: The mechanisms that underlie the pathogenesis of chronic rhinosinusitis without nasal polyps (CRSsNP), chronic rhinosinusitis with nasal polyps (CRSwNP), and aspirin-exacerbated respiratory disease (AERD) are not clear.Objectives: To first evaluate the inflammatory profiles of CRSsNP and CRSwNP tissues and then to investigate whether clinical differences observed between CRSwNP and AERD are in part secondary to differences in inflammatory mediator expression within nasal polyp (NP) tissues.Methods: Expression levels of numerous inflammatory mediators were determined by quantitative real-time polymerase chain reaction, ELISA, and multiplex immunoassay.

Rationale: Nasal polyps (NPs) are characterized by intense edema or formation of pseudocysts filled with plasma proteins, mainly albumin. However, the mechanisms underlying NP retention of plasma proteins in their submucosa remain unclear. Objectives: We hypothesized that formation of a fibrin mesh retains plasma proteins in NPs. We assessed the fibrin deposition and expression of the components of the fibrinolytic system in patients with chronic rhinosinusitis (CRS). Methods:We assessed fibrin deposition in nasal tissue from patients with CRS and control subjects by means of immunofluorescence. Fibrinolytic components, d-dimer, and plasminogen activators were measured using ELISA, real-time PCR, and immunohistochemistry. We also performed gene expression and protein quantification analysis in cultured airway epithelial cells. Measurements and Main Results: Immunofluorescence data showed profound fibrin deposition in NP compared with uncinate tissue (UT) from patients with CRS and control subjects. Levels of the cross-linked fibrin cleavage product protein, d-dimer, were significantly decreased in NP compared with UT from patients with CRS and control subjects, suggesting reduced fibrinolysis (P , 0.05). Expression levels of tissue plasminogen activator (t-PA) mRNA and protein were significantly decreased in NP compared with UT from patients with CRS and control subjects (P , 0.01). Immunohistochemistry demonstrated clear reduction of t-PA in NP, primarily in the epithelium and glands. Th2 cytokine-stimulated cultured airway epithelial cells showed down-regulation of t-PA, suggesting a potential Th2 mechanism in NP. Conclusions: A Th2-mediated reduction of t-PA might lead to excessive fibrin deposition in the submucosa of NP, which might contribute to the tissue remodeling and pathogenesis of CRS with nasal polyps.

Background Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with Th2-dominant inflammation. Thymic stromal lymphopoietin (TSLP) is a cytokine that triggers dendritic cell-mediated Th2 inflammatory responses and that enhances IL-1-dependent Th2 cytokine production in mast cells. Although elevated levels of TSLP mRNA have been found in nasal polyps (NPs), expression of TSLP protein and its function in CRS have not been fully explored. Objectives The objective of this study was to investigate the role of TSLP in CRS. Methods We investigated the presence and stability of TSLP protein in NPs by ELISA and western blot, and the function of TSLP in nasal tissue extracts with a bioassay based upon activation of human mast cells. Results Although TSLP mRNA was significantly increased in NP tissue from patients with CRSwNP compared to uncinate tissue from patients with CRS or control subjects, TSLP protein was significantly decreased in NP tissue as detected by the commercial ELISA kit. We found that recombinant TSLP was time-dependently degraded by NP extracts and this degradation was completely inhibited by a protease inhibitor cocktail, suggesting that TSLP is sensitive to tissue proteases. Interestingly, NP extract-treated TSLP had higher activity in mast cells, although the amount of full length TSLP was reduced up to 85%. NP extracts significantly enhanced IL-1β-dependent IL-5 production in mast cells compared with uncinate tissue homogenates, and responses were significantly inhibited by anti-TSLP, suggesting that NP contain biologically relevant levels of TSLP activity. Conclusion TSLP and its metabolic products may play an important role in the inflammation in CRSwNP.

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BACKGROUND Chronic rhinosinusitis with nasal polyps (CRSwNP) is an inflammatory condition of the nasal passage and paranasal sinuses characterized by Th2 biased inflammation with elevated levels of BAFF, B-lymphocytes, and immunoglobulins. Since high levels of BAFF are associated with autoimmune diseases, we assessed for evidence of autoimmunity in patients with CRS. OBJECTIVES The objective of this study was to investigate for the presence of autoantibodies in sinonasal tissue from patients with CRS. METHODS Standardized nasal tissue specimens were collected from patients with CRS and control subjects and assayed for immunoglobulin production, autoantibody levels, tissue distribution of immunoglobulins and binding potential of antibodies in nasal tissue using a multiplexed autoantibody microarray, ELISA and immunofluoresence. RESULTS Elevated levels of several specific autoantibodies were found in nasal polyp tissue in comparison with control tissue and inflamed tissue from non-polypoid CRS (CRSsNP) (p<0.05). In particular, nuclear-targeted autoantibodies such as anti-dsDNA IgG and IgA antibodies were found at elevated levels in nasal polyps (p<0.05) and particularly in nasal polyps from patients requiring revision surgery for recurrence. Direct immunofluorescence staining demonstrated diffuse epithelial and sub-epithelial deposition of IgG and increased numbers of IgA secreting plasma cells not seen in control nasal tissue. CONCLUSIONS Autoantibodies, particularly those against nuclear antigens, are present at locally elevated levels in nasal polyps. The presence of autoantibodies suggests that the microenvironment of a nasal polyp promotes the expansion of self-reactive B-cell clones. While the pathogenicity of these antibodies remains to be elucidated, the presence of elevated anti-dsDNA antibodies is associated with a clinically more aggressive form of CRSwNP requiring repeated surgery.