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Increased lipopolysaccharide content is positively correlated with glucocorticoid receptor-beta expression in chronic rhinosinusitis with nasal polyps.

ABSTRACT: INTRODUCTION:Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common and frequently occurring disease of the upper respiratory tract. The nasal instillation of the Gram-negative (G- ) bacterial product lipopolysaccharide (LPS) can induce not only acute sinusitis but also the development of CRSwNP in animal models. Nevertheless, the expression and distribution of LPS in patients with CRSwNP have not been investigated. And the study was to investigate the expression of LPS and its relationship with glucocorticoid receptors (GRs) in CRSwNP. METHODS:Multiple methods, including bacterial culture and immunohistochemistry, were used to detect and analyze nasal bacteria, plasma LPS content, and the levels of LPS and GR-?/?, cluster of differentiation 68 (CD68), and myeloperoxidase (MPO) expression, as well as their relationship in CRSwNP. RESULTS:The number of G- bacteria and Escherichia coli (E. coli) was not significantly different between CRSwNP subjects and the controls. However, the positive rate of LPS was much higher than that of E. coli in CRSwNP subjects and was significantly higher in noneosinophilic CRSwNP subjects than in eosinophilic CRSwNP subjects. Moreover, the LPS levels were positively correlated with GR-? but not GR-? expression in CRSwNP. Immunofluorescence assays showed that LPS was mainly detected in CD68+ macrophages and MPO+ neutrophils, in addition to histiocytes, in CRSwNP. CONCLUSIONS:Persistent LPS in CRSwNP can lead to unresolved mucosal inflammation, eventually leading to tissue remodeling and the development of CRSwNP. Our findings suggest that increased LPS content and possible resistance to glucocorticoids may be one of the important pathogenic mechanisms of G- bacteria in CRSwNP.

SUBMITTER: Wang SB

PROVIDER: S-EPMC7654414 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Increased lipopolysaccharide content is positively correlated with glucocorticoid receptor-beta expression in chronic rhinosinusitis with nasal polyps.

Wang Shui-Bin SB Chen Shi-Ming SM Zhu Ke-Sheng KS Zhou Bin B Chen Long L Zou Xiao-Yan XY

Immunity, inflammation and disease 20200901 4

<h4>Introduction</h4>Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common and frequently occurring disease of the upper respiratory tract. The nasal instillation of the Gram-negative (G<sup>-</sup> ) bacterial product lipopolysaccharide (LPS) can induce not only acute sinusitis but also the development of CRSwNP in animal models. Nevertheless, the expression and distribution of LPS in patients with CRSwNP have not been investigated. And the study was to investigate the expression of LPS ...[more]

PMID: 32870597

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Project description:BackgroundChronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory disease of the upper airways frequently associated with asthma. Bacterial infection is a feature of CRSwNP that can aggravate the disease and the response to glucocorticoid treatment.ObjectiveWe examined whether the bacterial product lipopolysaccharide (LPS) reduces glucocorticoid receptor (GR) function in control nasal mucosa (NM) fibroblasts and in nasal polyp (NP) fibroblasts from patients with CRSwNP and asthma.MethodsNP (n = 12) and NM fibroblasts (n = 10) were in vitro pre-incubated with LPS (24 hours) prior to the addition of dexamethasone. Cytokine/chemokine secretion was measured by ELISA and Cytometric Bead Array. GRα, GRβ, mitogen-activated protein-kinase phosphatase-1 (MKP-1) and glucocorticoid-induced leucine zipper (GILZ) expression was measured by RT-PCR and immunoblotting, GRα nuclear translocation by immunocytochemistry, and GRβ localization by immunoblotting. The role of MKP-1 and GILZ on dexamethasone-mediated cytokine inhibition was analyzed by small interfering RNA silencing.ResultsPre-incubation of nasal fibroblasts with LPS enhanced the secretion of IL-6, CXCL8, RANTES, and GM-CSF induced by FBS. FBS-induced CXCL8 secretion was higher in NP than in NM fibroblasts. LPS effects on IL-6 and CXCL8 were mediated via activation of p38α/β MAPK and IKK/NF-κB pathways. Additionally, LPS pre-incubation: 1) reduced dexamethasone's capacity to inhibit FBS-induced IL-6, CXCL8 and RANTES, 2) reduced dexamethasone-induced GRα nuclear translocation (only in NM fibroblasts), 3) did not alter GRα/GRβ expression, 4) decreased GILZ expression, and 5) did not affect dexamethasone's capacity to induce MKP-1 and GILZ expression. MKP-1 knockdown reduced dexamethasone's capacity to suppress FBS-induced CXCL8 release.ConclusionThe bacterial product LPS negatively affects GR function in control NM and NP fibroblasts by interfering with the capacity of the activated receptor to inhibit the production of pro-inflammatory mediators. This study contributes to the understanding of how bacterial infection of the upper airways may limit the efficacy of glucocorticoid treatment.

Project description:Background:Local and systemic glucocorticoids are mainstay therapies for chronic rhinosinusitis. With respect to local glucocorticoids, nasal spray is used extensively, but some patients do not benefit from short-course treatment. Recently, some clinicians have focused on the effects of high-dose local glucocorticoids in chronic rhinosinusitis with nasal polyps (CRSwNP), such as treatment using nasal irrigation, transnasal nebulization, and nose-dripping therapy (nasal drop) with high-dose budesonide. However, there are little data comparing the effect of short-course high-dose local glucocorticoids with regular nasal spray and oral steroids in the treatment of preoperative CRSwNP patients. Furthermore, the appropriate use of different types of glucocorticoids in different endotypes of CRSwNP remains unclear. Methods:This randomized controlled clinical research study was performed at a single academic center. Patients who satisfied the criteria of chronic rhinosinusitis with bilateral nasal polyps were randomly assigned in a 1:1:1 ratio to receive oral methylprednisolone, 24 mg/d and budesonide nasal spray, 256 ?g/d, or intranasal budesonide suspension, 1 mg/d and budesonide nasal spray, 256 ?g/d, or budesonide nasal spray, 256 ?g/d for one week. Symptoms, endoscopic scores, and tissue and blood inflammatory cells were recorded before and after the study. Adverse events were recorded by clinicians. Results:A total of 127 patients with CRSwNP underwent randomization. The total nasal symptoms scores (TNSS) decreased significantly in all groups compared to those at baseline. The assessment of the reduction in TNSS demonstrated that the change was significantly greater in the nasal drop group than in the nasal spray group (-7.47 vs -4.10, P = 0.032), and it was also greater in the oral steroid group than in the nasal spray group (-7.30 vs -4.10, P = 0.039). A similar trend also appeared in the reduction in Sinonasal-Outcome Test 22 (SNOT-22). After treatment, a significantly reduction in NP score was observed in the nasal drop group (-0.82) and oral steroid group (-0.85) compared with that in the nasal spray group (-0.10), and there was no significant difference between the nasal drop and oral steroid groups (P = 0.98). While calculating the percentage of patients who were sensitive to glucocorticoid treatment, there was 10.26% in the nasal spray group, 47.37% in the nasal drop group, and 52.50% in the oral steroid group that were sensitive to glucocorticoid treatment. The reduction in NP score was more significant in patients with eosinophilic CRSwNP in the nasal drop group and oral steroid group than in the nasal spray group. However, in patients with non-eosinophilic CRSwNP, the change in NP size was similar in the different treatment groups. Conclusion:Budesonide suspension nasal drop can significantly improve the quality of life and reduce the endoscopic score following short-course treatment, and the treatment effect of nasal drop was better than that of regular nasal spray. Budesonide nasal suspension can be used as a regular treatment for eosinophilic CRSwNP and can be an alternative choice for patients with a high percentage of tissue eosinophil infiltration who cannot use oral glucocorticoids.

Project description:BackgroundChronic rhinosinusitis (CRS) is a multifactorial disease of unknown cause characterized by sinonasal inflammation, increased mucus production, and defective mucociliary clearance. Expression of Pendrin, an epithelial anion transporter, is increased in asthma and chronic obstructive pulmonary disease. Pendrin increases mucus production and regulates mucociliary clearance.ObjectivesWe sought to investigate the expression of pendrin and the mucus-related protein Muc5AC in sinonasal tissues of control subjects and patients with CRS and to evaluate the regulation of pendrin expression in nasal epithelial cells (NECs) in vitro.MethodsThe expression and distribution of pendrin in sinonasal tissues was analyzed by using real-time PCR, immunoblot analysis, and immunohistochemistry. Differentiated NECs were used to study the regulation of pendrin expression.ResultsIncreased pendrin expression was observed in nasal polyp (NP) tissue of patients with CRS. Immunohistochemistry analysis revealed that pendrin was largely restricted to the epithelial layer. Pendrin expression significantly correlated with inflammatory cell markers, suggesting that the factors made by these cells might induce pendrin expression. Furthermore, both pendrin and periostin levels (a biomarker in asthma) correlated with IL-13 levels, suggesting that pendrin can be induced by this cytokine in sinonasal tissues. Expression of the mucus component protein Muc5AC correlated weakly with pendrin expression, indicating that pendrin might modulate mucus production in NPs. In cultured NECs pendrin expression was induced by TH2 cytokines and induced synergistically when TH2 cytokines were combined with IL-17A. Interestingly, human rhinovirus had a potentiating effect on IL-13-induced pendrin expression. Dexamethasone suppressed pendrin expression, suggesting that the therapeutic benefit of dexamethasone in asthmatic patients and those with CRS might involve regulation of pendrin expression.ConclusionsTH2-mediated pendrin expression is increased in NPs of patients with CRS and might lead to increased inflammation, mucus production, and decreased mucociliary clearance.

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Increased lipopolysaccharide content is positively correlated with glucocorticoid receptor-beta expression in chronic rhinosinusitis with nasal polyps.

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Increased lipopolysaccharide content is positively correlated with glucocorticoid receptor-beta expression in chronic rhinosinusitis with nasal polyps.

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