The Crucial Role of CXCL8 and Its Receptors in Colorectal Liver Metastasis.
Bie Yaqin,Ge Wei,Yang Zhibin,Cheng Xianshuo,Zhao Zefeng,Li Shengjie,Wang Wenchao,Wang Yu,Zhao Xiaofeng,Yin Zhengfeng,Li Yunfeng
CXCL8 (also known as IL-8) can produce different biological effects by binding to its receptors: CXCR1, CXCR2, and the Duffy antigen receptor for chemokines (DARC). CXCL8 and its receptors are associated with the development of various tumor types, especially colorectal cancer and its liver metastases. In addition to promoting angiogenesis, proliferation, invasion, migration, and the survival of colorectal cancer (CRC) cells, CXCL8 and its receptors have also been known to induce the epithelial-mesenchymal transition (EMT) of CRC cells, to help them to escape host immunosurveillance as well as to enhance resistance to anoikis, which promotes the formation of circulating tumor cells (CTCs) and their colonization of distant organs. In this paper, we will review the established roles of CXCL8 signaling in CRC and discuss the possible strategies of targeting CXCL8 signaling for overcoming CRC drug resistance and cancer progression, including direct targeting of CXCL8/CXCR1/2 or indirect targeting through the inhibition of CXCL8-CXCR1/2 signaling.
Interleukin-8 gene expression in chronic sinusitis.
Takeuchi K,Yuta A,Sakakura Y
American journal of otolaryngology
PURPOSE:Interleukin-8 (IL-8), a monocyte-derived and macrophage-derived cytokine, displays potent chemotactic activating properties toward neutrophils and thus may contribute to the pathogenesis of chronic sinusitis. The object of this investigation was to show the expression of the IL-8 gene in chronic sinusitis by Northern blot analysis and a reverse transcription-polymerase chain reaction (RT-PCR). MATERIALS AND METHODS:For Northern blot analysis, RNAs were extracted from maxillary mucosa and nasal polyps from two patients with chronic sinusitis, respectively, and from the inferior turbinate of a nasal allergy patient. For RT-PCR, RNAs were extracted from 11 patients with chronic sinusitis, 8 patients with allergic rhinitis, and 4 patients with hypertrophic rhinitis. RESULTS:Whereas IL-8 mRNA was expressed in the maxillary mucosa, IL-8 transcript was not detected in the inferior turbinate by Northern blot analysis. IL-8 transcripts were detected in 45% of chronic sinusitis RNAs (5/11) and in 50% of allergic rhinitis RNAs (5/10) by RT-PCR. CONCLUSION:These data suggest IL-8 may contribute to neutrophil involvement in chronic sinusitis.
Mechanism of neutrophil recruitment induced by IL-8 in chronic sinusitis.
Suzuki H,Takahashi Y,Wataya H,Ikeda K,Nakabayashi S,Shimomura A,Takasaka T
The Journal of allergy and clinical immunology
BACKGROUND:The mechanism of neutrophil recruitment in patients with chronic sinusitis is unclear. OBJECTIVE:This study aims to elucidate the role of IL-8 in inducing neutrophil accumulation in the nasal discharge of patients with chronic sinusitis. METHODS:Nasal discharge and mucosal specimens were obtained from two groups of patients, those with chronic sinusitis and those with allergic rhinitis. The samples were subjected to immunohistochemical examination and in situ hybridization. The IL-8 level in the nasal discharge was measured by enzyme immunoassay. RESULTS:Immunoreactivity to IL-8 was observed in polymorphonuclear cells of nasal smear, in nasal gland duct cells, and in epithelial cells of the chronic sinusitis group; whereas those of the allergic rhinitis group mostly showed little or no reaction. Similar patterns of localization were shown by in situ hybridization for IL-8 messenger RNA. The IL-8 level in nasal discharge was significantly higher in the chronic sinusitis group than in the allergic rhinitis group. CONCLUSION:These results suggest that chemotactic factors in sinus effusion, including IL-8 derived from nasal gland duct cells and epithelial cells, attract neutrophils out of mucosa, and the neutrophils that have emigrated into the sinus effusion secrete IL-8. This induces further neutrophil accumulation in the sinus effusion of patients with chronic sinusitis.
Myeloperoxidase and interleukin-8 levels in chronic sinusitis.
Demoly P,Crampette L,Mondain M,Enander I,Jones I,Bousquet J
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology
We have recently phenotyped inflammation in non-infectious allergic and non-allergic chronic maxillary sinusitis using sinus biopsies and lavage fluids. In this first paper, we have concentrated our work on the eosinophil, T cell, mast cell and macrophage infiltrates. However, many unresolved questions remain and particularly the role of neutrophils needed to be addressed. In the present study, we focused on the neutrophilic inflammation: myeloperoxidase (MPO) and interleukin-8 (IL-8) were measured by immunoassays and neutrophils were enumerated by conventional staining in the sinus lavage fluids of 16 patients with chronic sinusitis and six control subjects. Both MPO and IL-8 levels were significantly higher in patients than in controls (P < 0.01 and 0.005, respectively). There was a significant correlation between MPO levels and neutrophil numbers, and between MPO and IL-8 levels in the sinus lavage fluid (P < 0.0001, Spearman rank correlation). The presence of high levels of IL-8 in the lavage fluids of patients suffering from chronic sinusitis, levels which correlate with those of MPO, suggests that this cytokine may activate neutrophils in this chronic disease.
Effects of long-term low-dose macrolide administration on neutrophil recruitment and IL-8 in the nasal discharge of chronic sinusitis patients.
Suzuki H,Shimomura A,Ikeda K,Oshima T,Takasaka T
The Tohoku journal of experimental medicine
Effects of long-term low-dose macrolide administration were studied in patients with chronic sinusitis. Twelve patients with non-allergic chronic sinusitis were orally given 150 mg roxithromycin once a day without other treatments. The patients underwent computed tomography before and after the treatment, and paranasal sinus aeration was analyzed quantitatively. The number of neutrophils in the nasal smear was semiquantitatively assessed on a grading scale, and the IL-8 concentration in the nasal discharge was measured by enzyme immunoassay. The aeration of all four sinuses significantly improved, and recruited neutrophils and the IL-8 level in the nasal discharge were simultaneously reduced after the treatment. These findings suggest that long-term low-dose roxithromycin administration inhibits the positive feedback mechanism of neutrophil recruitment and IL-8 production by the recruited neutrophils, which is considered to be an essential cause of the prolongation of sinusitis.
Erythromycin modulates IL-8 expression in normal and inflamed human bronchial epithelial cells.
Takizawa H,Desaki M,Ohtoshi T,Kawasaki S,Kohyama T,Sato M,Tanaka M,Kasama T,Kobayashi K,Nakajima J,Ito K
American journal of respiratory and critical care medicine
Erythromycin (EM) and its 14-member macrolide analogues have attracted attention for its effectiveness in a variety of airway diseases, including diffuse panbronchiolitis (DPB), sinobronchial syndrome, and chronic sinusitis. However, its mechanisms of action remain unelucidated. We evaluated the effects of several antibiotics on IL-8 expression by normal and transformed human bronchial epithelial cells, an important source of this potent chemokine involved in cell recruitment into the airways. EM and clarithromycin (CAM) uniquely suppressed mRNA levels as well as the release of IL-8 at the therapeutic and noncytotoxic concentrations (% inhibition of IL-8 protein release: 25.0 +/- 5.67% and 37.5 +/- 8.99%, respectively, at 10(-6) M). The other antimicrobes, including a 16-member macrolide josamycin, showed no effect. Bronchial epithelial cells from very peripheral airways as well as from main bronchi were obtained from patients with chronic airway inflammatory diseases, and EM and CAM inhibited IL-8 release from these cells. Among five patients who underwent bronchoscopy before and after macrolide treatment, four showed decreased levels of IL-8 expression in airway epithelium as assessed by reverse transcription and polymerase chain reaction. Our findings showed these 14-member macrolides had inhibitory effect on IL-8 expression in human bronchial epithelial cells, and this new mode of action may have relevance to their clinical effectiveness in airway diseases.
Inhibitory effect of macrolides on interleukin-8 secretion from cultured human nasal epithelial cells.
Suzuki H,Shimomura A,Ikeda K,Furukawa M,Oshima T,Takasaka T
The mechanism of macrolide therapy in chronic sinusitis patients is unclear. The authors studied the effect of macrolides on interleukin (IL)-8 secretion from cultured human nasal epithelial cells. Epithelial cells harvested from the nasal polyps of patients with chronic sinusitis were primary-cultured, and secreted IL-8 in culture media was measured by enzyme immunoassay. The cells secreted considerable amounts of IL-8 constitutively and in response to lipopolysaccharide. The secretion was significantly inhibited by 10(-5) M of erythromycin, clarithromycin, roxithromycin, and josamycin. 10(-6) M erythromycin still showed the inhibitory effect, whereas the same concentration of josamycin did not. These results indicate that macrolide antibiotics may act as an immunomodulator to reduce IL-8 in inflammatory sites and, at least partially, account for the clinically discrepant effects between 14- and 16-membered ring macrolides in long-term low-dose therapy for chronic sinusitis.
Cytokines in nasal polyposis, acute and chronic sinusitis.
Rudack C,Stoll W,Bachert C
American journal of rhinology
Cytokines are potent biologic factors involved in the regulation of inflammation, immune defense, and wound healing. Recently, growing interest has developed in the role of cytokines in chronic sinusitis and nasal polyposis. In the present study, we investigated the cytokine profile of different types of rhinosinusitis in order to evaluate whether a specific form of rhinosinusitis is associated with the expression of a certain cytokine profile. Sinus mucosa from patients with acute sinusitis (n = 10), chronic sinusitis (n = 7), antrochoanal polyp (n = 10), nasal polyps (n = 8) and controls of turbinate mucosa (n = 7) were sampled. The cytokine protein content (IL-1 beta, IL-3, IL-4, IL-5, IL-6, IL-8, IL-13, GM-CSF, interferon-gamma) of tissue homogenates was measured using ELISA technique. In acute sinusitis, the synthesis of proinflammatory cytokines and of the neutrophil chemokine IL-8 and IL-3 appeared to be upregulated. Chronic sinusitis mucosa demonstrated no significantly increased concentrations of the measured cytokines. In bilateral nasal polyposis, but not in antrochoanal polyps, the eosinophil related cytokine IL-5 was strongly upregulated. From these findings, it appears that specific cytokine patterns are found in different forms of sinusitis, and that IL-5 may represent the most important cytokine responsible for tissue eosinophilia in nasal polyposis.
Sinus mucosal IL-8 gene expression in chronic rhinosinusitis.
Rhyoo C,Sanders S P,Leopold D A,Proud D
The Journal of allergy and clinical immunology
BACKGROUND:Epithelial hyperplasia and mucosal infiltration of leukocytes are common features of chronic rhinosinusitis. The epithelium can produce chemoattractant cytokines that may contribute to leukocyte infiltration in rhinosinusitis. OBJECTIVE:We sought to determine whether mucosal IL-8 gene expression is increased in chronic rhinosinusitis and to relate IL-8 gene expression to disease severity. METHODS:We used both a noncompetitive and a quantitative, competitive reverse transcription-polymerase chain reaction to examine IL-8 gene expression in samples of sinus mucosal tissue obtained during surgery from 22 patients with chronic rhinosinusitis and 9 normal control subjects. IL-8 gene expression was related to disease severity assessed by sinus computed tomography (CT) scores and to symptom scores assessed by means of a questionnaire. RESULTS:Sinus mucosal IL-8 gene expression was not detected in any of the control subjects but was present in 12 of 22 (55%) patients with rhinosinusitis. Sinus CT scores and symptom scores were both significantly higher in patients with positive mucosal IL-8 gene expression than in subjects with no detectable IL-8 gene expression. Positive IL-8 gene expression was not predicted by history of prior surgery nor by atopic or asthmatic status. In 9 subjects with positive IL-8 gene expression, levels of mRNA expression, assessed by competitive reverse transcription-polymerase chain reaction, correlated significantly (rho = 0.72, P <.05) with sinus CT scores. CONCLUSION:Sinus mucosal expression of the gene for IL-8 is increased in patients with chronic rhinosinusitis, and the level of IL-8 gene expression correlates with disease severity.
Inhibitory effect of erythromycin on interleukin-8 secretion from exudative cells in the nasal discharge of patients with chronic sinusitis.
Suzuki H,Asada Y,Ikeda K,Oshima T,Takasaka T
OBJECTIVES:The mechanism of the efficacy of long-term low-dose macrolide therapy for chronic sinusitis is not fully understood. The authors studied the inhibitory effect of erythromycin on interleukin-8 (IL-8) secretion from exudative cells in the nasal discharge of patients with chronic sinusitis. STUDY DESIGN AND METHODS:Exudative cells in the nasal discharge were isolated from six patients with nonallergic chronic sinusitis. The cells, more than 90% of which were neutrophils, were incubated with or without erythromycin in the presence of 10 micrograms/mL of lipopolysaccharide. The IL-8 concentrations in the culture supernatants were measured by enzyme-linked immunoassay. RESULTS:The amount of secreted IL-8 in the absence of erythromycin was 682 +/- 226 pg/10(6) cells/24 h. The IL-8 secretion was significantly reduced to 66 +/- 15% and 46 +/- 13% of the control in the presence of 10(-6) and 10(-5) M of erythromycin, respectively. CONCLUSION:Erythromycin may act as a biologic modulator that inhibits IL-8 secretion from exudative cells and thereby blocks the vicious circle of neutrophil recruitment and IL-8 generation in the inflammatory site in chronic sinusitis.
Effects of macrolides on interleukin-8 secretion from human nasal epithelial cells.
Fujita K,Shimizu T,Majima Y,Sakakura Y
European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery
Low-dose, long-term macrolide treatment has recently been reported to be very effective in patients with chronic airway diseases. We examined the in vivo and in vitro effects of 14-membered macrolide antibiotics erythromycin (EM) and clarithromycin (CAM) on interleukin (IL)-8 secretion from human nasal epithelial cells. Fifteen patients with chronic sinusitis received macrolide treatment (CAM 400 mg/day) for 1 to 3 months. The number of infiltrated neutrophils and IL-8 concentrations in the nasal discharges of these patients decreased significantly at 1 to 2 months after the treatment. In vitro effects of EM and CAM on IL-8 secretion were examined in nasal epithelial cells cultured at the air-liquid interface. After 14-day culture in the air-liquid interface, macrolide antibiotics were added in medium for 24 h. EM and CAM at concentrations of 10(-4) M did not affect spontaneous secretions or IL-1 beta-induced secretions of IL-8 either apically or basolaterally. When cells were preincubated with 10(-4) M CAM for 7 days, the IL-1 beta-induced secretion of IL-8 decreased significantly. However, no difference was observed between the effects of 10(-4) M CAM and 10(-4) M josamycin, a 16-membered macrolide. These results suggest that macrolide treatment inhibits neutrophil infiltration and IL-8 secretion in nasal epithelium in vivo and that these clinical effects depend on a mechanism other than the direct action of macrolide on nasal epithelial cells.
Macrolide treatment decreased the size of nasal polyps and IL-8 levels in nasal lavage.
Yamada T,Fujieda S,Mori S,Yamamoto H,Saito H
American journal of rhinology
Recently, epidemiologic and experimental studies have been reported that long-term macrolides are effective for the treatment of chronic airway inflammatory diseases including diffuse panbronchiolitis, chronic rhinosinusitis, and cystic fibrosis (Jaffe A, Francis J, Rosenthal M, et al. Long-term azithromycin may improve lung function in children with cystic fibrosis. Lancet 351:420, 1998), and that macrolides can directly reduce the production of IL-8 by nasal epithelial cells (Suzuki H, Shimomura A, Ikeda K, et al. Inhibitory effect of macrolides on interleukin-8 secretion from cultured human nasal epithelial cells. Laryngoscope 107:1661-1666, 1997). In this study we administered macrolides with 14-membered rings to patients with nasal polyps due to chronic rhinosinusitis for at least 3 months and measured the IL-8 level in nasal lavage from those patients. The IL-8 levels in nasal lavage from patients with nasal polyps were reduced during macrolide treatment. There was significant correlation between decreased IL-8 levels in nasal lavage and the clinical effect of macrolides on the size of the nasal polyps. In the group whose polyps were reduced in size, the IL-8 levels dramatically decreased from 231.2 pg/mL to 44.0 pg/mL (p < 0.05), and were significantly higher before macrolide treatment than those in the group whose polyps showed no change (p < 0.005). This reduction in IL-8 may be an important aspect of the effect of macrolide treatment on nasal polyps in chronic rhinosinusitis.
The role of cytokines in rhinosinusitis.
Min Y G,Lee K S
Journal of Korean medical science
Since the last decade, new insights into inflammatory processes have become possible by investigating the pattern of cytokines in acute and chronic sinus diseases. This review aims to update and discuss the findings of in vitro and in vivo studies concerning the role of cytokines in sinusitis and nasal polyposis. The proinflammatory cytokines interleukin-1beta, interleukin-6 and the neutrophil-chemoattractant interleukin-8 may play a major role in acute sinusitis, as shown in viral and allergic rhinitis. In chronic sinusitis interleukin-3 dominates the cytokine profiles, giving support to a variety of inflammatory cells. Interleukin-5 is a key protein in the pathogenesis of nasal polyposis. Activation and survival of eosinophils in nasal polyps are thought to be regulated by interleukin-5. Further investigation of cytokine expression patterns in inflammatory sinus diseases will lead to a better understanding of their pathogenesis and to a development of new therapeutic modality.
Nuclear factor-kappa B activation in the nasal polyp epithelium: relationship to local cytokine gene expression.
Takeno Sachio,Hirakawa Katsuhiro,Ueda Tsutomu,Furukido Kyosuke,Osada Rika,Yajin Koji
OBJECTIVES:A panel of cytokines has been found to be important for eosinophil accumulation and activation in nasal polyps. The aims of this study were to ascertain whether the activation of nuclear factor-kappa B (NF-kappaB) occurred in the polyp epithelium, and to examine the relationship between the degree of activation and local cytokine gene expression. STUDY DESIGN/METHODS:Nasal polyp specimens were obtained from 26 untreated patients. The proportion of nuclear translocation of the NF-kappaB p50 subunit in the polyp epithelium was quantitatively analyzed by a combination of fluorescent immunohistochemistry and a laser scanning confocal microscope image system. The levels of GM-CSF, IL-5, IL-8, IL-16, and eotaxin mRNA expression in the same speci-mens were measured using reverse transcription-polymerase chain reaction. RESULTS:Both cytoplasmic and nuclear localization of the p50 subunit was observed mainly in the epithelial layer in all specimens. The percentages of epithelial cells with nuclear translocation ranged from 4.5% to 40.5% (median, 18%). Significant correlations were observed between the degree of epithelial NF-kappaB activation and the levels of IL-8, IL-16, and eotaxin mRNA expression (r = 0.468, 0.47, and 0.739, respectively). CONCLUSION:The activation of NF-kappaB in the nasal polyp epithelium is responsible for the recruitment of inflammatory cells, particularly eosinophils, through the initiation of the transcriptional pathway of the related cytokines. The increased NF-kappaB activity in the polyp epithelium may reflect hypersensitivity to unknown stimuli.
Clarithromycin suppresses lipopolysaccharide-induced interleukin-8 production by human monocytes through AP-1 and NF-kappa B transcription factors.
Kikuchi Tohru,Hagiwara Koichi,Honda Yoshihiro,Gomi Kazunori,Kobayashi Takao,Takahashi Hiroshi,Tokue Yutaka,Watanabe Akira,Nukiwa Toshihiro
The Journal of antimicrobial chemotherapy
Erythromycin and other macrolides are effective for the treatment of chronic inflammatory airway diseases such as diffuse panbronchiolitis (DPB) and chronic sinusitis. The effect of macrolides in DPB is suggested to be anti-inflammatory rather than antibacterial. We investigated the effects of clarithromycin on interleukin-8 (IL-8) production using human peripheral monocytes and the human monocytic leukaemia cell line, THP-1. Bacterial extracts from Escherichia coli, Pseudomonas aeruginosa and Helicobacter pylori, as well as E. coli-derived lipopolysaccharide (LPS), induced IL-8 production. Clarithromycin suppressed this production in a dose-dependent manner in both monocytes and THP-1 cells (49.3-75.0% inhibition at 10 mg/L). A luciferase reporter gene assay with plasmids containing a serially deleted IL-8 promoter fragment showed that both the activator protein-1 (AP-1) and/or the nuclear factor-kappa B (NF-kapp aB) binding sequences were responsible for the LPS and clarithromycin responsiveness of the IL-8 promoter. Consistently, in an electromobility shift assay, LPS increased the specific binding of both AP-1 and NF-kappaB, whereas clarithromycin suppressed it. Moreover, LPS and clarithromycin regulated three other promoters that have either the NF-kappa B or the AP-1 binding sequences: two synthetic (pAP-1-Luc and pNF-kappa B-Luc) and one naturally occurring (ELAM-Luc). Our results indicate that clarithromycin modified inflammation by sup-pressing IL-8 production and that clarithromycin may affect the expression of other genes through AP-1 and NF-kappa B. In addition to treatment of airway diseases, the anti-inflammatory effect of macrolides may be beneficial for the treatment of other inflammatory diseases such as chronic gastritis caused by H. pylori.
[The effect of proinflammatory cytokines in pathogenesis of chronic sinusitis].
Li Yanzhong,Fang Zhensheng,Du Zhihua,Zhao Wenbo
Lin chuang er bi yan hou ke za zhi = Journal of clinical otorhinolaryngology
OBJECTIVE:To investigate the effect of the proinflammatory cytokines, including IL-1, IL-8 and TNF in the pathogenesis of chronic sinusitis. METHOD:Using immunohistochemical streptavidin-biotin peroxide complex (SABC) method to investigate the expression of interleukin-1 (IL-1), IL-8 and tumor necrosis factor (TNF) in the local mucosa of the two type chronic sinusitis. RESULT:There were significantly large numbers of IL-1+, IL-8+ and TNF+ cell in chronic sinusitis type I compared with healthy control (P < 0.01). The numbers of IL-8+ and TNF+ cell in the chronic sinusitis type II were significantly larger than that in the healthy control (P < 0.01). The numbers of IL-1+ cell in chronic sinusitis type I were significantly larger than that in chronic sinusitis type II (P < 0.01). CONCLUSION:This study indicates that proinflammatory cytokines may play an important role in the pathogenesis of chronic sinusitis. It appears that specific cytokine patterns are found in different forms of sinusitis. The investigation of different cytokine patterns may help to understand the different pathogenesis in chronic sinusitis subgroups.
Mode of action of long-term low-dose macrolide therapy for chronic sinusitis in the light of neutrophil recruitment.
Suzuki Hideaki,Ikeda Katsuhisa
Current drug targets. Inflammation and allergy
Chronic sinusitis is a common inflammatory upper respiratory tract disease. One of the prominent features of this disease is persistent purulent effusion containing numerous emigrated neutrophils in the paranasal sinuses. Recent advances in sinusitis research have revealed two positive feedback mechanisms that explain the chronic neutrophil accumulation in the sinus. First, interleukin (IL)-1beta secreted by monocytes, macrophages and fibroblasts upregulates the expression of E-selectin and intercellular adhesion molecule-1 (ICAM-1) in vascular endothelial cells, and thereby induces the extravascular transmigration of neutrophils. The emigrated neutrophils then secrete IL-1beta, which amplifies the expression of E-selectin and ICAM-1, resulting in further neutrophil infiltration. Second, chemoattractants including IL-8 in the sinus effusion initiate neutrophil exudation. Emigrated neutrophils then secrete IL-8, which elicits further neutrophil accumulation in the sinus effusion. Long-term low-dose macrolide therapy was first introduced for the treatment of diffuse panbronchiolitis in the 1980's. In the 1990's it was also shown to be an effective treatment for chronic sinusitis. The inhibitory effect of macrolides on neutrophil infiltration in inflammatory sites has been well documented in these diseases. Several lines of evidence indicate that macrolides do not function simply as a bactericide. In vitro studies have demonstrated various effects of macrolides on immunocompetent cells, inflammatory cells and airway epithelial cells. It has been shown that macrolides inhibit the production of IL-8 and IL-1beta and the expression of ICAM-1, suggesting that macrolides block the aforementioned dual positive feedback system of neutrophil recruitment and thereby exert their clinical efficacy in the treatment of chronic sinusitis. The inhibitory effects of macrolides on multiple steps in the process of neutrophil recruitment are presumably mediated by the inhibition of transcription factors such as nuclear factor-kB and activator protein-1. Further investigation of the mode of action of macrolides at the molecular level would lead to the development of safer and more effective drugs for the treatment of chronic sinusitis. In addition, the possible risk of this therapy such as the occurrence of resistant strains have to be carefully surveyed hereafter.
Role of interleukins and transforming growth factor-beta in chronic rhinosinusitis and nasal polyposis.
Bradley Dewayne T,Kountakis Stilianos E
OBJECTIVES:To determine the role of interleukin (IL)-4, IL-4 receptor (R), IL-6, IL-8, IL-11, and transforming growth factor (TGF)-beta in chronic rhinosinusitis (CRS) and chronic rhinosinusitis with nasal polyposis (CRS/NP). METHODS:Sinus tissue from patients undergoing endoscopic sinus surgery for CRS and CRS/NP was collected. Sinus tissue was then analyzed using reverse-transcription polymerase chain reaction (RT-PCR) to detect transcription of IL-4R, IL-6, IL-8, and IL-11. Sinus tissue samples were also cultured in vitro, treated with IL-4 for 24 hours, and real-time PCR was used to quantify the transcription of TGF-beta. RESULTS:Twenty patients were evaluated, 9 with CRS/NP and 11 with CRS alone. The mean age was 43 (20-74) years, with 13 females and 7 males. IL-4R, IL-6, IL-8, and IL-11 were identified by RT-PCR in all 20 patients. The transcription of TGF-beta was found to be 3.2 times greater in patients with CRS/NP than in patients with CRS alone (P = .047). CONCLUSION:IL-6, IL-8, and IL-11 are nonspecific markers of sinus inflammation being transcribed in patients with CRS and patients with CRS/NP. However, patients with CRS/NP demonstrate increased transcription of TGF-beta in response to IL-4 treatment, suggesting an IL-4 mediated mechanism for stromal proliferation in the formation of nasal polyposis.
Expression of interleukin-5, interleukin-8, and interleukin-10 mRNA in the osteomeatal complex in nasal polyposis.
Chen Yue-Shih,Arab Sonja F,Westhofen Martin,Lorenzen Johann
American journal of rhinology
BACKGROUND:Several cytokines are expressed in chronic sinusitis with and without underlying allergy. Their local production and regulation in the osteomeatal complex, the key area of paranasal sinuses, still is not fully understood. This study was performed to investigate differences of cytokine messenger RNA (mRNA) expression between the medial and the lateral part of the middle turbinate and anterior ethmoid mucosa of allergic and nonallergic patients. METHODS:Using the LightCycler system for real-time reverse-transcription polymerase chain reaction, we investigated the content of interleukin (IL)-5, IL-8, and IL-10 mRNA in tissue samples from middle turbinates and anterior ethmoids of 18 patients with chronic sinusitis and nasal polyps. Inferior turbinate mucosa of six control subjects without sinusitis and allergy served as control. RESULTS:IL-5 mRNA was detectable in 32 (60%) of 54 samples (two of six controls) in significant different amounts between the various locations (p < or = 0.001). Anterior ethmoid mucosa (0.96+/-0.99) expressed the highest amount of IL-5 mRNA followed by the lateral (0.37+/-0.54) and the medial portion of the middle turbinate (0.12+/-0.29) with no difference between allergic and nonallergic subgroups. IL-8 was detected in significant higher amounts in all three origins with no significant difference in concentrations between the examined locations as compared with controls. Patients expressed either IL-5 or IL-8 or both cytokine mRNA. IL-10 was expressed in all three specimens from five of eight allergic patients. All five individuals with clinical symptoms of allergy at the time of operation expressed IL-10 in at least one specimen. CONCLUSION:IL-5 cytokine expression in the osteomeatal complex is linked to the presence of nasal polyps, whereas IL-8 is up-regulated without distinct correlation to nasal polyps. IL-10 expression was detectable in five of eight allergic patients.
In vivo relationship between collagenase-2 and interleukin-8 but not tumour necrosis factor-alpha in chronic rhinosinusitis with nasal polyposis.
Kostamo K,Sorsa T,Leino M,Tervahartiala T,Alenius H,Richardson M,Toskala E
BACKGROUND:The characteristic feature of chronic rhinosinusitis with nasal polyposis (CRSwNP) is eosinophilic inflammation of the sinus mucosa; a type of inflammation also seen in asthmatic airways. Similar histopathologic findings of airway remodelling are present in both diseases. Remodelling is tightly controlled by matrix metalloproteinases (MMP). Increase of collagenase-2 (MMP-8) expression in the bronchial epithelial cells has been described in asthmatic patients, but it has not been studied in CRSwNP. METHODS:The concentrations and degree of activation of MMP-8 were analysed by immunofluorometric assay and Western blotting, respectively, in sinus mucus samples from CRSwNP patients and in nasal lavages from healthy controls in relation to inductive cytokines interleukin-8 (IL-8) and tumour necrosis factor-alpha (TNF-alpha). RESULTS:Significantly elevated levels of MMP-8 and IL-8 but not TNF-alpha were found in CRSwNP patients relative to controls. In particular, the activation of mesenchymal-type MMP-8 but not polymorphonuclear-type MMP-8 was associated with elevated IL-8 levels. CONCLUSIONS:The IL-8 and MMP-8 seemingly form an inductive cytokine-proteinase cascade in CRSwNP pathogenesis. Together they provide a target for novel therapies and a diagnostic tool for monitoring CRSwNP treatment.
Induction of CXC chemokines in A549 airway epithelial cells by trypsin and staphylococcal proteases - a possible route for neutrophilic inflammation in chronic rhinosinusitis.
Sachse F,von Eiff C,Stoll W,Becker K,Rudack C
Clinical and experimental immunology
While various microorganisms have been recovered from patients with chronic rhinosinusitis, the inflammatory impact of virulence factors, in particular proteases from Staphylococcus aureus and coagulase negative staphylococci on the nasal epithelium, has not yet been investigated. Expression of CXC chemokines was determined in the epithelium of patients with chronic rhinosinusitis by immunohistochemistry. In a cell culture system of A549 respiratory epithelial cells, chemokine levels were quantified by enzyme-linked immunosorbent assay (ELISA) after stimulation with supernatants originating from three different staphylococcal strains or with trypsin, representing a serine protease. Inhibition experiments were performed with prednisolone, with the serine protease inhibitor 4-(2-aminoethyl)-benzenesulphonylfluoride (AEBSF) and with the nuclear transcription factor (NF)-kappaBeta inhibitor (2E)-3-[[4-(1,1-dimethylethyl)phenyl]sulphonyl]-2-propenenitrite (BAY) 11-7085. Electromobility shift assays (EMSA) were used to demonstrate NF-kappaB-dependent protein synthesis. CXC chemokines interleukin (IL)-8, growth-related oncogene alpha (GRO-alpha) and granulocyte chemotactic protein-2 (GCP-2) were expressed in the patients' epithelium whereas epithelial cell-derived neutrophil attractant 78 (ENA-78) was rarely detected. In A549 cells, chemokines IL-8, ENA-78 and GRO-alpha but not GCP-2 were induced by trypsin and almost equal levels were induced by staphylococcal supernatants. IL-8, GRO-alpha and ENA-78 synthesis was suppressed almost completely by AEBSF and BAY 11-7085, whereas prednisolone reduced chemokine levels differentially dependent on the supernatant added. CXC chemokines were detectable in the epithelium of patients with chronic rhinosinusitis. Staphylococcal serine proteases induced CXC chemokines in A549 cells, probably by the activation of proteases activated receptors, and thus might potentially be involved in neutrophilic inflammation in chronic sinusitis.
A correlative study of NF-kappaB activity and cytokines expression in human chronic nasal sinusitis.
Xu R,Xu G,Shi J,Wen W
The Journal of laryngology and otology
A growing body of literature suggests that cytokines play an important part in the pathogenesis of chronic nasal sinusitis. However, the mechanism by which the expression of cytokines in chronic nasal sinusitis is upregulated has not been well documented. The present study investigated the role of nuclear factor-kappa B (NF-kappaB) activation in upregulating the expression of interleukin-5, -6 and -8 (IL-5, IL-6 and IL-8). We titrated the levels of IL-5, IL-6 and IL-8 in nasal mucosa in 52 cases of chronic nasal sinusitis and 12 normal subjects using enzyme-linked immunosorbent assay. According to whether allergic rhinitis was associated or not, we subdivided the patients into the AR group (with allergic rhinitis) and the NAR group (without allergic rhinitis). Semi-quantitative reverse transcription-polymerase chain reaction and immunohistochemical staining were used to evaluate expression and activation of NF-kappaB P50 and P65 subunits in nasal mucosa. The correlation between activities of P50 and P65 and cytokines expression was analysed. Our results showed that IL-5, IL-6 and IL-8 in both the AR and NAR groups were strikingly elevated in comparison with the control group (all p < 0.01 for AR group; p < 0.05, 0.05, 0.01, respectively, for NAR group); and they were even higher in the AR group than those in the NAR group (p < 0.01, 0.05, 0.01, respectively). P50 and P65 mRNA levels in both AR and NAR groups were markedly greater than those in the control group (all p < 0.01); and the AR group had further higher levels as compared with the NAR group (both p < 0.05). Immunohistochemical study revealed that nucleus-positive rates of P50 and P65 in both AR and NAR groups were significantly higher than those of the control group (all p < 0.01), and they were much greater in the AR group in comparison with the NAR group (all p < 0.01). Pearson correlation analysis demonstrated that P50 and P65 nucleus-positive rates were closely correlated with IL-6 and IL-8 levels, but not IL-5, with a correlation coefficient of 0.49 for P50 and IL-6, 0.54 for P50 and IL-8, 0.61 for P65 and IL-6, and 0.66 for P65 and IL-8 (all p < 0.01). In conclusion, upregulated expression and activation of NF-kappaB P50 and P65 might be one of the mechanisms for induction of IL-6 and IL-8 expression in chronic nasal sinusitis. Association of allergic rhinitis with chronic nasal sinusitis further enhanced NF-kappaB activity, and subsequently lead to even stronger expression of IL-6 and IL-8. IL-5 expression appeared to be independent of NF-kappaB pathway in chronic nasal sinusitis.
Relationship between matrix metalloproteinases MMP-2, MMP-9, tissue inhibitor of matrix metalloproteinases-1 and IL-5, IL-8 in nasal polyps.
Chen Y-S,Langhammer T,Westhofen M,Lorenzen J
BACKGROUND:Nasal polyps (NP), a subgroup of chronic rhinosinusitis, are characterized by interleukin 5 (IL-5) mediated infiltration of eosinophils in sinus mucosa, leading to pseudostratified ciliated columnar epithelium, thickening of the epithelial basement membrane and tissue edema. Matrix metalloproteinases (MMP) constitute a large group of Zn2+ dependent endopeptidases with the ability to degrade extracellular matrix and are possibly responsible for the development of tissue edema in chronic sinusitis. OBJECTIVE:The aim of this study was to determine the expression of MMP-2, MMP-9 and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) mRNA and to locate the distribution of MMP-2, MMP-9 and TIMP-1 by immunohistochemistry in ethmoid sinus mucosa in NP. Furthermore the correlation between IL-5 or IL-8 and MMP-2, MMP-9 or TIMP-1 is examined. METHODS:Nasal polyps of 33 patients and 18 specimens of inferior turbinate mucosa were examined by real time RT-PCR for MMP-2, MMP-9, TIMP-1, IL-5 and IL-8 mRNA expression. Immunohistochemical labeling for MMP-2, MMP-9 and TIMP-1 was performed. RESULTS:Differences between both locations were detectable for MMP-9 (P < 0.001) and IL-5 (P=0.003) but not for MMP-2 (P=0.278), TIMP-1 (P=0.515) and IL-8 (P=0.386). Correlation was detected only between TIMP-1 and IL-5 (r=0.422, P =0.014). Cytoplasmic staining of MMP-2 was present in the apical part of the ciliated cells, submucosal glands and in smooth muscle cells. Matrix metalloproteinase-9 was expressed in surface epithelium, in seromucous glands and in polymorphonuclear cells. CONCLUSIONS:Expression of MMP-9 and IL-5 mRNA are associated with NP. The correlation between IL-5 and TIMP-1 indicates the role of TIMP-1 in maintaining the homeostasis in NP.
Sinonasal epithelial cell expression of toll-like receptor 9 is decreased in chronic rhinosinusitis with polyps.
Ramanathan Murray,Lee Won-Kyung,Dubin Marc G,Lin Sandra,Spannhake Ernst W,Lane Andrew P
American journal of rhinology
BACKGROUND:Innate immune recognition of pathogens by sinonasal epithelial cells may play an important role in the pathogenesis of chronic rhinosinusitis (CRS). Previous studies have indicated that toll-like receptor (TLR) mRNA is present in sinonasal mucosa, and levels of TLR9 expression are decreased in recalcitrant CRS with nasal polyps (CRSwNP). However, the cellular source and function of TLR9 in the sinonasal epithelium is not known. In this study, primary epithelial cell cultures were analyzed from control subjects and CRSwNP patients to determine the presence and function of TLR9 protein. METHODS:Primary epithelial cell cultures were established from 5 controls and 10 CRSwNP patients undergoing sinus surgery. Flow cytometry was used to confirm purity of epithelial cells and to assess expression of TLR9 protein. Epithelial cells were stimulated with TLR9 agonist, and mRNA was analyzed by real-time PCR for expression of human beta-defensin (HBD) 2 and interleukin (IL)-8. RESULTS:Flow cytometry showed TLR9 protein in 100% of epithelial cells from controls and CRSwNP patients. The level of expression was 50% lower in CRS patients than in controls. Stimulation of epithelial cells with TLR9 agonist produced a 1.5- to 9-fold increase in HBD-2 and IL-8 mRNA expression. CONCLUSION:Functional TLR9 protein is expressed by normal and diseased sinonasal epithelial cells. The level of TLR9 expression is decreased in CRSwNP patients, consistent with the previous finding of decreased TLR9 mRNA in whole sinonasal tissue. These findings suggest that impaired innate immune responses to pathogens via TLR9 on sinonasal epithelial cells may represent a critical mechanism in chronic inflammatory sinus disease.
PAR-2 activation regulates IL-8 and GRO-alpha synthesis by NF-kappaB, but not RANTES, IL-6, eotaxin or TARC expression in nasal epithelium.
Rudack C,Steinhoff M,Mooren F,Buddenkotte J,Becker K,von Eiff C,Sachse F
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology
BACKGROUND:The effects of protease-activated receptor-2 (PAR-2) stimulation on inflammation mechanisms of chronic rhinosinusitis (CRS) are still unknown. METHODS:PAR-2 receptor expression was investigated by immunohistochemistry and Taqman mRNA analysis in the mucosa of different rhinosinusitis entities. In primary nasal epithelial cell cultures, the function of PAR-2 and its ability to produce CXC, CC chemokines, and IL-6 were measured by calcium mobilization and stimulation tests. Inhibition tests were performed using cortisone, serine protease inhibitors, cysteine protease inhibitors, Pertussis toxin (PTX) and nuclear transcription factor (NF-kappaB) inhibition (BAY 11-7085). Signal transduction pathways were analysed by electromobility shift assays (EMSA) and NF-kappaB binding studies. RESULTS:The expression of PAR-2 was found to be increased in CRS specimens. The activation of PAR by trypsin or PAR-2-specific activating peptide (AP) caused an increase in cytosolic calcium, as well as the release of the CXC chemokines IL-8 and growth-related oncogene (GRO)-alpha, but not the release of CC chemokines or IL-6. AP-induced CXC chemokine was sensitive to PTX and activation of NF-kappaB was inhibited by BAY11-7085. Furthermore, a serine protease inhibitor significantly inhibited chemokine synthesis stimulated by trypsin and culture supernatants of staphylococci, whereas steroids and cysteine protease inhibitors had little effect. CONCLUSION:PAR-2 plays a role in serine protease-mediated regulation - staphylococcal and non-staphylococcal origin - of IL-8 and GRO-alpha in nasal epithelial cells, but not in the regulation of CC chemokines. PAR-2 may therefore be involved in the pathophysiology of CRS and NP at different sites of activation, namely (i) proteases, (ii) the PAR-2 receptor itself or (iii) the application of novel agents that block NF-kappaB/IkappaB-alpha signalling.
Proinflammatory impact of Staphylococcus epidermidis on the nasal epithelium quantified by IL-8 and GRO-alpha responses in primary human nasal epithelial cells.
Sachse F,von Eiff C,Becker K,Steinhoff M,Rudack C
International archives of allergy and immunology
BACKGROUND:Bacterial etiology of chronic rhinosinusitis (CRS) still remains controversial. Whereas Staphylococcus aureus enterotoxins have been detected in CRS, the impact of Staphylococcus epidermidis, a major commensal inhabitant of the nose, has not been studied. Among others, serine and cysteine proteases have been identified as factors of virulence in S. epidermidis. METHODS:S. epidermidis was examined in tissue biopsies of 30 CRS patients (16 with nasal polyposis) using standard procedures. Primary human nasal epithelial cells from inferior nasal turbinates (HNECs), from nasal polyps (NPECs) and A549 airway epithelial cells were stimulated with S. epidermidis supernatants DSM20044 or ATCC35984 and the IL-8 and GRO-alpha response was quantified by ELISA. Protease-triggered chemokine responses and involvement of NF-kappaB were investigated by addition of protease or NF-kappaB inhibitors. Activation of NF-kappaB was demonstrated by quantitative DNA binding assay. RESULTS:S. epidermidis was the most frequently isolated bacteria in the majority of CRS patients. HNECs and NPECs revealed no different IL-6 and IL-8 synthesis following stimulation with DSM20044 or ATCC35984. Stimulation of HNECs and A549 cells with S. epidermidis supernatants resulted in increased IL-8 and GRO-alpha expression which could be suppressed by the serine protease inhibitor AEBSF and the NF-kappaB inhibitor BAY 11 but not by the cysteine protease inhibitor E64. Results obtained for A549 cells were similar to HNECs. CONCLUSION:S. epidermidis was present in the majority of CRS specimens. Proinflammatory impact of S. epidermidis supernatants on nasal epithelial cells was demonstrated by serine protease-triggered and NF-kappaB-dependent chemokine responses.
The role of cytokines in chronic rhinosinusitis with nasal polyps.
Otto Bradley A,Wenzel Sally E
Current opinion in otolaryngology & head and neck surgery
PURPOSE OF REVIEW:This article reviews the recent literature regarding select cytokines involved in chronic rhinosinusitis with nasal polyps. Chronic rhinosinusitis with nasal polyps is generally characterized by eosinophilic infiltration and a Th2-biased cytokine profile. However, the mechanisms that lead to nasal polyps are not clear. RECENT FINDINGS:There has been a significant amount of work identifying cytokines that are either upregulated or downregulated in chronic rhinosinusitis with nasal polyps. In general, Th2 cytokines such as IL-4 and IL-5 are upregulated. IL-4 promoter polymorphisms are associated with nasal polyps, and IL-4 appears to potentiate the immune response of fibroblasts. IL-5 release from nasal polyps is induced by Staph enterotoxin B and upregulation may be localized to nasal polyps. IL-8 appears to be upregulated by Staphylococcus epidermidis and may modulate remodeling in nasal polyps. Interferon-gamma and transforming growth factor-beta have antagonistic roles to Th2 inflammation and both are downregulated in nasal polyps. Tumor necrosis factor-alpha and IL-1 are pro-inflammatory cytokines that are upregulated in nasal polyps. Single nucleotide polymorphisms for both cytokines have been identified in nasal polyps. SUMMARY:Several studies have reported on various cytokines that correlate to the chronic rhinosinusitis with nasal polyps phenotype; however, more insight into the mechanisms that lead to altered cytokine profiles and the nasal polyps phenotype is needed.
[Expressions of LL-37 and IL-8 in chronic sinusitis with nasal polyps].
Xie Dan,Guo Yunkai,Wu Dan,Xie Dinghua
Lin chuang er bi yan hou tou jing wai ke za zhi = Journal of clinical otorhinolaryngology, head, and neck surgery
OBJECTIVE:To investigate the expressions of LL-37 and IL-8 in chronic sinusitis with nasal polyps. METHOD:Semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemical staining were used to detect the expressions of LL-37 and IL-8 in nasal polyp tissues of 31 patients with chronic sinusitis and inferior turbinate tissues of 11 patients with chronic rhinitis. RESULT:LL-37 and IL-8 mRNA were all positively expressed in all nasal polyps and inferior turbinate tissues. There were significant increases of LL-37 and IL-8 mRNA expressions in nasal polyps compared with the inferior turbinate tissues (P < 0.01). There were also significant increases of positive expression rates of LL-37 and IL-8 protein in nasal polyps, compared with the inferior turbinate tissues (P < 0.01). There was a positive relationship between the mRNA and protein expressions of LL37 and IL-8 (P < 0.01). CONCLUSION:The expressions of LL-37 and IL-8 in nasal polyps suggest that they may play a role in the pathogenesis of chronic sinusitis. Besides its innate immune, LL-37 could enhance human body's anti-infected function by increasing acquired immune.
Induction of interleukin-8 from nasal epithelial cells during bacterial infection: the role of IL-8 for neutrophil recruitment in chronic rhinosinusitis.
Yoon Bit-Na,Choi Nan-Geum,Lee Hyun-Sun,Cho Kyu-Sup,Roh Hwan-Jung
Mediators of inflammation
OBJECTIVES:The aim of this study was to elucidate the role of IL-8 for neutrophil recruitment in nonallergic CRS patients. METHODS:After coculture of Streptococcus pneumoniae (SP) with the mucosal epithelial cells (MECs) from non-CRS patients, at three different SP/MEC (1/1, 10/1, 100/1) ratios, the expression of IL-8 mRNA and the concentration of IL-8 were measured by RT-PCR and ELISA. The expression of CD11b/CD18 on neutrophils and E-selectin/ICAM-1 on endothelial cells and the adherence between neutrophils and human umbilical vascular endothelial cells (HUVECs) were determined by flow cytometric analysis, ELISA, and RIA, respectively. RESULTS:IL-8 concentration and IL-8 mRNA expression continued to increase from 3 hours after incubation in SP number-dependent manner. The expression of CD11b/CD18 on neutrophils and E-selectin/ICAM-1 on HUVECs, and the adherence between neutrophils and HUVECs were significantly increased in 10 SP/MEC-CM, and the increments were significantly blocked by anti-IL-8 antibody. CONCLUSION:MEC and IL-8 are major factors for neutrophil recruitment in nonallergic CRS.
Sinus aspirates in chronic rhinosinusitis: fungal colonization of paranasal sinuses, evaluation of ICAM-1 and IL-8 and studying of immunological effect of long-term macrolide therapy.
Elmorsy Shawky,El-Naggar Mohammed M,Abdel aal Sanaa M,Abou-elela Mohammad A
PURPOSE:In patients with chronic fungal sinusitis, concentrations of interleukin-8 (IL-8), immunoglobulin E (IgE), and soluble intercellular adhesion molecule-1 (sICAM-1) were compared in paranasal sinus aspirates and serum. Furthermore, immunological effects of macrolide treatment of our patients with chronic fungal rhinosinusitis were also studied. MATERIAL AND METHODS:In our cohort study, 108 patients with chronic rhinosinusitis undergoing sinus surgery were selected. Sinus aspirates were collected, and used for immunological assasy and cultured for fungal study. All patients were examined for the presence of characteristic allergic mucin of chronic allergic fungal rhinosinusitis and this was confirmed later by measurement of total serum IgE. RESULTS:Our cases were classified into 3 groups: chronic rhinosinusitis with positive fungal culture and negative allergic mucin, chronic rhinosinusitis with positive fungal culture and positive allergic mucin and chronic rhinosinusitis without fungal growth. A control group was included. We found 57.4% of the patient cultures positive for fungus and 36.4% of the control subjects. Aspergillus ssp. were the most prevalent followed by Bipolaris ssp., and Curvularia. IgE levels were increased in group II compared to group I, III and IV. ICAM-1 and IL-8 levels were increased in groups I, II and III compared to the control group. Erythromycin given in group II decreased the levels of IL-8 and ICAM-1. CONCLUSION:Aspergillus species were the most common. These results confirm the role of ICAM-1 and IL-8 in all types of rhinosinusitis. Erythromycin modulated the immune status of the patients.
Hypoxia induces cysteine-rich 61, vascular endothelial growth factor, and interleukin-8 expressions in human nasal polyp fibroblasts: An implication of neutrophils in the pathogenesis of nasal polyposis.
Shun Chia-Tung,Lin Sze-Kwan,Hong Chi-Yuan,Huang Hung-Meng,Liu Chia-Ming
American journal of rhinology & allergy
BACKGROUND:The purpose of this article was to elucidate the roles of neutrophils and angiogenesis factors in the pathogenesis of nasal polyposis. The effect of hypoxia on the expressions of angiogenesis factors as cysteine-rich 61 (Cyr61) and vascular endothelial growth factor (VEGF) and neutrophil chemoattractant as interleukin (IL)-8 in nasal polyp fibroblasts (NPFs), and the role of nuclear factor kappa B (NF-kappaB) in this reaction were investigated. The action of Cyr61 on the synthesis of VEGF and IL-8 in NPFs was also examined. METHODS:Primary cultures of NPFs were established from nasal polyps (NPs). Productions of Cyr61, VEGF, and IL-8 by NPFs under hypoxia were detected by Western blot (Cyr61 and VEGF) or enzyme-linked immunosorbent assay (ELISA; IL-8). Immunohistochemical staining was used to examine the relation between fibroblastic expression of Cyr61 and neovascularization/neutrophil infiltration in NPs. RESULTS:Western blot showed that the hypoxia inducer CoCl(2) stimulated Cyr61 synthesis in NPFs in a time-dependent manner, reaching a peak at 24 hours. Bay-117082 (a specific NF-kappaB inhibitor) attenuated the levels of Cyr61 stimulated by hypoxia. Cyr61 induced IL-8 secretion and VEGF synthesis by NPFs, as evidenced by Western blot and ELISA analysis. Bay-117082 abolished hypoxia-stimulated IL-8 and VEGF synthesis, whereas Cyr61 restored the stimulative effect of hypoxia readily. Immunohistochemical staining revealed the presence of Cyr61 and IL-8 in NPFs. Neutrophils and capillaries aggregating around these NPFs were frequently found. CONCLUSION:Under hypoxia, NPFs contribute to NP propagation by expressing Cyr61, which subsequently stimulates VEGF and IL-8 production, leading to angiogenesis and activating neutrophil infiltration in NPs.
Effects of a novel nonantibiotic macrolide, EM900, on cytokine and mucin gene expression in a human airway epithelial cell line.
Otsu Kazuya,Ishinaga Hajime,Suzuki Shinya,Sugawara Akihiro,Sunazuka Toshiaki,Omura Satoshi,Jono Hirofumi,Takeuchi Kazuhiko
BACKGROUND/AIMS:Long-term macrolide therapy is an effective treatment for chronic sinusitis and diffuse panbronchiolitis. However, long-term use of macrolides may promote the growth of drug-resistant bacteria; therefore, development of macrolides with no antibacterial action is desirable. A new erythromycin (EM) derivative, (8R,9S)- 8,9-dihydro-6,9-epoxy-8,9-anhydropseudoerythromycin A (EM900), does not possess antibacterial action. METHODS:To determine whether EM900 induced a clinically relevant anti-inflammatory response and repressed mucin gene expression in cells derived from human airway epithelia, we assessed the effects of EM900 on IL-1β-induced inflammatory cytokines in A549 cells and MUC5AC gene expression in HM3-MUC5AC cells. We also investigated the effects of EM900 on IL-1β-induced NF-κB activation. We performed reporter gene assays and quantitative PCR in A549 and HM3-MUC5AC cells. RESULTS:Both EM and EM900 suppressed IL-1β-induced IL-8 expression in A549 cells. EM900 also suppressed IL-1β-induced IL-1β and TNF-α expression in A549 cells. EM900 inhibited IL-1β-induced MUC5AC expression in HM3-MUC5AC cells. Both EM and EM900 suppressed IL-1β-induced NF-κB activation in A549 cells. CONCLUSION:This study demonstrated that EM900 suppressed the induction of inflammatory cytokines and MUC5AC gene expression in cells derived from human airway epithelia, and our findings indicate that these effects may be mediated by the suppression of NF-κB activation.
Primary human sinonasal epithelial cell culture model for topical drug delivery in patients with chronic rhinosinusitis with nasal polyposis.
Bleier Benjamin S,Mulligan Ryan M,Schlosser Rodney J
The Journal of pharmacy and pharmacology
OBJECTIVES:The primary human sinonasal epithelial cell culture (HSNEC) allows for in-vitro modelling of mucosal responses to topical therapy. Cultures grown from healthy donors may underestimate changes in individuals with chronic sinonasal disease thereby yielding inaccurate results with respect to this large patient population. The purpose of this study was to analyse HSNECs derived from patients with chronic rhinosinusitis with nasal polyposis (CRSwNP) to determine whether expected disease dependent variables salient to topical drug delivery persist in culture. METHODS:Cultures were grown from patients with CRSwNP. Ciliary beat frequency (CBF) (basal and stimulated), permeability (trans and paracellular), inflammatory response, and glucocorticoid dose response were measured and compared with healthy controls. KEY FINDINGS:Methylcholine stimulated CBF was greater in CRSwNP versus controls (ΔCBF(60 min) 7.25 ± 1.02 vs 0.89 ± 1.04 Hz, respectively). Paracellular permeability was greater in CRSwNP versus controls (basolateral dextran(120 min) 18.97 ± 3.90 vs 11.31 ± 4.35 µg/ml, respectively). Lipopolysaccharide (0.1 mg/ml) stimulated interleukin-6 (IL-6) and IL-8 secretion was increased in CRSwNP versus controls (IL-6 Δbaseline 1738.72 ± 654.82 vs 1461.61 ± 533.51%, respectively; IL-8 Δbaseline 137.11 ± 0.83 vs 111.27 ± 0.67%, respectively). CRSwNP cultures were more sensitive than controls to dexamethasone (1 µg/ml) dependent IL-6 and IL-8 suppression. CONCLUSIONS:HSNECs derived from patients with CRSwNP retained their primary phenotype with respect to ciliary function, epithelial permeability, irritant induced inflammatory cytokine secretion, and glucocorticoid dose response.
The role of High Mobility Group Box 1 chromosomal protein in the pathogenesis of chronic sinusitis and nasal polyposis.
Bellussi L M,Chen L,Chen D,Passali F M,Passali D
Acta otorhinolaryngologica Italica : organo ufficiale della Societa italiana di otorinolaringologia e chirurgia cervico-facciale
Chronic rhinosinusitis with nasal polyposis is considered to be a multifactorial disease where different stimuli (mechanical, viral, bacterial, fungal infection, immunological disorders or dysreactivity, environmental pollution), acting on the mucosa of nasal cavities and paranasal sinuses, lead to epithelial damage and mucosal inflammation. Inflammatory cell infiltration (predominantly eosinophils, but also neutrophils, mast cells, macrophages and lymphocytes), cytokine release and sub-epithelial oedema are the histological pictures that are associated, from the clinical point of view, with nasal congestion, secretion and/or post-nasal drip and facial pain/headache. Recently, the importance of the HMG B-1 protein in the pathogenesis of several inflammatory diseases has been demonstrated. This protein is released from necrotic/damaged cells or immune-activated cells, and by acting on specific membrane receptors causes the release of pro-inflammatory mediators, endothelial activation and the survival of inflammatory cells. The objective of the present study was: i) to determine whether HMG B1 is augmented in chronic rhinosinusitis with nasal polyps; ii) if its expression is associated with eosinophils, TNF-α, IL 5 and IL 8 cytokines typically present in chronic inflammation of the nose and paranasal sinuses; iii) to investigate a hypothetical role of this protein in the pathogenesis of nasal polyposis. Nasal polyps tissue from 21 patients affected by CRSwNP and nasal mucosa from 8 controls was collected at the ENT Department of the Chinese PLA General Hospital and underwent immunohistological staining for detection of HMG B1 protein and IL -5, IL -8 and TNF-α inflammatory cytokines. The degree of HMG B1 protein expression was evaluated by dividing the stained sections in 4 portions: 1) nucleus of epithelial cells, 2) cytoplasm of epithelial cells, 3) focal extracellular infiltration, 4) inflammatory cells. HMG B1 was more expressed in the nucleus of epithelial cells of patients compared with controls. In contrast, epithelial cytoplasm HMG B1 staining was significant lower in patients. Sub-epithelial focal infiltration of HMG B1 protein expression was lower in controls, whereas the expression of HMG B1 in the inflammatory cells in patients was significantly increased in comparison with controls. These data, together with the correlation we found between HMG B1 protein expression in different portions and the number of eosinophils infiltrating cells, or IL -5, IL -8 and TNF-α positive cells in patients, suggest that HMG B1 may play a crucial role in the pathogenesis of chronic rhinosinusitis with nasal polyps.
Cytokine correlation between sinus tissue and nasal secretions among chronic rhinosinusitis and controls.
Oyer Samuel L,Mulligan Jennifer K,Psaltis Alkis J,Henriquez Oswaldo A,Schlosser Rodney J
OBJECTIVES/HYPOTHESIS:Compare cytokine levels in sinus tissue to sinus secretions from controls and chronic rhinosinusitis patients. STUDY DESIGN:In vitro. METHODS:Polyurethane foam sponges were placed into middle meati of patients with chronic rhinosinusitis without nasal polyps (CRSsNP), with polyps (CRSwNP), and controls. Sinus biopsies were then taken from the same location. Protein levels of tumor necrosis factor-alpha (TNF-α), interferon-γ (IFN-γ), and interleukins (IL) 2, 4, 6, 8, 10, and 17A were measured via cytometric bead assay for each sample. Protein values from sinus tissue and secretions were compared with Pearson's correlation between samples as well as one-way ANOVA with posthoc t test between groups. RESULTS:Samples from 43 patients in total were examined. Mucus was measured from 10 controls, 11 CRSsNP and 10 CRSwNP, and sinus tissue was measured from 10 controls, 15 CRSsNP and 10 CRSwNP. IL-8 and IFN-γ levels were outside of the detectable range of the assay. Levels of secreted IL-2, 4, 6, 10, and 17A correlated with tissue levels (P < 0.05 for all, r > 0.49) while TNF-α did not (P = 0.71). CRSsNP had elevated mucus levels of IL-2, 4, 6, 10, and 17A compared to controls. CRSwNP had elevated mucus levels of IL-4, 6, 10, 17A, and TNF-α compared to controls. CONCLUSIONS:Cytokine levels in sinus secretions correlate with levels in sinus tissue and are elevated in CRS versus control based on Th1/Th2 skewing.
Increase of high mobility group box chromosomal protein 1 in eosinophilic chronic rhinosinusitis with nasal polyps.
Chen Daishi,Mao Mingfeng,Bellussi Luisa M,Passali Desiderio,Chen Lei
International forum of allergy & rhinology
BACKGROUND:Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by eosinophil-dominant infiltration in Europe and the United States. However, CRSwNP in Asia has shown different immunopathologic features. High-mobility group protein box 1 (HMGB1) is a DNA-binding protein that has been suggested to be involved in various chronic inflammatory diseases. The objective of this study is to investigate whether HMGB1 is augmented in the Chinese eosinophilic CRSwNP and if non-eosinophilic CRSwNP is associated with interleukin 5 (IL-5), IL-8, and tumor necrosis factor α (TNF-α). METHODS:Nasal polyps specimens were collected from 41 patients with CRSwNP (20 eosinophilic and 21 non-eosinophilic) undergoing functional endoscopic sinus surgery (FESS). Biopsies of uncinate process, and ethmoidal mucosa from 9 non-CRS patients were used as controls by means of immunohistochemistry (IHC) staining, Western blotting, and quantitative reverse-transcription polymerase chain reaction (qRT-PCR). RESULTS:HMGB1-positive expression was significantly increased in the epithelium and among the large inflammatory cells infiltration in Eos CRSwNP and non-Eos CRSwNP as compared with controls (p < 0.001). The HMGB1 protein and messenger RNA (mRNA) levels of HMGB1, IL-5, IL-8, and TNF-α were significantly higher in eosinophilic CRSwNP than those from controls and non-eosinophilic CRSwNP, but no significant differences in these markers were found between non-eosinophilic CRSwNP and controls. HMGB1 expression levels correlated significantly and positively with IL-5, IL-8, and TNF-α (rs = 0.665, 0.771, and 0.724, respectively; p < 0.001) and slightly with eosinophil infiltration (rs = 0.149; p = 0.012) and the blood eosinophils count (rs = 0.225; p = 0.001) in all samples. CONCLUSION:Upregulation of HMGB1 could be a significant marker typically in eosinophilic CRSwNP and it may also contribute to the pathogenesis of CRSwNP along with IL-5, IL-8, and TNF-α.
P-glycoprotein promotes epithelial T helper 2-associated cytokine secretion in chronic sinusitis with nasal polyps.
Bleier Benjamin S,Nocera Angela L,Iqbal Hufsa,Hoang John D,Alvarez Ulises,Feldman Rachel E,Han Xue
International forum of allergy & rhinology
BACKGROUND:Sinonasal epithelial cells are recognized as drivers of inflammation in chronic sinusitis with nasal polyps (CRSwNP) through secretion of T helper 2 (Th2)-promoting cytokines. P-glycoprotein (P-gp) is overexpressed in nasal polyps and modulates epithelial cytokine secretion in healthy mucosa. The objective of this study is to determine whether P-gp overactivity promotes Th2-associated cytokine secretion in CRSwNP. METHODS:Polyp explants (n = 4) and primary epithelial cell cultures (n = 5) were cultivated from patients with CRSwNP. Explant P-gp activity was determined using a calcein assay. In culture, P-gp was quantified by enzyme-linked immunosorbent assay (ELISA) and sensitivity to PSC-833 inhibition was determined using a calcein assay. Lipopolysaccharide (LPS)-stimulated cytokine secretion of interleukin 6 (IL-6), IL-8, IL-25, and granulocyte macrophage colony stimulating factor (GM-CSF) were quantified by ELISA and compared to secretion following P-gp inhibition. Differences in P-gp expression and cytokine secretion were compared using a Mann-Whitney U test. Secretion was correlated with P-gp expression using a Pearson correlation coefficient. RESULTS:Calcein retention is increased in P-gp inhibited vs uninhibited polyp explants (mean ± standard deviation [SD]; 5.17 ± 1.76 vs 2.55 ± 0.62; p < 0.05) but not in controls, indicating increased nasal polyp P-gp activity. P-gp is sensitive to dose-dependent P-gp inhibition with PSC-833 in vitro. LPS-stimulated secretion of normalized GM-CSF (45.21 ± 41.39) and IL-6 (63.16 ± 36.37) were significantly reduced following P-gp inhibition (8.47 ± 3.28; p < 0.01, and 39.94 ± 31.07; p < 0.05; respectively) and secretion was highly correlated with P-gp expression(r = 0.824, p < 0.05, and r = 0.833, p < 0.05; respectively). CONCLUSION:P-gp overactivity promotes Th2-associated epithelial cytokine secretion in nasal polyps, suggesting a novel mechanism for maintaining chronic inflammation in CRSwNP.
Level of secreted HMGB1 correlates with severity of inflammation in chronic rhinosinusitis.
Min Hyun Jin,Kim Su Jin,Kim Tae Hoon,Chung Hyo Jin,Yoon Joo-Heon,Kim Chang-Hoon
OBJECTIVE:High mobility group box 1 (HMGB1) protein is a chromatin protein that functions as a proinflammatory cytokine when secreted in response to inflammatory stimuli. The purpose of this study was to determine the relationship between the HMGB1 level in nasal secretions and the severity of inflammation in chronic rhinosinusitis. STUDY DESIGN:This was a cross-sectional study. METHODS:Nasal secretions were obtained by irrigation of the affected sinonasal cavities with normal saline. Total 63 nasal lavage fluid samples were collected from 38 patients with chronic rhinosinusitis who underwent endoscopic sinus surgery. Levels of HMGB1 and tumor necrosis factor alpha, interleukin (IL)-1β, and IL-8 were determined by enzyme-linked immunoassay. Severity of inflammation was assessed by the Lund-Mackay scoring system, which is based on preoperative computed tomography scans. Concurrent medical disorders, presence of nasal polyps, septal deviation, and allergic rhinitis were also investigated. RESULTS:The level of HMGB1 in nasal lavage fluid was positively correlated with the Lund-Mackay score. The score was the only factor associated with HMGB1 by univariate and multivariate analysis. Other cytokines, with the exception of IL-8, were not correlated with the Lund-Mackay score. CONCLUSION:Our results showed that HMGB1 is secreted into the extracellular area space in the upper airway, and HMGB1 levels in nasal lavage fluid correlate with severity of inflammation, as assessed by the Lund-Mackay staging system for chronic rhinosinusitis. These results provide evidence for HMGB1 as an inflammatory mediator associated with the severity of chronic rhinosinusitis.
Involvement of B2 receptor in bradykinin-induced proliferation and proinflammatory effects in human nasal mucosa-derived fibroblasts isolated from chronic rhinosinusitis patients.
Tsai Yih-Jeng,Hao Sheng-Po,Chen Chih-Li,Lin Brian J,Wu Wen-Bin
Chronic rhinosinusitis (CRS) is a chronic inflammatory disease of the sinonasal mucosa either accompanied by polyp formation (CRSwNP) or without polyps (CRSsNP). CRSsNP accounts for the majority of CRS cases and is characterized by fibrosis and neutrophilic inflammation. However, the pathogenesis of CRS, especially CRSsNP, remains unclear. Immunohistochemistry of CRSsNP specimens in the present study showed that the submucosa, perivascular areas, and the mucous glands were abundant in fibroblasts. Therefore, we investigated the effects bradykinin (BK), an autacoid known to participate in inflammation, on human CRSsNP nasal mucosa-derived fibroblasts (NMDFs). BK increased CXCL1 and -8 secretion and mRNA expression with EC50 ranging from 0.15~0.35 μM. Moreover, BK enhanced cell proliferation and upregulated the expressions of proinflammatory molecules, including cell adhesion molecules (CAMs) and cyclooxygenase (COX)-1 and -2. These functionally caused an increase in monocyte adhesion to fibroblast monolayer. Using pharmacological intervention and BKR siRNA knockdown, we demonstrated that the BK-induced CXCL chemokine release, cell proliferation and COX and CAM expressions were mainly through the B2 receptor (B2R). Accordingly, the B2R was preferentially expressed in the NMDFs than B1R. The B2R was highly expressed in the CRSsNP than the control specimens, while the B1R and kininogen (KNG)/BK expression slightly increased in the CRSsNP mucosa. Collectively, we report here for the first time that fibroblasts, KNG/BK, and BKRs are overexpressed in CRSsNP mucosa and BK upregulates chemokine expression, proliferation, and proinflammatory molecule expression in NMDFs via B2R activation, which lead to a functional increase in monocyte-fibroblast interaction. Our findings reveal a critical role of fibroblast, KNG/BK, and BKRs in the development of CRSsNP.
Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers.
Tomassen Peter,Vandeplas Griet,Van Zele Thibaut,Cardell Lars-Olaf,Arebro Julia,Olze Heidi,Förster-Ruhrmann Ulrike,Kowalski Marek L,Olszewska-Ziąber Agnieszka,Holtappels Gabriele,De Ruyck Natalie,Wang Xiangdong,Van Drunen Cornelis,Mullol Joaquim,Hellings Peter,Hox Valerie,Toskala Elina,Scadding Glenis,Lund Valerie,Zhang Luo,Fokkens Wytske,Bachert Claus
The Journal of allergy and clinical immunology
BACKGROUND:Current phenotyping of chronic rhinosinusitis (CRS) into chronic rhinosinusitis with nasal polyps (CRSwNP) and chronic rhinosinusitis without nasal polyps (CRSsNP) might not adequately reflect the pathophysiologic diversity within patients with CRS. OBJECTIVE:We sought to identify inflammatory endotypes of CRS. Therefore we aimed to cluster patients with CRS based solely on immune markers in a phenotype-free approach. Secondarily, we aimed to match clusters to phenotypes. METHODS:In this multicenter case-control study patients with CRS and control subjects underwent surgery, and tissue was analyzed for IL-5, IFN-γ, IL-17A, TNF-α, IL-22, IL-1β, IL-6, IL-8, eosinophilic cationic protein, myeloperoxidase, TGF-β1, IgE, Staphylococcus aureus enterotoxin-specific IgE, and albumin. We used partition-based clustering. RESULTS:Clustering of 173 cases resulted in 10 clusters, of which 4 clusters with low or undetectable IL-5, eosinophilic cationic protein, IgE, and albumin concentrations, and 6 clusters with high concentrations of those markers. The group of IL-5-negative clusters, 3 clusters clinically resembled a predominant chronic rhinosinusitis without nasal polyps (CRSsNP) phenotype without increased asthma prevalence, and 1 cluster had a TH17 profile and had mixed CRSsNP/CRSwNP. The IL-5-positive clusters were divided into a group with moderate IL-5 concentrations, a mixed CRSsNP/CRSwNP and increased asthma phenotype, and a group with high IL-5 levels, an almost exclusive nasal polyp phenotype with strongly increased asthma prevalence. In the latter group, 2 clusters demonstrated the highest concentrations of IgE and asthma prevalence, with all samples expressing Staphylococcus aureus enterotoxin-specific IgE. CONCLUSION:Distinct CRS clusters with diverse inflammatory mechanisms largely correlated with phenotypes and further differentiated them and provided a more accurate description of the inflammatory mechanisms involved than phenotype information only.
HMGB1-TLR4 signaling contributes to the secretion of interleukin 6 and interleukin 8 by nasal epithelial cells.
Shimizu Shino,Kouzaki Hideaki,Kato Tomohisa,Tojima Ichiro,Shimizu Takeshi
American journal of rhinology & allergy
BACKGROUND:Alarmins play important roles in the pathogenesis of inflammatory and autoimmune diseases. However, the role of the alarmin protein high-mobility group box 1 (HMGB1) in upper airway inflammation is unclear. OBJECTIVE:To determine if HMGB1 is present in the nasal mucosa and, if so, to elucidate its role in upper airway inflammation. METHODS:Nasal secretions were collected from a total of 32 patients with chronic rhinosinusitis with nasal polyp, allergic rhinitis, and control subjects. The concentration of HMGB1 in nasal secretions and its tissue and cellular localization were examined by enzyme immunoassays and immunofluorescent staining of nasal polyps and cultured nasal epithelial cells. We then examined whether nasal epithelial cells secrete HMGB1 after inflammatory stimulation by tumor necrosis factor (TNF) α. The effects of HMGB1 on the production and secretion of interleukin (IL) 6 and IL-8 were also examined in cultured nasal epithelial cells. RESULTS:Significantly higher concentrations of HMGB1 were found in nasal secretions from patients with chronic rhinosinusitis with nasal polyp or allergic rhinitis compared with the control subjects. HMGB1 expression was localized in the nuclei of epithelial cells and other constitutive cells in nasal polyps and in the nuclei of cultured nasal epithelial cells. TNF-α stimulated the production and secretion of HMGB1 by cultured nasal epithelial cells. HMGB1 stimulated the production and secretion of IL-6 and IL-8 by cultured nasal epithelial cells, and anti-toll-like receptor 4 blocking antibody significantly inhibited HMGB1-induced secretion of IL-6 and IL-8. CONCLUSIONS:Nasal secretions contain substantial amounts of HMGB1. TNF-α stimulates the production of HMGB1, which, in turn, upregulates the production and secretion of IL-6 and IL-8 by nasal epithelial cells via toll-like receptor 4, which indicated that HMGB1 plays an important role in the pathogenesis of upper airway inflammation.
Thromboxane A2 Regulates CXCL1 and CXCL8 Chemokine Expression in the Nasal Mucosa-Derived Fibroblasts of Chronic Rhinosinusitis Patients.
Tsai Yih-Jeng,Hao Sheng-Po,Chen Chih-Li,Wu Wen-Bin
BACKGROUND:Chronic rhinosinusitis without nasal polyps (CRSsNP) is a common chronic disease and the etiology remains unclear. Thromboxane A2 (TXA2) participates in platelet aggregation and tissue inflammation. In this study, the CXCL1/8 chemokine and TXA2-TP receptor expression in the CRSsNP mucosa was investigated. EXPERIMENTAL APPROACH:Immunohistochemistry, chemokine release assay by ELISA, RT-PCR, Real-time PCR, Western blotting, pharmacological and siRNA knockdown analysis were applied in the CRSsNP tissue specimen and cultured nasal mucosa-derived fibroblasts. RESULTS:The immunohistochemistry results indicated that CXCL1 and CXCL8 were highly expressed in the CRSsNP mucosa compared with the controls; however, the TP receptors were expressed in both mucosa. Therefore, U46619 and IBOP, a TXA2 analog and TP agonist, were used to explore the role of TP activation in CXCL1/8 expression; both of these induced CXCL1/8 mRNA and protein expression in CRSsNP mucosa-derived fibroblasts. U46619 phosphorylated PI-3K, cyclic AMP (cAMP)/PKA, PKC, and cAMP response element (CREB). Activation of cAMP/PKA, PKC, and CREB was the major pathway for cxcl1/8 gene transcription. Pharmacological and siRNA knockdown analyses revealed that activation of cAMP/PKA and PKCμ/PKD pathways were required for CREB phosphorylation and PKA/C crosstalked with the PI-3K pathway. CONCLUSION AND IMPLICATIONS:Our study provides the first evidence for abundant TP receptor and CXCL1/8 expression in human CRSsNP mucosa and for TXA2 stimulation inducing CXCL1/8 expression in nasal fibroblasts primarily through TP receptor, cAMP/PKA, PKCμ/PKD, and CREB-related pathways.
Diversity of T cytokine profiles in patients with chronic rhinosinusitis: A multicenter study in Europe, Asia, and Oceania.
Wang Xiangdong,Zhang Nan,Bo Mingyu,Holtappels Gabriele,Zheng Ming,Lou Hongfei,Wang Hong,Zhang Luo,Bachert Claus
The Journal of allergy and clinical immunology
BACKGROUND:To date, no study has evaluated the diversity of T cell cytokine patterns of patients with chronic rhinosinusitis (CRS) among centers in different continents using identical methods. OBJECTIVE:We sought to assess T cytokine profiles in patients with CRS from Europe, Asia, and Australia. METHODS:Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP; n = 435) and control subjects (n = 138) were recruited from centers in Adelaide, Benelux, Berlin, Beijing, Chengdu, and Tochigi. Nasal mucosal concentrations of T2, T17, and T1 cytokines; eosinophilic cationic protein (ECP); myeloperoxidase (MPO); IL-8; and tissue total and Staphylococcus aureus enterotoxin (SE)-specific IgE were measured by using identical tools. RESULTS:Combinations of T1/T2/T17 cytokine profiles in patients with CRSwNP varied considerably between regions. CRSwNP tissues from patients from Benelux, Berlin, Adelaide, and Tochigi were T2 biased, whereas those from Beijing mainly demonstrated T2/T1/T17 mixed patterns, and patients from Chengdu showed an even lower T2 expression. Concentrations of IL-8 and tissue total IgE in patients with CRSwNP were significantly higher than those in control subjects in all regions. More than 50% of patients with CRSwNP in Benelux, Berlin, Adelaide, and Tochigi showed a predominantly eosinophilic endotype compared with less than 30% of patients in Beijing and Chengdu. SE-specific IgE was found in significantly greater numbers in patients with CRSwNP from Benelux, Adelaide, and Tochigi and significantly lower numbers in patients from Beijing and Chengdu. Moreover, the T1/T2/T17 cytokine profiles in patients with CRSsNP showed diversity among the 6 regions. CONCLUSION:T cytokine levels, eosinophilic/neutrophilic patterns, and SE-specific IgE expressions show extreme diversity among patients with CRS from Europe, Asia, and Oceania.
ROS-dependent HMGB1 secretion upregulates IL-8 in upper airway epithelial cells under hypoxic condition.
Min H J,Kim J-H,Yoo J E,Oh J-H,Kim K S,Yoon J-H,Kim C-H
High-mobility group box 1 (HMGB1) mediates various functions according to the location. We tried to investigate the role of HMGB1 in upper airway under hypoxic conditions. We cultured primary normal human nasal epithelium (NHNE) cells under hypoxic conditions and evaluated the movement of HMGB1 by western blotting, immunofluorescence, and enzyme-linked immunosorbent assay (ELISA). Reactive oxygen species (ROS) level was evaluated to estimate the translocation mechanism of HMGB1. The role of secreted HMGB1 was evaluated by ELISA assay. Furthermore, we collected human nasal mucosa samples and nasal lavage fluids from patients conditioned under hypoxic and non-hypoxic environment, and compared the expression of HMGB1 in human nasal mucosa samples by immunohistochemistry and the levels of HMGB1 in lavage fluids using ELISA assay. Hypoxia induced translocation of HMGB1 into the extracellular area and it was dependent on ROS produced by dual oxidase 2. Secreted HMGB1 was involved in the upregulation of interleukin (IL)-8. In human samples, HMGB1 was translocated from nucleus to the cytoplasm in hypoxic-conditioned nasal mucosa. HMGB1 was increased in nasal lavage samples of chronic rhinosinusitis patients, whose sinus mucosa was supposed to be hypoxic as compared with controls. We suggest that HMGB1 is secreted in hypoxic condition via ROS-dependent mechanism and secreted HMGB1 participates in IL-8 upregulation mediating inflammatory response.
The Role of Macrolides in Chronic Rhinosinusitis (CRSsNP and CRSwNP).
Oakley Gretchen M,Harvey Richard J,Lund Valerie J
Current allergy and asthma reports
PURPOSE OF REVIEW:We assess the literature on the pharmacokinetics, indications, important considerations, and effectiveness of long-term, low-dose macrolide antibiotics in chronic rhinosinusitis (CRS). RECENT FINDINGS:The key to effective implementation of macrolide therapy in CRS is appropriate patient selection. Macrolides have demonstrated the most benefit in Th1-mediated non-eosinophilic CRS when used for durations of at least 3 months. Macrolide antibiotics have demonstrated great benefit when used for their anti-inflammatory or immunomodulatory properties, which include the blockage of pro-inflammatory cytokines, such as interleukin (IL)-8 and tumor necrosis factor-α (TNF-α). They have been used in CRS patients not responding to traditional corticosteroid-based treatment regimens, but appear to be most effective specifically in Th1-mediated non-eosinophilic CRS in long durations and low doses. Further research is needed to better identify characteristics known to correlate with macrolide response so early directed therapy can be implemented.
Multidimensional endotypes of chronic rhinosinusitis and their association with treatment outcomes.
Liao B,Liu J-X,Li Z-Y,Zhen Z,Cao P-P,Yao Y,Long X-B,Wang H,Wang Y,Schleimer R,Liu Z
BACKGROUND:The expression of chronic rhinosinusitis (CRS) is multidimensional. Disease heterogeneity in patients with CRS remains poorly understood. This study aimed to identify endotypes of CRS using cluster analysis by integrating multidimensional characteristics and to explore their association with treatment outcomes. METHODS:A total of 28 clinical variables and 39 mucosal cellular and molecular variables were analyzed using principal component analysis. Cluster analysis was performed on 246 prospectively recruited Chinese CRS patients with at least 1-year postoperative follow-up. Difficult-to-treat CRS was characterized in each generated cluster. RESULTS:Seven subject clusters were identified. Cluster 1 (13.01%) was comparable to the classic well-defined eosinophilic CRS with polyps, having severe disease and the highest proportion of difficult-to-treat CRS. Patients in cluster 2 (16.26%) and cluster 4 (13.82%) had relatively lower proportions of presence of polyps and presented mild inflammation with moderate proportions of difficult-to-treat cases. Subjects in cluster 2 were highly atopic. Cluster 3 (7.31%) and cluster 6 (21.14%) were characterized by severe or moderate neutrophilic inflammation, respectively, and with elevated levels of IL-8 and high proportions of difficult-to-treat CRS. Cluster 5 (4.07%) was a unique group characterized by the highest levels of IL-10 and lacked difficult-to-treat cases. Cluster 7 (24.39%) demonstrated the lowest symptom severity, a low proportion of difficult-to-treat CRS, and low inflammation load. Finally, we found that difficult-to-treat CRS was associated with distinct clinical features and biomarkers in the different clusters. CONCLUSIONS:Distinct clinicopathobiologic clusters of CRS display differences in clinical response to treatments and characteristics of difficult-to-treat CRS.
[Mechanisms underlying glucocorticoid resistance in chronic rhinosinusitis with nasal polyps].
Zhang Y Y,Lou H F,Wang C S,Zhang L
Zhonghua er bi yan hou tou jing wai ke za zhi = Chinese journal of otorhinolaryngology head and neck surgery
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory disease that occurs in the nasal and sinus mucosa, which is a common disease in otorhinolaryngology. At present, CRSwNP can be effectively treated by glucocorticoids (GC). GC binds to GC receptors in the nasal mucosa, affects the expression of inflammatory genes, inhibits the activation and action of eosinophils, T cell-associated inflammatory responses in nasal polyps, as well as tissue remodeling. However, there are some patients fall reponse to GC, so called GC resistance. The study suggests that the possible mechanism of CRSwNP GC resistance is mainly related to GC receptor abnormal, the role of cytokines and transcription factors, such as Th cells and IL-8. In addition, MAPK-related kinases and histone deacetylase in the GC signaling pathway also play important roles in the GC resistance process. This paper reviews the mechanism of GC treatment of CRSwNP, the mechanism of GC resistance and alternative treatment of GC.
FcγRIII stimulation breaks the tolerance of human nasal epithelial cells to bacteria through cross-talk with TLR4.
The nasal cavity displays immune tolerance to commensal bacteria under homeostatic conditions, which is rapidly converted to a pro-inflammatory response upon infection. Yet, the factors that control this conversion are still largely unknown. Here, we provide evidence that Fc gamma receptor III (FcγRIII) stimulation breaks immune tolerance to bacteria in the human nasal cavity through activation of nasal epithelial cells, which are the first line of defense against invading microbes. While under steady-state conditions human nasal epithelial cells were completely non-responsive to Gram-negative bacteria P. aeruginosa or TLR4 ligand LPS, IgG opsonization of bacteria, as occurs upon infection, strongly induced production of pro-inflammatory agents such as IL-6 and IL-8. This breaking of tolerance to bacteria was completely dependent on FcγRIII, which amplified cytokine gene transcription through cross-talk with TLR4. In addition, we identified that epithelial cells from patients suffering from chronic rhinosinusitis with nasal polyps do not display LPS tolerance, thereby providing an explanation for the disturbed host defense responses of these patients. Taken together, these data are the first to identify FcγR expression on nasal epithelial cells, as well as to identify its important role in controlling the balance between tolerance and inflammation in the nasal cavity.
Chronic Rhinosinusitis without Nasal Polyps in Asian Patients Shows Mixed Inflammatory Patterns and Neutrophil-Related Disease Severity.
Kim Dae Woo,Eun Kyoung Mi,Roh Eun Youn,Shin Sue,Kim Dong-Kyu
Mediators of inflammation
Chronic rhinosinusitis (CRS) shows heterogeneous immunologic features. Western studies revealed that CRS without nasal polyps (CRSsNP) showed a predominantly type 1 immune response and CRS with nasal polyps (CRSwNP) was characterized by type 2 immune response; however, the detailed immunologic profile of CRSsNP in Asian patients has not been thoroughly investigated. Therefore, we investigated the inflammatory endotypes of CRSsNP in Asian patients. Patients with CRSsNP ( = 57), patients with CRSwNP ( = 13), and a control group ( = 10), who underwent endoscopic sinus surgery, were enrolled; uncinate process (UP) tissues were harvested from all patients. Homogenates were prepared from the UP of each group, and immunologic profiles were analyzed, including major cytokines (32 inflammatory mediators). When comparing the UPs between groups, CRSsNP patients showed higher levels of Th2 cytokines (IL-4 and IL-13), eosinophilic chemokines (CCL-11 and CCL-24), ECP, and total IgE expression than control subjects. In addition, several neutrophilic markers (IL-1, IL-6, IL-8, CXCL-1, CXCL-2, and MPO), IL-17A, IL-22, and TNF- were dominant in CRSsNP patients. Among these inflammatory mediators, IL-17A showed higher expression levels in CRSsNP patients than in the control group and CRSwNP patients. However, IFN- expression was not significantly elevated in CRSsNP patients. The levels of neutrophil-associated cytokines were well correlated with each other; of which, CXCL2, IL-8, and MMP-9/TIMP-1 levels were significantly correlated with disease extent ( = 0.338, = 0.317, and = 0.424, respectively). However, the levels of eosinophil-associated cytokines showed little correlation with each other and were not correlated with disease extent. Our study revealed that Asian CRSsNP patients showed a mixed (types 2 and 17) immune response, but neutrophil-related markers were dominant and associated with disease extent. Knowledge of this immunologic feature may help clinicians make better individual treatment decisions for Asian CRSsNP patients.
Desmoglein 3 Silencing Inhibits Inflammation and Goblet Cell Mucin Secretion in a Mouse Model of Chronic Rhinosinusitis via Disruption of the Wnt/β-Catenin Signaling Pathway.
Cheng Jinzhang,Yang Jingpu,Xue Kai,Zhao Yin,Zhao Chang,Li Song,Wang Zonggui
Chronic rhinosinusitis (CRS) is a common disease characterized by inflammation of the nose and paranasal sinuses lasting over 12 weeks. This study aims to evaluate the effect of desmoglein 3 (DSG3) on inflammatory response and goblet cell mucin secretion in a mouse model of CRS. The CRS-related differentially expressed genes and disease genes were screened using microarray-based gene expression analysis. Subsequently, CRS mouse models were established. The levels of pro-inflammatory factors TNF-α, IL-6, and IL-8 were measured by ELISA. In addition, loss-of-function experiment was conducted using siRNAs targeting DSG3 and β-catenin. The secretion of mucins MUC5B and MUC5AC in goblet cells was detected, and the apoptosis of goblet cells was assessed. The regulatory effect of DSG3 on the Wnt/β-catenin signaling pathway was analyzed by determining the mRNA and protein levels of DSG3, Wnt, β-catenin, and GSK3β. DSG3 was identified to be an upregulated gene in CRS, which was further documented in CRS mice models. Elevated inflammation and mucin production were noted in CRS mice models. Also, it was found that DSG3 or β-catenin silencing could decrease the levels of TNF-α, IL-6, and IL-8, and the positive rates of MUC5B and MUC5AC while enhancing goblet cell apoptosis. The Wnt/β-catenin signaling pathway was blocked by DSG3, evidenced by downregulated Wnt and β-catenin as well as upregulated GSK3β mRNA and protein levels. Overall, this study provides evidence that silencing DSG3 could inhibit the activation of the Wnt/β-catenin signaling pathway, thus alleviating CRS.
Hypomethylation of the IL8 promoter in nasal epithelial cells of patients with chronic rhinosinusitis with nasal polyps.
Li Jingyun,Jiao Jian,Wang Ming,Gao Yunbo,Li Ying,Wang Yang,Zhang Yuan,Wang Xiangdong,Zhang Luo
The Journal of allergy and clinical immunology
BACKGROUND:IL-8 is an important chemokine implicated in the pathogenesis of chronic rhinosinusitis (CRS), but little is known about epigenetic regulation of IL8 in the pathogenesis of CRS. OBJECTIVE:We sought to investigate the relationship between the DNA methylation level in the IL8 proximal promoter and CRS in Han Chinese subjects. METHODS:Patients with chronic rhinosinusitis with nasal polyps (CRSwNP; n = 187), patients with chronic rhinosinusitis without nasal polyps (CRSsNP; n = 89), and control subjects (n = 57) were enrolled in 2 independent cohorts. Purified human nasal epithelial cells from each participant were assessed for percentage DNA methylation of CpG sites in the IL8 proximal promoter by using bisulfite pyrosequencing and for functional aspects of methylation status by using in vitro assays. RESULTS:DNA methylation of CpG sites 1, 2, and 3, respectively, in the IL8 proximal promoter was significantly decreased in human nasal epithelial cells of patients with CRSwNP compared with that in patients with CRSsNP (P < .001) and control subjects (P < .001). Percentage of DNA methylation of the CpG3 site was correlated negatively with both tissue eosinophilic cationic protein (P < .01) and myeloperoxidase (P < .05) levels. IL-1β (P < .001) and TNF-α (P < .01) significantly increased IL8 expression accompanied by a reduction in methylation at the CpG3 site (P < .001). Electrophoretic mobility shift assays demonstrated that methylation status of CpG3 changed the binding of octamer-binding transcription factor 1 and nuclear factor κB. CONCLUSION:Decreased DNA methylation of particularly CpG sites in the IL8 proximal promoter might play a role in the pathogenesis of CRSwNP.
The Role of NF-κB in Chronic Rhinosinusitis With Nasal Polyps.
Jung Hahn Jin,Zhang Yu Lian,Kim Dong Kyu,Rhee Chae Seo,Kim Dong Young
Allergy, asthma & immunology research
PURPOSE:Whereas the majority of nasal polyps observed in Western populations are eosinophilic, non-eosinophilic nasal polyps are significantly more frequent in Asian countries. Given the importance of nuclear factor-kappa B (NF-κB) in inflammation, this study focused on the role of NF-κB in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNPs) in Asian patients. METHODS:A total of 46 patients were enrolled in this study (22 diagnosed with CRSwNPs, 10 with chronic rhinosinusitis without nasal polyps [CRSsNP], and 14 control subjects). Nasal polyps and uncinate tissues (UTs) were collected and the tissues prepared for hematoxylin-eosin staining and immunohistochemistric (IHC) analysis. Total RNA was isolated for real-time polymerase chain reaction for p65, interleukin (IL)-6, IL-8, intracellular adhesion molecule (ICAM)-1, IL-1β, tumor necrosis factor (TNF)-α, and eotaxin. RESULTS:In the CRSwNPs group, 50% of nasal polyps were non-eosinophilic. IHC revealed a significantly higher fraction of NF-κB p65-positive cells in nasal polyps of the CRSwNPs group than in the UTs of control and CRSsNP groups. No difference in NF-κB p65-positive cell fraction was observed between eosinophilic and non-eosinophilic nasal polyps. The mRNA expression of p65, IL-6, IL-8, and eotaxin was significantly higher in nasal polyps of the CRSwNPs than in the UTs of control and CRSsNP group. However, no difference in expression was observed between eosinophilic and non-eosinophilic nasal polyps, with the exception of IL-1β expression. CONCLUSIONS:Elevated expression of NF-κB- and NF-κB-associated inflammatory cytokines suggests NF-κB as the key factor for CRSwNPs pathogenesis in Asian patients. Understanding NF-κB-associated mechanisms will provide a deeper insight into CRSwNPs pathogenesis and ultimately improve therapeutic strategies for CRSwNPs.
Predictive markers of long-term recurrence in chronic rhinosinusitis with nasal polyps.
Rosati Davide,Rosato Chiara,Pagliuca Giulio,Cerbelli Bruna,Della Rocca Carlo,Di Cristofano Claudio,Martellucci Salvatore,Gallo Andrea
American journal of otolaryngology
BACKGROUND:In last years, many attempts were made to recognize chronic rhinosinusitis with nasal polyps (CRSwNP) phenotypes focusing on identifying relevant key pathogenic molecules. Polyps recurrence rate ranges from 4% to 60%, so it's clear that not all clinical and immunologic factors associated with recurrence are known. OBJECTIVE:We investigate the inflammatory profile in patients with long term recurrent and non-recurrent CRSwNPs and if a specific profile is associated with recurrence, comparing eosinophilic, neutrophilic and lymphocytic infiltration, as well as IL-5 and IL-8 expression to long term recurrence rate. METHODS:This prospective study included 44 adult patients with CRSwNP treated with endoscopic sinus surgery between 2008 and 2010. Long term follow-up data (8-10 years) indicated that among 44 patients, 18 (40.1%) experienced long term recurrence of nasal polyposis needing maximal medical treatment or revision surgery. We realized two groups: one with patients who didn't present long term recurrence (26 patients) and another with patients who presented long term recurrence (18 patients) and in both groups eosinophilic, neutrophilic and lymphocytic infiltration and IL-5 and IL-8 expression were measured. RESULTS:The parameters that reached statistical significance (p < 0.05) comparing the two groups were eosinophilic infiltration and IL-5 expression, whereas neutrophilic and lymphocytic infiltration, as IL-8 expression didn't show any significant difference. Asthma and aspirin intolerance seemed significantly more frequent in patients with recurrence, while allergy presented not statistically significant difference between two groups. CONCLUSIONS:We can conclude that high eosinophilic infiltration and high IL-5 expression in CRSwNP correlate with higher rate of long term recurrence, while neutrophilic and lymphocytic infiltration, and IL-8 expression don't correlate with it. These findings provide the opportunity to improve our ability to predict the prognosis of surgical intervention, although it is still needed to explore the optimal predictor of outcome in CRSwNP.
Nasal fluid cytology and cytokine profiles of eosinophilic and non-eosinophilic chronic rhinosinusitis with nasal polyps.
Zhu Z,Wang W,Zhang X,Wang X,Zha Y,Chen Y,Zhou L,Lv W
BACKGROUND:Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous disease with different clinical characteristics and different treatment responsiveness. The aims of this study were to compare the nasal fluid cytology and cytokines between eosinophilic CRSwNP (eCRSwNP) and non-eosinophilic CRSwNP (neCRSwNP) and establish a new multivariate model to predict eCRSwNP before surgery to improve personalized treatment for CRSwNP patients. METHODS:Eighty-six consecutive patients with CRSwNP and sixteen healthy controls were recruited in this study. Nasal fluid (NF) was collected from all subjects and nasal polyp tissue was collected during the surgery. The differential cell counts and concentrations of IL-6, IL-8, TNF-77; and IL-10 in NF were measured. Univariate and multivariate logistic regression were used to identify predictors for eCRSwNP. RESULTS:There were more inflammatory cells in NF of CRSwNP than controls. The eosinophil percentage was significantly higher in eCRSwNP than neCRSwNP and controls. The level of IL-8 was significantly higher in neCRSwNP than in eCRSwNP and controls. Blood eosinophilia, nasal fluid eosinophilia, higher total ethmoid score / total maxillary score (E/M ratio) and higher visual analogue scale (VAS) score of CRS were associated with eCRSwNP, the area under receiver operating characteristic curve (AUC) was 0.800, 0.755, 0.703 and 0.648, respectively. Using the coefficients of multivariate regression, we set up a scoring system to predict eCRSwNP with three of the variates and the AUC was 0.883. CONCLUSION:ECRSwNP, neCRSwNP and healthy controls demonstrated different cytology and cytokine profiles in NF. A new preoperational multivariate prediction model for eCRSwNP with NF eosinophilia, blood eosinophilia and higher E/M ratio was established.
Azithromycin and ciprofloxacin inhibit interleukin-8 secretion without disrupting human sinonasal epithelial integrity in vitro.
Lim Dong-Jin,Thompson Harrison M,Walz Christopher R,Ayinala Samrath,Skinner Daniel,Zhang Shaoyan,Grayson Jessica W,Cho Do-Yeon,Woodworth Bradford A
International forum of allergy & rhinology
BACKGROUND:We recently developed a ciprofloxacin and azithromycin sinus stent (CASS) to target recalcitrant infections in chronic rhinosinusitis (CRS). The objective of this study was to evaluate the anti-inflammatory activity of azithromycin released from the CASS and assess the impact on the integrity and function of primary human sinonasal epithelial cells (HSNECs). METHODS:Pseudomonas aeruginosa lipopolysaccharide (LPS)-stimulated HSNECs were treated with azithromycin and/or ciprofloxacin at concentrations attainable from CASS release. Interleukin-8 (IL-8) secretion was quantified by enzyme-linked immunosorbent assay (ELISA). Epithelial integrity (transepithelial resistance [TEER], paracellular permeability [fluorescein isothiocyanate-labeled dextran], lactate dehydrogenase [LDH] assays) and function (ciliary beat frequency [CBF]) were also evaluated. RESULTS:Azithromycin significantly reduced secreted IL-8 from P. aeruginosa LPS-stimulated HSNECs at all concentrations tested (mean ± standard deviation; control = 5.77 ± 0.39 ng/mL, azithromycin [6 μg/mL] = 4.58 ± 0.40 ng/mL, azithromycin [60 µg/mL] = 4.31 ± 0.06, azithromycin [180 µg/mL] = 4.27 ± 0.26 ng/mL, p < 0.05). Co-incubation with azithromycin (6 µg/mL) and ciprofloxacin (2.4 µg/mL) in LPS-stimulated HSNECs also displayed a significant reduction in secreted IL-8 when compared to P. aeruginosa LPS alone (co-treatment = 4.61 ± 0.29 ng/mL, P. aeruginosa LPS = 7.35 ± 0.89 ng/mL, p < 0.01). The drugs did not negatively impact TEER, paracellular permeability, LDH release, or CBF, indicating retention of cell integrity and function. CONCLUSION:Azithromycin decreased P. aeruginosa LPS IL-8 production in HSNECs at drug concentrations attainable with sustained release of azithromycin from the CASS. In addition to antibacterial activity, anti-inflammatory properties of the CASS should provide further benefit for patients with recalcitrant CRS.
The Role of Epigenetics in the Chronic Sinusitis with Nasal Polyp.
Liu Tiancong,Sun Yang,Bai Weiliang
Current allergy and asthma reports
PURPOSE OF REVIEW:Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common and heterogeneous inflammatory disease. The underlying epigenetic mechanisms and treatment of CRSwNP are partially understood. Of the different epigenetic changes in CRSwNP, histone deacetylases (HDACs), methylation of DNA, and the levels of miRNA are widely studied. Here, we review the human studies of epigenetic mechanisms in CRSwNP. RECENT FINDINGS:The promoters of COL18A1, PTGES, PLAT, and TSLP genes are hypermethylated in CRSwNP compared with those of controls, while the promoters of PGDS, ALOX5AP, LTB4R, IL-8, and FZD5 genes are hypomethylated in CRSwNP. Promoter hypermethylation suppresses the gene expression, while promoter hypomethylation increases the gene expression. Studies have shown the elevation in the levels of HDAC2, HDAC4, and H3K4me3 in CRSwNP. In CRSwNP patients, there is also an upregulation of certain miRNAs including miR-125b, miR-155, miR-19a, miR-142-3p, and miR-21 and downregulation of miR-4492. Epigenetics takes part in the immunology of CRSwNP and may give rise to endotypes of CRSwNP. Both HDAC2 and the miRNA including miR-18a, miR-124a, and miR-142-3p may take function in the regulation of glucocorticoid resistance. HDAC inhibitors and KDM2B have shown effectiveness in decreasing nasal polyp, and DNA methyltransferase (DNMT) or HDAC inhibitors may have a potential efficacy for the treatment of CRSwNP. Recent advances in the epigenetics of CRSwNP have led to the identification of several potential therapeutic targets for this disease. The use of epigenetics may provide novel and effective biomarkers and therapies for the treatment of nasal polyp.