Article

Neurohormonal markers in chronic rhinosinusitis

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Abstract

Chronic rhinosinusitis (CRS), especially with nasal polyps, continues to elude precise pathogenesis and effective treatment. Prior work in our laboratory demonstrated interleukin-33 (IL-33) and Substance P (SP) activation of mast cells, and inhibitory effect of interleukin-37 (IL-37). Our objective is to study the expression of these neurohormonal mediators in mast cell stimulation of nasal polyposis. This was a prospective research study involving collection of nasal lavage fluid and nasal polyp tissue from adult patients with CRS. The study was divided into two arms. First, nasal lavage fluid was collected from normal controls, and patients with allergic rhinitis, CRS, or CRS with nasal polyposis. The second arm was collection of nasal tissue from normal controls undergoing inferior turbinoplasty, or patients with nasal polyposis. Enzyme-linked immunosorbent assay and quantitative polymerase chain reaction techniques were used to determine levels in the lavage fluid and relative gene expression in the tissue of SP, IL-33, and IL-37. In total, 70 lavage and 23 tissue specimens were obtained. The level of SP was highest in patients with polyps; however, gene expression was reduced compared to normal controls. The level of IL-33 was reduced in patients with polyps as compared to patients with allergy and sinusitis, and its gene expression was not significantly different from normal controls. IL-37 was elevated in the lavage fluid of patients with nasal polyps and its gene expression was increased in the polyp tissue. Levels of SP and IL-37 were elevated in the lavage fluid of patients with nasal polyps as compared to normal controls and other sinonasal pathologies, and gene expression of IL-37 was significantly increased in the polyp tissue itself. These findings implicate these neurohormonal molecules in the pathophysiology of nasal polyposis and provide possible novel therapeutic targets.

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... [3][4][5] On the other hand, Clara cell protein 16 (CC16), which is produced by specialized secretory Clara cells, situated within the respiratory epithelium, has a strong anti-inflammatory effect and participates in the repair process of the nasal mucosa. 1,6 Neurogenic inflammation of the nasal mucosa is mediated by the release of neuropeptides, especially substance P, at the endings of sensory nerve fibers, and, apart from allergic and nonallergic rhinitis, it also plays a role in the pathogenesis of NP. 7,8 Within the NP, we distinguish a special clinical phenotype in which CRSwNP is associated with hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) and nonallergic asthma. This aspirin-exacerbated respiratory disease (AERD) is characterized by a particularly severe clinical feature with rapid disease progression and frequent relapses relatively soon after endoscopic surgical treatment. ...
... The intensity of eosinophilic activity can be monitored by measuring the concentration of ECP, while the activity of mast cells is best monitored by determining the concentration of tryptase in nasal secretions. 18,19 Neurogenic inflammation plays an important role in the pathogenesis of allergic and nonallergic chronic rhinitis, although some data suggest a role in the pathogenesis of NP. 7,8,[20][21][22] Monitoring the concentration of substance P in nasal secretions could help us with that. The course of inflammation mediated by proinflammatory mediators in the mucosa of the upper respiratory tract is somewhat limited by the activity of anti-inflammatory mediators, and one of the most important is CC16. ...
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Background: The aim of this cross-sectional study was to compare the levels of inflammatory mediators in nasal secretions in patients with aspirin-exacerbated respiratory disease (AERD) and in those with nasal polyposis (NP) without aspirin-sensitivity and to correlate nasal fluid mediator concentrations with clinical parameters of the disease. Methods: A total of 30 patients with AERD, 30 chronic rhinosinusitis (CRS) with NP patients without aspirin sensitivity (CRSwNP), and 30 control subjects without inflammation of the nasal mucosa (C), selected for surgical treatment entered the study. The total nasal symptom score (TNSS), endoscopic score (ES), and Lund-Mackay score (LMS), were evaluated. The concentrations of eosinophil cationic protein (ECP), tryptase, heat shock protein 70 (HSP70), substance P and Clara cell protein 16 (CC16) were determined in nasal secretions. Results: Higher concentrations of ECP, tryptase, and HSP70 were measured in the AERD patients than in the CRSwNP patients and the C group (p < .001; p < .001, respectively for all mediators). However, levels of CC16 were higher in the C group than in the AERD and CRSwNP groups (p < .001; p < .001, respectively). A positive correlation between the TNSS and CC16 and a negative one between CC16 and tryptase levels were found in the C group. The CRSwNP group showed positive correlations between ECP, HSP70, and tryptase and negative correlations between substance P, ES, and LMS, as well as between CC16 and tryptase levels. In the AERD group, we found a positive correlation between HSP70 and ECP levels and a negative correlation between the TNSS and CC16 concentration. Conclusion: The obtained results indicate the increased production of mediators of eosinophil and mast cell function, and the decreased production of biomarker of respiratory epithelial function in AERD patients. Clinical and biochemical parameters correlate in different ways in the AERD and CRSwNP patients.
... The reciprocal interactions between MCs and eosinophils have been well characterized, and their common activating factor, interleukin-5 (IL5), is released by both cell types [23]. Over the last decade, many studies have identified a list of other activating and inhibitory molecules and pathways for MCs in CRSwNP, and a summary of these factors is given in Table 1 [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40]. Indeed, the use of single-cell technologies (that is, the multi-omics analysis of the transcriptome, metabolome, proteome, . . ...
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Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common inflammatory disorder whose complex immunopathogenesis has yet to be fully elucidated. Endotype-2 CRSwNP is the most common form of disease where eosinophils are the main drivers of inflammation. Traditional treatments for CRSwNP have centered around intranasal or systemic corticosteroids and endoscopic sinus surgery (ESS). However, recent advancements in targeted therapies have introduced novel biological agents that specifically target key inflammatory mediators such as IL-4, IL-5, and IL-13. These biologics offer promising options for patients with CRSwNP, particularly those who do not respond adequately to conventional treatments. Nonetheless, some patients do not satisfactorily respond to these drugs because of an insufficient blockade of the inflammatory process. The mast cell (MC) is another important (and somehow neglected) actor in the pathogenesis of CRSwNP, and the latest clinical and translational evidence in this field has been reviewed in the present paper.
... It has long been known that MCs are activated by various substances, including IgE, which crosslinks the FceRI receptor; however, a variety of biological molecules cannot stimulate MCs to produce inflammatory substances [115]. Upon activation with various triggers [116][117][118], MCs immediately release proinflammatory mediators, such as tryptase and histamine. These compounds are released (in seconds), while subsequently (after several hours) MCs release proinflammatory cytokines (IL-1, IL-6, and IL-33), chemokines (CCL2, IL-8, and CXCL8), prostaglandin (PGD2), and leukotrienes (LTC4, LTD4, and LTE4) [119][120][121]. ...
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Much evidence suggests autoimmunity in the etiopathogenesis of periodontal disease. In fact, in periodontitis, there is antibody production against collagen, DNA, and IgG, as well as increased IgA expression, T cell dysfunction, high expression of class II MHC molecules on the surface of gingival epithelial cells in inflamed tissues, activation of NK cells, and the generation of antibodies against the azurophil granules of polymorphonuclear leukocytes. In general, direct activation of autoreactive immune cells and production of TNF can activate neutrophils to release pro-inflammatory enzymes with tissue damage in the gingiva. Gingival inflammation and, in the most serious cases, periodontitis, are mainly due to the dysbiosis of the commensal oral microbiota that triggers the immune system. This inflammatory pathological state can affect the periodontal ligament, bone, and the entire gingival tissue. Oral tolerance can be abrogated by some cytokines produced by epithelial cells and activated immune cells, including mast cells (MCs). Periodontal cells and inflammatory–immune cells, including mast cells (MCs), produce cytokines and chemokines, mediating local inflammation of the gingival, along with destruction of the periodontal ligament and alveolar bone. Immune-cell activation and recruitment can be induced by inflammatory cytokines, such as IL-1, TNF, IL-33, and bacterial products, including lipopolysaccharide (LPS). IL-1 and IL-33 are pleiotropic cytokines from members of the IL-1 family, which mediate inflammation of MCs and contribute to many key features of periodontitis and other inflammatory disorders. IL-33 activates several immune cells, including lymphocytes, Th2 cells, and MCs in both innate and acquired immunological diseases. The classic therapies for periodontitis include non-surgical periodontal treatment, surgery, antibiotics, anti-inflammatory drugs, and surgery, which have been only partially effective. Recently, a natural cytokine, IL-37, a member of the IL-1 family and a suppressor of IL-1b, has received considerable attention for the treatment of inflammatory diseases. In this article, we report that IL-37 may be an important and effective therapeutic cytokine that may inhibit periodontal inflammation. The purpose of this paper is to study the relationship between MCs, IL-1, IL-33, and IL-37 inhibition in acute and chronic inflamed gingival tissue.
... (Figure 2). High positive correlation between BK level in nasal secretions and Lund-Mackay CT score was found in both non-AERD and AERD patients ( The results of our study show higher concentrations of SP and BK in the nasal secretions of patients with NP, compared to subjects without nasal inflammation and these data are consistent with the results of a study by Compton et al. 28 Among patients with NP, those with sensitivity to aspirin have higher concentrations of these neuropeptides than those who are not sensitive to NSAIDs. These data suggest that patients with AERD have higher levels of neurogenic inflammation in the nasal mucosa/paranasal sinuses compared to patients who are not sensitive to aspirin. ...
Article
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Objective The role of neurogenic inflammation in pathogenesis of chronic rhinitis is well known. However, very little is known about its importance in pathogenesis of nasal polyposis (NP), especially in form of NP which appears as a part of aspirin‐exacerbated respiratory disease (AERD). The aim of this study was to examine the concentrations of neuropeptides substance P (SP) and bradykinin (BK) in nasal secretions of patients with NP. Methods Fourteen patients with NP as a part of AERD with mild persistent asthma, 14 patients with NP without aspirin sensitivity, and 14 control subjects without nasal inflammation (C) entered this cross‐sectional study. Clinical parameters (symptoms, endoscopic, and radiological findings) were assessed. The concentrations of SP and BK were measured in the nasal secretion samples using commercial human enzyme immunoassay kits. Results The concentration of SP in nasal secretions was significantly higher in NP patients without aspirin sensitivity and AERD patients compared to controls (p = .022; p < .0001, respectively), but higher in AERD than in non‐AERD patients (p = .018). The level of BK in nasal fluid was higher in non‐AERD and AERD NP patients than in controls (p < .0001; p < .0001, respectively), but also higher in AERD than in non‐AERD patients (p < .0001). We found high positive correlations between BK in nasal fluid and Lund–Mackay computed tomography (CT) score in both non‐AERD and AERD groups of NP patients. Conclusion Our results suggest more intense release of SP and BK from the nasal mucosa in patients with AERD than in patients with NP who do not have aspirin sensitivity. The strong correlation between concentration of BK in nasal secretions and CT score suggests that BK in nasal fluid could be used as a marker for disease severity as measured by the Lund–Mackay score.
... In addition to the inhibitory receptor, inhibitory cytokines, such as IL-37, may also function to suppress excessive activation of mast cells [88]. Thus, these natural inhibitors of immune responses could also be used as therapeutic agents. ...
Article
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Mucosal mast cells (MMCs) localized in the intestinal mucosa play a key role in the development of IgE-mediated food allergies. Recent advances have revealed that MMCs are a distinctly different population from connective tissue mast cells localized in skin and other connective tissues. MMCs are inducible and transient cells that arise from bone marrow-derived mast cell progenitors, and their numbers increase rapidly during mucosal allergic inflammation. However, the mechanism of the dramatic expansion of MMCs and their cell functions are not well understood. Here, we review recent findings on the mechanisms of MMC differentiation and expansion, and we discuss the potential for the inducers of differentiation and expansion to serve as targets for food allergy therapy. In addition, we also discuss the mechanism by which oral immunotherapy, a promising treatment for food allergy patients, induces unresponsiveness to food allergens and the roles of MMCs in this process. Research focusing on MMCs should provide useful information for understanding the underlying mechanisms of food allergies in order to further advance the treatment of food allergies.
... Furthermore, decreased proteoglycan loss in human OA cartilage with IL-37 via inhibition of MMP-3 expression and the protection of stem cells in an inflammatory osteoarthritis-like microenvironment for cartilage formation support IL-33 and IL-37 as potential therapeutics [20,[85][86][87]. IL-33 and IL-37 play a counteractive role in regulating inflammation involving the activation of mast cells in chronic rhinosinusitis with a differential expression in allergy and sinusitis compared to polyp, which further suggests IL-33 and IL-37 as novel therapeutic targets, and the findings of this study support this [88]. The therapeutic efficacy of IL-37 in attenuating inflammation by inhibiting the transcription of pro-inflammatory genes by blocking IL-1 receptors [89]. ...
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Chronic joint inflammation due to increased secretion of pro-inflammatory cytokines, the accumulation of inflammatory immune cells (mainly macrophages), and vitamin D deficiency leads to cartilage degeneration and the development of osteoarthritis (OA). This study investigated the effect of vitamin D status on the expression of mediators of inflammation including interleukin (IL)-33, IL-37, IL-6, tumor necrosis factor (TNF)-α, toll-like receptors (TLRs), damage-associated molecular patterns (DAMPs), and matrix metalloproteinases (MMPs) in degenerating the cartilage of hyperlipidemic microswine. Additionally, in vitro studies with normal human chondrocytes were conducted to investigate the effect of calcitriol on the expression of IL-33, IL-37, IL-6, TNF-α, TLRs, DAMPs, and MMPs. We also studied the effects of calcitriol on macrophage polarization using THP-1 cells. The results of this study revealed that vitamin D deficiency is associated with an increased expression of IL-33, IL-37, IL-6, TNF-α, TLRs, DAMPs, and MMPs, while vitamin D supplementation is associated with a decreased expression of the former. Additionally, vitamin D deficiency is associated with increased M1, while vitamin D-supplemented microswine cartilage showed increased M2 macrophages. It was also revealed that calcitriol favors M2 macrophage polarization. Taken together, the results of this study suggest that modulating expression of IL-33, IL-6, TNF-α, TLRs, DAMPs, and MMPs with vitamin D supplementation may serve as a novel therapeutic to attenuate inflammation and cartilage degeneration in osteoarthritis.
... Mast cells have also been implicated in the inflammatory mechanism of oral diseases such as periodontitis [14]. The neurohormonal mediators interleukin-33 (IL-33) and Substance P (SP) stimulate mast cells and have been suggested in the pathophysiology of nasal polyposis [15]. ...
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Significance IL-37, an antiinflammatory cytokine, is increased along with the proinflammatory cytokine IL-18 and its receptor IL-18R in the amygdala and dorsolateral prefrontal cortex of children with autism spectrum disorder (ASD). IL-37 inhibits neurotensin (NT)-stimulated secretion and gene expression of IL-1β and CXCL8 from cultured human microglia, the resident immune cells of the brain. Moreover, NT, IL-1β, and TNF increase gene expression of IL-37 in these microglia. These findings highlight the important role of NT in the activation of microglia and of IL-37 in the inhibition of inflammation, thus supporting the development of IL-37 as a treatment for ASD.
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Background: The role of IL-37, an immunosuppressive cytokine, in patients with inflammatory diseases is unclear. Objective: We sought to explore the expression and pathogenic function of IL-37 in patients with chronic rhinosinusitis (CRS). Methods: Expression levels of IL-37, IL-18 receptor α, IL-1 receptor 8, Mex3 RNA binding family member B (Mex3B), and thymic stromal lymphopoietin (TSLP) in nasal samples were studied by using quantitative RT-PCR, immunohistochemistry, Western blotting, and ELISA. Human nasal epithelial cells (HNECs) and the BEAS-2B cell line were stimulated with various cytokines and Toll-like receptor (TLR) agonists. In some experiments BEAS-2B cells were transfected with Mex3B small interfering RNA or overexpressing lentiviruses. Genes regulated by IL-37b in HNECs were studied by using RNA sequencing analysis. IL-37b function was confirmed in mice in vivo. Results: Compared with control subjects, although mRNA and protein expression of IL-37 were upregulated in diseased tissues, especially in nasal epithelial cells, in patients with CRS without nasal polyps or in patients with chronic rhinosinusitis with nasal polyps (CRSwNP), IL-37 levels in nasal secretions were reduced in patients with eosinophilic CRSwNP. Type 2 cytokines inhibited IL-37 secretion from HNECs. HNECs expressed IL-37 receptors, IL-18 receptor α, and IL-1 receptor 8. IL-37b downregulated the expression of Mex3B, a TLR3 coreceptor, in HNECs. IL-37b suppressed polyinosinic-polycytidylic acid-induced TSLP production in HNECs in vitro and in murine nasal epithelial cells in vivo. Knocking down or overexpressing Mex3B in BEAS-2B cells abolished the inhibitory effect of IL-37b. Secreted IL-37 levels negatively correlated with Mex3B and TSLP levels and eosinophil numbers in patients with eosinophilic CRSwNP. Conclusions: The suppressed IL-37 secretion caused by a type 2 milieu can enhance Mex3B-mediated TLR3 activation and subsequent TSLP production in nasal epithelial cells and therefore promotes eosinophilic inflammation in patients with CRSwNP.
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Objective Activation of mast cells associates with eosinophilic inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP). The disease‐specific mast cell‐triggering mechanisms apart from immunoglobulin E are poorly understood in CRSwNP. CD30L/CD30 are members of the tumor necrosis factor/receptor superfamily and display immune modulatory function on mast cells. The aim of this study was to explore the expression and function of CD30 and CD30L in CRSwNP. Methods The mRNA expression of CD30 and CD30L was analyzed by real‐time polymerase chain reaction. The cellular expression of CD30L was determined by immunofluorescence staining. The soluble CD30 levels in nasal tissues were detected by enzyme‐linked immunosorbent assay. HMC‐1 cells, a human mast cell line, were cultured and stimulated with CD30. Results Compared with control tissues, CD30 mRNA expression levels were increased in eosinophilic polyps, and soluble CD30 protein levels were upregulated in both eosinophilic and noneosinophilic polyps with a greater increase in eosinophilic type. CD30 was expressed by T cells and B cells in nasal polyps. The CD30L mRNA expression levels and the number of CD30L⁺ cells and CD30L⁺tryptase⁺ mast cells were increased in eosinophilic polyps but not in noneosinophilic polyps as compared with control tissues. Mast cells accounted for 60% of CD30L⁺ cells in eosinophilic polyps. CD30 induced HMC‐1 cells to produce interleukin (IL)‐4 and IL‐13 without degranulation. Mast cells expressed IL‐4 and IL‐13 in eosinophilic polyps. The number of CD30L⁺tryptase⁺ mast cells was positively correlated with the number of eosinophils and total inflammatory cells in eosinophilic polyps. Conclusion CD30/CD30L‐mediated mast cell activation may promote the eosinophilic inflammation in CRSwNP. Level of Evidence NA. Laryngoscope, 2018
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The aim of the is study is to examine the role of serum substance P (SP) levels as a simple biomarker for rheumatoid arthritis (RA) disease activity, its correlation with other markers of disease activity, and with selected clinical parameters. The study comprised 90 RA patients and 24 healthy controls. RA activity was assessed by means of the disease activity 28-C-reactive protein (DAS28-CRP) index and ultrasound power Doppler (USPD) by the German ultrasound score based on seven joints. SP serum values were obtained by means of an ELISA commercial kit. Statistics were achieved by the Student’s t test and Spearman correlation analysis with Bonferroni correction. As a group, RA patients had significantly increased levels of SP compared with healthy controls (p < 0.0001). SP levels correlated with DAS28-CRP (r = 0.5050, p < 0.0001), number of tender joints (NTJ, r = 0.4668, p < 0.0001), number of swollen joints (NSJ, r = 0.4439, p < 0.0001), visual analogue scale (VAS, r = 0.5131, p < 0.0001). However, SP did not correlate with CRP levels (r = 0.0468, p = 0.6613), nor with the USPD (r = 0.1740, p = 0.1009). Elevated serum SP is a common feature of RA patients, which also appears to correlate with clinical measurements of disease activity and with subjective clinical data (NTJ and VAS). Thus, although SP is higher in RA patients with high disease activity, it also detects subtle RA disease activity even in patients in apparent remission, which suggests its usefulness for therapeutic decisions.
Article
Background: Chronic rhinosinusitis (CRS) is a heterogeneous disease characterized by epithelial inflammation and tissue eosinophilic infiltration. Interleukin-33 (IL-33) is a key inflammatory cytokine that mediates eosinophilic infiltration. Objective: The aim of our study was to investigate the expression and role of IL-33 in eosinophilic CRS with nasal polyps (ECRSwNP) and in noneosinophilic CRS with nasal polyps (nECRSwNP), and to analyze their correlation with clinical severity. Methods: The study enrolled 25 patients with ECRSwNP, 27 patients with nECRSwNP, and 12 control subjects, based on immunohistochemical staining. Protein and mRNA expressions of IL-33 in sinus mucosal samples were determined by immunohistochemistry and real-time polymerase chain reaction. Sino-Nasal Outcome Test-20 (SNOT-20) score, visual analog scale (VAS) score, endoscopy score, and computed tomography (CT) score were assessed preoperatively. Results: IL-33 expression levels in the CRSwNP group were significantly higher than those in the control group (p < 0.01), especially in the ECRSwNP group (p < 0.05). There were no significant differences between the ECRSwNP and nECRSwNP groups with respect to SNOT-20 score, VAS score, endoscopy score, or CT score. IL-33 mRNA expression showed a positive correlation with the number of eosinophils (p < 0.05) and endoscopy score (p < 0.05) but not with VAS score and CT score. Conclusion: IL-33 expression plays an important role in patients with CRSwNP. No significant differences were observed between the ECRSwNP and nECRSwNP groups with respect to SNOT-20 score, VAS score, endoscopy score, or CT score. IL-33 expression was correlated with eosinophil counts and endoscopy score.
Article
Mast cells (MCs) are implicated in an array of diseases, especially those involving a mucosal surface, including intestine. On appropriate activation from cytoplasmatic granules, MCs release preformed chemical mediators and generate inflammatory lipids and cytokines/chemokines. Intracellular signal and Lyn activation pathways can cause the degranulation of MCs and the generation of lipid mediators and cytokines/chemokines. MCs undergo maturation and polarization in gut mucosal surfaces where they are constitutively present, and can alter intestinal permeability, an important factor in many inflammatory mucosal disorders including autoimmune diseases. On the other hand, since they are immununosuppressive, MCs have potential anti-inflammatory properties by producing TGF-β1, interleukin (IL)-4, IL-10, IL-13 and histamine. In addition, MC chymase, located in the sub-mucosa, acts on intestinal permeability by protecting the bowel. To carry the inflammatory response, MCs need to be attracted by CC chemokines such as RANTES (CCL5) and MCP-1(CCL2), an effect absent in genetically W/W(v) mast cell-deficient mice, where the inflammatory reaction is not present. Here, we focused our attention on recent findings regarding how MCs can initiate and develop the cellular immune response in the gut and mediate inflammation, an effect that can be inhibited by IL-37. These studies contribute to clarify the mechanisms by which MCs profoundly affect immunity and inflammation of the intestine.
Article
Background Chronic rhinosinusitis with nasal polyps (CRSwNP) has been categorized into 2 subtypes in the Asian population: eosinophilic chronic rhinosinusitis (ECRS; similar to CRSwNP in Western countries) and non-ECRS (characterized by inflammation dominated by T-helper cell type 1). The pathogenesis of CRSwNP and the role of mast cells are poorly understood. Objective To investigate the distribution, phenotypes, and immunoglobulin E (IgE) positivity of mast cells in these 2 subtypes of CRSwNP. Methods We collected nasal tissue from patients with CRSwNP and control subjects. The mRNA for mast cell proteases tryptase and chymase was measured using real-time polymerase chain reaction, and the distribution of each type of protease-positive mast cell was examined using immunohistochemistry and immunofluorescence. IgE distribution on mast cells was determined using double-immunofluorescent staining for IgE and tryptase. Results Expression of tryptase mRNA was significantly increased in nasal polyps from patients with the 2 subtypes of CRSwNP compared with controls. Immunohistochemistry showed increased numbers of tryptase-positive mast cells in the epithelium, glands, and submucosa of ECRS polyps, whereas the number of tryptase- and chymase-positive mast cells was increased in the glands and submucosa of non-ECRS polyps. IgE-positive mast cells were abundant in the epithelial, glandular, and submucosal regions of ECRS polyps but few were detected in non-ECRS polyps. Conclusion The present study demonstrates that the distribution, subtype population, and IgE positivity of mast cells is different between ECRS and non-ECRS nasal polyps. Our results suggest a role for IgE-mediated mast cell activation in the pathogenesis of ECRS.
Article
Mast cells (MC) are critical for allergic reactions, but are also important in inflammatory processes. Stimulation by neuropeptides, such as substance P (SP) and neurotensin (NT) leads to release of pre-formed molecules stored in numerous MC secretory granules and newly-synthesized pro-inflammatory mediators, including tumor necrosis factor (TNF), interleukin 8 (CXCL8) and vascular endothelial growth factor (VEGF). Here, we investigate the role of mammalian target of rapamycin (mTOR) signaling in the stimulation of cultured human LAD2 MC by NT or SP, and the inhibitory effect of the natural flavonoids 3',4',5,7-tetrahydroxyflavone (luteolin) and its novel structural analog 3 ',4',5,7-tetramethoxyluteolin (methoxyluteolin). Stimulation by NT (10[micro]M) or SP (1[micro]M) increases (p <0.001) the gene expression (after 6 h) and release (after 24 h) of TNF, CXCL8 and VEGF. This occurs via activation of both mTOR complexes, as denoted by the increased phosphorylated (p) protein levels (p<0.0001) of the downstream mTORC1 substrate pp70S6KThr389 and mTORC2 component pmTORSer2448. Pre-treatment of human MC using the mTORC1 inhibitor rapamycin or the mTORC1/mTORC2 inhibitor Torin1 or the two flavonoids decreases both gene expression and release (p<0.0001) of all three mediators. Methoxyluteolin is more potent human MC inhibitor than luteolin or Torin1, implicating other MC protein targets in addition to the mTOR complex. The present findings indicate that mTOR is partially involved in the neuropeptide-stimulation of MC, but the novel flavonoid methoxyluteolin inhibits the response entirely suggesting, that it may be developed for treatment of allergic and inflammatory diseases.
Article
This article provides an overview of recent developments concerning the physiology and pathobiology of mast cells and discusses current diagnostic and therapeutic approaches to mast-cell disorders, with an emphasis on mastocytosis.
Article
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a complex inflammatory condition that affects a large proportion of the population world-wide and is associated with high cost of management and significant morbidity. Yet, there is a lack of population-based epidemiologic studies using current definitions of CRSwNP, and the mechanisms that drive pathogenesis in this disease remain unclear. In this review, we summarize the current evidence for the plethora of factors that likely contribute to CRSwNP pathogenesis. Defects in the innate function of the airway epithelial barrier, including diminished expression of antimicrobial products and loss of barrier integrity, combined with colonization by fungi and bacteria likely play a critical role in the development of chronic inflammation in CRSwNP. This chronic inflammation is characterized by elevated expression of many key inflammatory cytokines and chemokines, including IL-5, thymic stromal lymphopoietin and CCL11, that help to initiate and perpetuate this chronic inflammatory response. Together, these factors likely combine to drive the influx of a variety of immune cells, including eosinophils, mast cells, group 2 innate lymphoid cells and lymphocytes, which participate in the chronic inflammatory response within the nasal polyps. Importantly, however, future studies are needed to demonstrate the necessity and sufficiency of these potential drivers of disease in CRSwNP. In addition to the development of new tools and models to aid mechanistic studies, the field of CRSwNP research also needs the type of robust epidemiologic data that has served the asthma community so well. Given the high prevalence, costs and morbidity, there is a great need for continued research into CRS that could facilitate the development of novel therapeutic strategies to improve treatment for patients who suffer from this disease.
Article
In this study we found a significantly lower eosinophilia in nasal polyps surgically removed from second-generation Asian patients, similar to studies of native-born patients in Asian countries, suggesting the hypothesis that there may be genetic regulation of eosinophilia.
Article
Exogenous substance P (10–80 nmol/ml) induced a dose-dependent increase in nasal symptoms in asymptomatic allergics with rhinitis (n = 15) and controls (n = 8), but did not release any mediators. However, comparing the antigen-evoked release of mediators into nasal secretions with that of a substance P-pretreated antigen challenge, we found a significant enhancement of kinins, TAME esterase activity (p < 0.05−0.01), and histamine (p < 0.001, NS) 10–20 min after antigen challenge. These results suggest 1) that substance P-induced increase in nasal congestion is mediated through direct neurokinin receptor activation independently of mast cell activation, and 2) that during the allergic reaction there is a substance P-mast cell interaction that enhances the mediator response to nasal allergen challenge.
Article
The function of interleukin 37 (IL-37; formerly IL-1 family member 7) has remained elusive. Expression of IL-37 in macrophages or epithelial cells almost completely suppressed production of pro-inflammatory cytokines, whereas the abundance of these cytokines increased with silencing of endogenous IL-37 in human blood cells. Anti-inflammatory cytokines were unaffected. Mice with transgenic expression of IL-37 were protected from lipopolysaccharide-induced shock, and showed markedly improved lung and kidney function and reduced liver damage after treatment with lipopolysaccharide. Transgenic mice had lower concentrations of circulating and tissue cytokines (72-95% less) than wild-type mice and showed less dendritic cell activation. IL-37 interacted intracellularly with Smad3 and IL-37-expressing cells and transgenic mice showed less cytokine suppression when endogenous Smad3 was depleted. IL-37 thus emerges as a natural suppressor of innate inflammatory and immune responses.
Article
Sixteen unselected patients with nasal polyps had the levels of substance P and IgE decapeptide measured by ELISA in the oedema fluids and their matched sera. All 16 samples had low levels of substance P in their sera and had high level of substance P in eight samples of nasal polyp oedema. There was a considerable variation in the values of IgE decapeptide found in the sera but 14 polyp oedema fluids had high levels of IgE decapeptide. This study supports the idea that there is a linkage between the cellular and neurovascular responses. High levels of IgE decapeptide suggest that mast cell reactions occur in the majority of cases and that IgE may be implicated in the process of mast cell degranulation.
The role of IL-25 and IL-33 in chronic rhinosinusitis with or without nasal polyps
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