transforming-growth-factor-beta and Sinusitis

Periostin is known to be a useful biomarker for various diseases. In this article, we focus on allergic diseases and pulmonary fibrosis, for which we and others are now developing detection systems for periostin as a biomarker. Biomarker-based precision medicine in the management of type 2 inflammation and fibrotic diseases since heterogeneity is of utmost importance. Periostin expression is induced by type 2 cytokines (interleukin-4/-13) or transforming growth factor-β, and plays a vital role in the pathogenesis of allergic inflammation or interstitial lung disease, respectively, andits serum levels are correlated disease severity, prognosis and responsiveness to the treatment. We first summarise the importance of type 2 biomarker and then describe the pathological role of periostin in the development and progression of type 2 allergic inflammation and pulmonary fibrosis. In addition, then, we summarise the recent development of assay methods for periostin detection, and analyse the diseases in which periostin concentration is elevated in serum and local biological fluids and its usefulness as a biomarker. Furthermore, we describe recent findings of periostin as a biomarker in the use of biologics or anti-fibrotic therapy. Finally, we describe the factors that influence the change in periostin concentration under the healthy conditions.

Topics: Biomarkers; Cell Adhesion Molecules; Chronic Disease; Cytokines; Eosinophilia; Fibrosis; Humans; Idiopathic Pulmonary Fibrosis; Immunoglobulin E; Inflammation; Interleukin-13; Lung; Precision Medicine; Prognosis; Pulmonary Fibrosis; Rhinitis; Sinusitis; Transforming Growth Factor beta

Topics: Animals; Asthma; Chronic Disease; Humans; Multigene Family; Rhinitis, Allergic; Signal Transduction; Sinusitis; Transforming Growth Factor beta

Topics: Adult; Chronic Disease; Humans; Inflammation; Male; Nasal Polyps; Oxidative Stress; Quality of Life; Rhinitis; Sinusitis; Transforming Growth Factor beta; Transforming Growth Factor beta1

Chronic rhinosinusitis is characterised by persistent inflammation of the sinonasal mucosa. Multiple pathophysiological mechanisms are likely to exist. Previous research has focused predominantly on T-helper type cytokines to highlight the inflammatory mechanisms. However, proteins such as nuclear factor kappa B and transforming growth factor beta are increasingly recognised to have important roles in sinonasal inflammation and tissue remodelling.. This review article explores the roles of T-helper type cytokines, nuclear factor kappa B and transforming growth factor beta in the pathophysiological mechanisms of chronic rhinosinusitis. An understanding of these mechanisms will allow for better identification and classification of chronic rhinosinusitis endotypes, and, ultimately, improved therapeutic strategies.

Topics: Anti-Inflammatory Agents; Chronic Disease; Cytokines; Humans; NF-kappa B; Rhinitis; Sinusitis; T-Lymphocytes, Helper-Inducer; Transforming Growth Factor beta

Transforming growth factor-beta (TGF-beta) as a main switch has a crucial role in chronic rhinosinusitis (CRS) subtypes. The physiological functions of the secreted inactive TGF-beta are precisely regulated by suppressing factors, such as latency-associated peptide (LAP), latent TGF-beta-binding protein (LTBP) and fibrillin, as well as activating factors, such as integrins, proteases and thrombospondin-1. With progress in understanding the factors responsible for regulating TGF-beta functions, it has been revealed that the dysregulation of TGF-beta activation is closely associated with lung fibrosis and chronic obstructive pulmonary disease. Since the imbalance between TGF beta-regulating factors may be one of the main reasons for different phenotypes of CRS, we reviewed the advancement in the research of TGF-beta activation and its role in CRS pathogenesis, to provide insight into the CRS investigation in human.

Topics: Chronic Disease; Humans; Latent TGF-beta Binding Proteins; Protein Binding; Rhinitis; Sinusitis; Transforming Growth Factor beta

To summarize the current knowledge on remodeling in chronic sinus disease.. Chronic sinus disease is characterized by persistent inflammation of the nasal and paranasal mucosa and is currently classified into two major subgroups on the basis of the absence (CRSsNP) or presence (CRSwNP) of nasal polyps. Transforming growth factor-beta and matrix metalloproteinases are critical factors involved in the remodeling process.. Remodeling is clearly present in chronic sinus disease. Transforming growth factor-beta has been implicated as an important factor in remodeling processes involved in chronic sinus disease, and serves as a main switch for different remodeling patterns in chronic sinus disease.

Topics: ADAM Proteins; Chronic Disease; Collagen; Extracellular Matrix; Humans; Inflammation Mediators; Matrix Metalloproteinases; Nasal Polyps; Plasminogen Activator Inhibitor 1; Platelet-Derived Growth Factor; Rhinitis; Sinusitis; Transforming Growth Factor beta

Chronic rhinosinusitis (CRS) is a heterogeneous group of inflammatory diseases of the nasal and paranasal cavities either accompanied by polyp formation (CRSwNP) or without polyps (CRSsNP). CRSsNP and CRSwNP are prevalent medical conditions associated with substantial impaired quality of life, reduced workplace productivity, and serious medical treatment costs. Despite recent research evidence that contributes to further unveiling the pathophysiology of these chronic airway conditions, the cause remains poorly understood and appears to be multifactorial. A diverse spectrum of alterations involving histopathology, inflammatory cell and T-cell patterns, remodeling parameters (eg, TGF-β), eicosanoid and IgE production, microorganisms, and epithelial barrier malfunctions is reported in the search to describe the pathogenesis of this heterogeneous group of upper airway diseases. Furthermore, novel evidence indicates considerable heterogeneity within the CRSwNP subgroup determining the risk of comorbid asthma. The characterization of specific disease subgroups is a challenging scientific and clinical task of utmost importance in the development of diagnostic tools and application of individualized treatments. This review focuses on recent evidence that sheds new light on our current knowledge regarding the inflammatory process of CRS to further unravel its pathogenesis.

Topics: Animals; Asthma; Chronic Disease; Eicosanoids; Humans; Immunoglobulin E; Inflammation; Rhinitis; Risk Factors; Sinusitis; T-Lymphocytes; Transforming Growth Factor beta

The effect of aspirin desensitization (AD) on immunologic profile of patients with AERD has been poorly understood. This study is aimed at investigating the effect of AD on clinical and immunological markers of patients with AERD. This randomized double-blind placebo-controlled trial comprised 34 adult patients (67.6% female) with chronic rhinosinusitis, nasal polyps, and aspirin-intolerant asthma. The active group underwent AD over a 2-day period with increasing doses of aspirin (60, 125, 325, and 625 mg), followed by receiving aspirin 625 mg twice daily for 6 months. Symptom scores and medication needs of patients with AERD who have undergone AD were significantly lower compared to the placebo group after 6 months (7.5 ± 3.5 vs. 10.6 ± 3.8 and 9.3 ± 2.0 vs. 11.0 ± 3.1, respectively, all p < 0.05). However, no significant difference was observed in serum concentration of IL-10, IFN-γ, and TGF-β between two groups neither at baseline nor at the end of study.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Asthma, Aspirin-Induced; Desensitization, Immunologic; Double-Blind Method; Female; Humans; Interferon-gamma; Interleukin-10; Male; Nasal Polyps; Rhinitis; Sinusitis; Transforming Growth Factor beta; Treatment Outcome; Young Adult

Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by chronic eosinophilic inflammation and new bone formation (NBF). These processes may be associated with each other in the pathogenesis and influence the severity and prognosis of the disease. However, it is still unclear how eosinophilic inflammation is involved in the NBF.. Sinus bone cells were isolated from ethmoid bone tissues of patients with CRSwNP and controls. Transforming growth factor beta 1 (TGFβ1) and alkaline phosphatase (ALP) expression in sinus bone cells was determined using quantitative RT-PCR, immunoblotting, and immunohistochemistry. The co-localization of TGFβ1 with eosinophils was assessed by immunofluorescence staining. Sinus bone cells were co-cultured with eosinophils (Eol-1 cell line), which were differentiated with butyrate, to measure the osteoblast differentiation activity of sinus bone cells.. TGFβ1 expression was increased in sinus bone tissues and correlated with CT scores in CRSwNP. TGFβ1 was also increased in the submucosa of CRSwNP and co-localized predominantly with eosinophils compared with neutrophils Differentiated Eol-1 cells-derived TGFβ1 increased ALP expression in sinus bone cells. Treatment with a TGFβ inhibitor attenuated TGFβ1-induced ALP expression and staining in sinus bone cells of CRSwNP, leading to loss of bone formation.. Eosinophil-derived TGFβ1 was enriched in the submucosa of CRSwNP, which induced ALP expression in sinus bone cells and NBF. Therefore, eosinophil-derived TGFβ1 may mediate aberrant bone remodeling in CRSwNP.

Topics: Chronic Disease; Eosinophils; Humans; Inflammation; Nasal Polyps; Osteogenesis; Rhinitis; Sinusitis; Transforming Growth Factor beta

The pathogenesis of chronic rhinosinusitis (CRS) is still unclear, and little is known about angiogenesis in this disease. We utilized a fully convolutional network (FCN), which has been extensively used in image processing to study angiogenesis in CRS.. To explore the tissue quantification of microvessels and their potential association with inflammation in CRS by using FCN to reflect the angiogenesis condition in CRS.. For endotyping of CRS, tissue homogenates of 79 patients with CRS who had undergone functional endoscopic sinus surgery and 17 control subjects were analyzed for interferon gamma, transforming growth factor beta, interleukin (IL)-1β, IL-5, IL-6, IL-8, IL-10, IL-17, tumor necrosis factor alpha, eosinophilic cationic protein, immunoglobulin E, and Staphylococcus aureus-immunoglobulin E(SE-IgE). A total of 552 hematoxylin and eosin-stained images of 27 CRS tissue samples were used to develop an FCN, going through training, validation, and evaluation processes. An optimized FCN was applied to quantify the microvessels of tissue samples of all subjects. Correlation analysis between microvessel quantification with phenotype, endotype, clinical characteristics, and cytokine expression of CRS was carried out.. Quantification of microvessels in type 2 and non-type 2 CRS demonstrated considerable differences, with a higher expression in type 2 CRS. There was a strong negative correlation between the area ratio of microvessels with tissue tumor necrosis factor alpha and transforming growth factor beta levels and a mildly positive correlation with tissue IL-5 and eosinophilic cationic protein concentration.. FCN proved to facilitate the analysis of microvessels in airway tissue samples. This study elucidated the close association of angiogenesis with endotyping, suggesting that treatment aiming at antagonizing angiogenesis may assist to the therapy for the recrudescent and refractory CRS.

Topics: Chronic Disease; Eosinophil Cationic Protein; Humans; Immunoglobulin E; Inflammation; Interleukin-5; Microvessels; Nasal Polyps; Neural Networks, Computer; Rhinitis; Sinusitis; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

The online version contains supplementary material available at 10.1007/s00531-022-02219-9.

Topics: Accidents, Occupational; Adult; Animals; Anxiety; beta Catenin; Chromatography, High Pressure Liquid; Chronic Disease; Cities; Depression; Drugs, Chinese Herbal; Flavonoids; Heat Stroke; Hesperidin; Humans; Hyperplasia; Hypoxia-Inducible Factor 1, alpha Subunit; Interleukin-10; Interleukin-6; Kruppel-Like Factor 4; Macrophages, Alveolar; Medical Staff; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Occupational Health; Occupational Injuries; Occupational Stress; Occupations; PPAR gamma; Pulmonary Fibrosis; RNA, Messenger; Sanitation; Silicon Dioxide; Sinusitis; Stress, Psychological; Surveys and Questionnaires; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; X-Box Binding Protein 1; Young Adult

Chronic rhinosinusitis without nasal polyposis (CRSsNP) and Chronic rhinosinusitis with nasal polyposis (CRSwNP) present distinct tissue remodeling processes. The proteins involved in the process of tissue remodeling have their production and activity related to the inflammatory environment they are. This study aimed to evaluate the protein expression of BMP-7, MMP-9, TGF-β in chronic sinusitis with and without nasal polyposis and their relations with IL-6 and IL-10.. Cross-sectional observational study with 86 participants was divided into three groups: patients with CRSwNP (n = 34), patients with CRSsNP (n = 26), and a control group (CG) without inflammatory disease of the nasal mucosa (n = 26). The primary outcomes were the concentrations of BMP-7, MMP-9, TGF-β, IL-6, and IL-10. Secondary outcomes were the correlations of these markers.. The TGF-β dosage was elevated in the CRSsNP group and reduced in the CSwNP group. The dosage of IL-6 was higher in the CSwNP group, and the IL-10 dosage lower in the groups with sinusitis, and IL-10 was positively correlated with BMP-7 in all groups. There was a negative correlation between IL-6 and IL-10 in all groups observed. The correlation between MMP-9 and interleukins was lost in the CRSsNP group. There was a positive correlation between TGF-β and IL-6 in the CG, and negative in the CRSsNP group.. An inflammation shown in rhinosinusitis with an increase in IL-6 and decrease in IL-10 when compared with the control group; only TGF-β was altered in the tissue remodeling process when compared with BMP-7 and MMP-9 in rhinosinusitis. There is a loss of correlation between tissue remodeling proteins and interleukins studied in CRSsNP.

Topics: Bone Morphogenetic Protein 7; Chronic Disease; Cross-Sectional Studies; Humans; Interleukin-10; Interleukin-6; Matrix Metalloproteinase 9; Nasal Mucosa; Nasal Polyps; Rhinitis; Sinusitis; Transforming Growth Factor beta

Topics: Animals; Blotting, Western; Chronic Disease; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Epithelial-Mesenchymal Transition; Gene Expression Regulation; Inflammation; Mice; Mice, Inbred C57BL; Nasal Mucosa; Rhinitis; RNA; Signal Transduction; Sinusitis; Smad2 Protein; T-Box Domain Proteins; Transforming Growth Factor beta

Type 2 inflammation and eosinophilic infiltration are prominent pathologic features of chronic rhinosinusitis with nasal polyps (CRSwNP). The purpose of the present study was to determine the roles of Tregs in controlling type 2 inflammation and inhibiting eosinophilic infiltration in CRSwNP. A total of 134 nasal polyps, 67 ostiomeatal complex from chronic rhinosinusitis (CRS) and 62 normal nasal tissues from controls were collected to study the enumeration and function of Tregs cells and the expressions of cytokine profiles via immunofluorescence staining, flow cytometry, qRT-PCR, ELISA, and/or H&E staining. The effects of Tregs on type2 and type3 inflammations were determined in an eosinophilic chronic sinusitis (ECRS) mice model. It was confirmed that the CRSwNP displayed the features of Th2 and Th17 cells-mediated inflammation, accompanying by an increased level of eosinophilic infiltration and the eosinophil cationic protein (ECP), with a decreased frequency of Treg cells. Furthermore, the percentages of CD4+CD25+CD127lowTreg and CD4+CD25+Foxp3+Treg were only decreased in the polyps of CRSwNP but not in the paired peripheral blood. The CRSwNP possessed the decreased Nrp1+Tregs, Helios+Treg, and low TGF-β and interleukin (IL)-10 expressions in Tregs. The ECRS mice showed similar inflammatory characteristics to CRSwNP patients. The adoptive transfer of CD4+CD25+Foxp3+ Treg cells significantly decreased the inflammatory cytokines, eosinophilic chemotactic factors in the mucosa of the ECRS mice without alteration of the immune balance in the peripheral blood and spleen. In conclusion, CRSwNP showed high type 2 and type3 inflammation and defective Tregs. The induced regulatory T cell (iTreg) may correct the imbalance between immune tolerance and effect via limiting the eosinophil recruitment of mucosa in CRSwNP.

Topics: Adult; Animals; Asian People; CD4 Antigens; Chronic Disease; Eosinophils; Female; Forkhead Transcription Factors; Gene Expression Regulation; Humans; Inflammation; Interleukin-10; Male; Mice, Inbred BALB C; Nasal Mucosa; Nasal Polyps; Rhinitis; Sinusitis; T-Lymphocytes, Regulatory; Th17 Cells; Th2 Cells; Transforming Growth Factor beta

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a persistent sinonasal mucosa inflammatory disease. MicroRNAs (miRNAs) that are involved in the pathogenesis of CRSwNP in Northern China remain unknown.. A miRCURY™ LNA Array was used to analyze miRNA profiles in nasal mucosa tissues of CRSwNP patients (n = 19) and healthy controls (n = 10). Subsequent pathways were predicted by DIANA-mirPath software.. Five upregulated miRNAs, including miR-210-5p, miR-3178, miR-585-3p, miR-3146, and miR-320e, and 19 downregulated miRNAs, including miR-32-3p, miR-1299, miR-3196, miR-3924, and miR-548e-3p, were differentially expressed (p < 0.05, fold change >2) in tissues of CRSwNP vs controls. Utilizing the Kyoto Encyclopedia of Genes and Genomes database (KEGG), which is an online database for pathway mapping, mucin type O-glycan biosynthesis pathway was significantly enriched in upregulated miRNAs. Transforming growth factor-beta (TGF-β), transient receptor potential (TRP) channels, and the mitogen-activated protein kinase (MAPK) signaling pathway were significantly linked to downregulated miRNAs.. The mucin type O-glycan biosynthesis pathway and TGF-β signaling pathway are regulated by miRNAs, which could be our focus in the future studies.

Topics: Adult; China; Chronic Disease; Female; Humans; Male; Microarray Analysis; MicroRNAs; Middle Aged; Mucins; Nasal Mucosa; Nasal Polyps; Protein Interaction Maps; Rhinitis; Signal Transduction; Sinusitis; Transforming Growth Factor beta; Young Adult

Chronic rhinosinusitis without nasal polyp (CRSsNP) is characterized by tissue remodeling and fibrosis. Transforming growth factor-β (TGF-β) is considered a master switch in the induction of the profibrotic program which can induce fibroblasts to synthesize and contract extracellular matrix (ECM) proteins. A previous study has shown TGF-β1 signaling and collagen overproduction in the CRSsNP, but the responsible cells and mechanism of action remain unclear. Therefore, this study was aimed to investigate the relationship between TGF-β1 stimulation and collagen expression and to explore the role of connective tissue growth factor (CTGF) during the remodeling process using human CRSsNP nasal mucosa tissues and mucosa-derived fibroblasts as main materials. We found that TGF-β1 and its isoforms could promote collagen protein expression. Concomitantly, TGF-β1 caused CTGF expression and secretion. An addition of exogenous CTGF to fibroblasts also caused collagen expression. In accordance with these observations, TGF-β1, CTGF, and collagen were highly expressed in the subepithelial stroma region of CRSsNP nasal mucosa, as determined by immunohistochemistry. The TGF-β1-mediated collagen expression could be blocked by actinomycin D and SIS3, suggesting that the induction was through transcriptional regulation and Smad2/3-dependent pathway. Finally, we demonstrated that CTGF small interfering RNA knockdown led to a substantial decrease in TGF-β1-mediated collagen expression. Collectively, our results provide first and further evidence that TGF-β1 mediates collagen expression-production through a canonical Smad2/3-dependent pathway and CTGF induction and secretion in human nasal fibroblasts. Moreover, TGF-β1, CTGF, and collagen are highly expressed in human CRSsNP nasal mucosa specimens, suggesting their roles in tissue remodeling during CRSsNP progression.

Topics: Cells, Cultured; Collagen; Connective Tissue Growth Factor; Fibroblasts; Fibrosis; Gene Expression Regulation; Humans; Nasal Mucosa; Nasal Polyps; Signal Transduction; Sinusitis; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta

Chronic rhinosinusitis with (CRSwNP) and without nasal polyps (CRSsNP) should be regarded as distinct clinical entities based on differential inflammatory mediator and remodeling profiles. Activin A, a member of the TGF-β superfamily, plays an important role in inflammation and remodeling in the lower airways, although its expression and release in the upper airways remain undescribed.. To investigate the expression of activin A and its inhibitor follistatin in nasal tissue samples from CRSsNP and CRSwNP patients, and to monitor the spontaneous release of these molecules in a human mucosal model.. Protein levels were determined using ELISA for activin A, follistatin, TGF-β1 and indicator proteins (IL-5, ECP, IFNγ) in 13 CRSsNP, 23 CRSwNP, and 10 control samples. The spontaneous release rate and the release ratios of activin A, follistatin and TGF-β1 were determined in 9 CRSsNP and 7 CRSwNP tissue fragments cultured ex-vivo. The induction of activin A and TGF-β1 by one another was studied in 7 CRSsNP tissue fragments cultured ex-vivo.. Significantly higher concentrations of activin A, follistatin, TGF-β1, and IFNγ were observed in CRSsNP compared with CRSwNP samples, whereas the concentrations of IL-5 and ECP were significantly lower. Follistatin was positively and linearly correlated with activin A in CRSsNP and CRSwNP. Activin A, follistatin and TGF-β1 were all spontaneously released by the samples, although the relative ratios released by tissue fragments from CRSsNP and CRSwNP samples were significantly different, with a higher follistatin/activin A-ratio and a follistatin/TGFß1-ratio (with less overall TGF-β1) in CRSwNP than in CRSsNP. Furthermore, TGF-β1 enhanced activin A secretion in CRSsNP tissue fragments cultured ex-vivo.. The differences in tissue concentrations and spontaneous release rates for activin A and follistatin in different CRS samples support the hypothesis that CRSsNP and CRSwNP are two distinct disease entities with respect to remodeling patterns.

Topics: Activins; Adolescent; Adult; Aged; Aged, 80 and over; Chronic Disease; Extracellular Matrix Proteins; Female; Follistatin; Humans; Inflammation; Interferon-gamma; Interleukin-5; Male; Middle Aged; Nasal Polyps; Sinusitis; Transforming Growth Factor beta; Young Adult

Monitoring of fractional concentrations of exhaled nitric oxide (FeNO) has become a reliable marker of inflammation in human nose and paranasal sinuses. However, it is still unknown to what extent nasal NO levels contribute to the pathology of chronic rhinosinusitis (CRS). In the present study, we aimed to examine FeNO levels and the underlying mechanism of NO production and metabolism in patients with eosinophilic chronic rhinosinusitis (ECRS) and non-ECRS.. Thirty-three untreated ECRS patients, 16 non-ECRS patients, and 38 normal subjects were enrolled in this cross-sectional study of FeNO levels. Oral and nasal FeNO levels were measured before treatment using an electrochemical NO analyzer (NObreath(®)) with a nose adaptor. The mRNA expression of three nitric oxide synthase (NOS) isoforms, interleukin-5 (IL-5), and transforming growth factor-beta (TGF-β) in the ethmoid sinus mucosa and nasal polyps were analyzed by real-time PCR. Immunohistological localization of inducible NOS (iNOS) and nitrotyrosine (NT), a marker for oxidized NO metabolites, was also examined.. ECRS patients showed significantly higher oral FeNO levels compared to non-ECRS patients and normal subjects (mean values, 47.6, 13.5, and 15.3ppb, respectively). Nasal FeNO levels of the non-ECRS patients (30.5ppb) were significantly lower than those of the ECRS patients (53.9ppb) and normal subjects (45.5ppb). Positive correlations existed between the blood eosinophil percentage and FeNO levels in ECRS patients. Histologically, ECRS patients showed higher eosinophil accumulation in the ethmoid mucosa than non-ECRS patients (103.1 vs. 16.3cells/HPF). Real-time PCR analysis showed significant upregulation of iNOS and IL-5 mRNA expression in the ethmoid mucosa of the ECRS patients compared to those of non-ECRS patients. Positive iNOS immunoreactivity was observed in ciliated epithelial cells, submucosal glands and associated inflammatory cells in both groups. NT immunoreactivity was detected in the epithelium and around inflammatory cells. Intense NT staining was co-localized with eosinophil accumulation and ECRS patients showed significantly higher rates of NT-positive cells than non-ECRS patients.. A combination of oral and nasal FeNO measurement is a valid marker for the classification and definition of different CRS subtypes in Japan. Higher levels of oral and nasal FeNO in ECRS patients may reflect the persistence of eosinophilic inflammation in sinus mucosa with concomitant iNOS upregulation and accompanying deposition of oxidized NO metabolites.

Topics: Adult; Aged; Breath Tests; Case-Control Studies; Chronic Disease; Cross-Sectional Studies; Eosinophilia; Ethmoid Sinus; Gene Expression Profiling; Humans; Interleukin-5; Middle Aged; Nasal Mucosa; Nasal Polyps; Nitric Oxide; Nitric Oxide Synthase; Real-Time Polymerase Chain Reaction; Respiratory Mucosa; Rhinitis; Sinusitis; Transforming Growth Factor beta; Young Adult

To evaluate TGF-β1 expression in polypoid mucosa (epithelium and stroma) of patients with chronic rhinosinusitis with nasal polyposis (CRSwNP).. Cross-sectional study with two groups: 17 patients with nasal polyposis and 11 controls. Polyps and normal nasal mucosa were processed by immunohistochemical methods for TGF-β1 visualization. Then, the percentage of TGF-β1 expression in stroma and epithelium was objectively quantified using UT Morph software.. A lower percentage of positive expression was found in the epithelium of CRSwNP patients (32.44%) versus normal controls (55.91%) (p < 0.05), and a higher percentage of positive expression in the stroma of CRSwNP patients (23.24%) versus controls (5.88%) (p < 0.05).. The lower percentage of TGF-β1 expression in the nasal epithelium of CRSwNP patients may have an impact on epithelium-directed topical treatments employed in this patient population.

Topics: Chronic Disease; Cross-Sectional Studies; Epithelium; Humans; Immunohistochemistry; Nasal Mucosa; Nasal Polyps; Rhinitis; Sinusitis; Stromal Cells; Transforming Growth Factor beta

It has been reported that there is a significant difference in the local tissue concentration of transforming growth factor (TGF)-β1 between chronic rhinosinusitis without nasal polyps (CRSsNP) and chronic rhinosinusitis without nasal polyps (CRSwNP) patients. TGF-β has been reported to play an important role in regulating epithelial cell repair in lower airway remodeling and may be a critical factor involved in the remodeling process of chronic rhinosinusitis (CRS).. Ethmoidal mucosal samples collected from CRS and healthy control patients were analyzed for TGF-β1, TGF-β receptor I, TGF-β receptor II, Smad3, phospho-Smad3, Smad7, and Smad anchor for receptor activation by Western blotting analysis. The proliferation of sinonasal epithelial cells at baseline and after TGF-β1 and/or EGF stimulation was evaluated by the MTT assay.. In CRSsNP, TGF-β1, TGF-β receptor I, TGF-β receptor II, and Smad3 protein levels were significantly higher than controls. In CRSwNP, TGF-β1, Smad3, and pSmad3 protein levels were significantly lower than controls. Smad7 protein was significantly higher in CRS than controls. In vitro experiments demonstrated that the baseline proliferation levels of sinonasal epithelial cells were lower in CRS than controls.. CRSwNP is characterized by a lower level of TGF-signaling compared with the control. In CRSsNP, although the upstream signaling of TGF-β was enhanced, the high Smad7 protein expression may restrain the downstream signaling components (e.g., pSmad3) and the TGF-β antiproliferative effect on sinonasal epithelium. The difference in the local tissue concentration of TGF-β1 between CRSsNP and CRSwNP patients did not result in significant differences in epithelial proliferation.

Topics: Adult; Aged; Benzamides; Cells, Cultured; Dioxoles; Female; Humans; Intracellular Signaling Peptides and Proteins; Male; Middle Aged; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Serine Endopeptidases; Signal Transduction; Sinusitis; Smad3 Protein; Smad7 Protein; Transforming Growth Factor beta; Transforming Growth Factor beta1; Young Adult

Chronic rhinosinusitis is an inflammatory disease with distinct cytokine and remodeling patterns.. The objective was to analyze the presence of TGF-beta isoforms, receptors, intracellular signaling, and collagen deposition in chronic rhinosinusitis.. Sinonasal mucosal samples obtained from chronic rhinosinusitis with nasal polyps (CRSwNP; n = 13), chronic rhinosinusitis without nasal polyps (CRSsNP; n = 13), and controls (n = 10) were analyzed for TGF-beta isoforms 1 and 2 by means of ELISA and IHC, and for TGF-beta R1, 2, and 3 by RT-PCR and IHC. As downstream proteins, phospho-Smad 2 (pSmad 2) and collagen were analyzed by performing immunostaining and picrosirius red staining, respectively.. TGF-beta 1 and 2 protein concentrations, TGF-beta receptor (R) I and TGF-beta RIII mRNA expression, the number of pSmad 2-positive cells, and total collagen amount were significantly higher in CRSsNP versus controls. In CRSwNP, TGF-beta 1 protein concentration, TGF-beta RII and TGF-beta RIII mRNA expression, the number of pSmad 2-positive cells, and total collagen amount were significantly lower versus controls. Only TGF-beta 2 protein was found higher in CRSwNP versus controls.. A high TGF-beta 1 protein expression, increased TGF-beta RI expression, and a high number of pSmad 2-positive cells all indicate an enhanced TGF-beta signaling in CRSsNP, whereas a low TGF-beta 1 protein concentration, a decreased expression of TGF-beta RII, and a low number of pSmad 2-positive cells in CRSwNP indicate a low level of TGF-beta signaling in CRSwNP. These findings are compatible with the remodeling patterns observed, reflected by a lack of collagen in CRSwNP, and excessive collagen production with thickening of the collagen fibers in the extracellular matrix in CRSsNP.

Topics: Adolescent; Adult; Aged; Chronic Disease; Collagen; Female; Humans; Male; Middle Aged; Nasal Polyps; Receptors, Transforming Growth Factor beta; Rhinitis; Signal Transduction; Sinusitis; Smad2 Protein; Transforming Growth Factor beta; Young Adult

Nasal polyposis has different etiologies in Western and Eastern countries. Furthermore, its pathogenesis is still poorly understood.. To determine the T-cell phenotypes involved in nasal polyposis in Chinese patients.. Twenty-four Chinese patients with nasal polyps were studied. CD4, CD8, Foxp3, and interleukin (IL) 17 were analyzed by immunohistochemical staining. Expression of T-bet, GATA-3, Foxp3, and RORgammat mRNA was detected by real-time polymerase chain reaction. The levels of T-cell cytokines (IL-4, IL-5, interferon [IFN] gamma, IL-10, IL-17, and transforming growth factor [TGF] beta) were determined using enzyme-linked immunosorbent assay, and serum immunoglobulin (Ig) E levels were measured using the UNICAP system.. Increased expression of CD4+ and CD8+ and decreased expression of Foxp3 and IL-17 were detected in nasal polyps compared with control tissue. Furthermore, expression of T-bet and GATA-3 mRNA was upregulated, whereas Foxp3 mRNA expression was markedly downregulated. Furthermore, increased levels of IFN-gamma, IL-4 and IL-5 and decreased levels of IL-10 and TGF-beta were found in nasal polyps. There was no association between Staphylococcus aureus exotoxin (SAE)-specific IgE and T regulatory cell (Treg) insufficiency in nasal polyps.. Our findings demonstrate that excessive infiltration of CD4+ and CD8+ T cells in nasal polyps may be associated with expression of Foxp3+ by Tregs but not with SAEs in Chinese patients.

Topics: Adult; CD4 Antigens; CD8 Antigens; China; Cytokines; Female; Forkhead Transcription Factors; GATA3 Transcription Factor; Humans; Immunoglobulin E; Immunophenotyping; Male; Middle Aged; Nasal Polyps; Rhinitis; Sinusitis; T-Box Domain Proteins; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Aspergillus fumigatus is ubiquitous and yet causes invasive, chronic and allergic disease of the lung. Chronic cavitary pulmonary aspergillosis (CCPA) is a slowly destructive form of pulmonary aspergillosis, without immunocompromise. We hypothesized that CCPA cytokine gene polymorphisms would differ from patients with allergic bronchopulmonary aspergillosis (ABPA) and uninfected controls. We have profiled functional cytokine gene polymorphisms for interleukin (IL)-10, IL-15, transforming growth factors (TGF)-beta1, tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma in patients with CCPA (n = 24) who were compared with other forms of aspergillosis (mostly ABPA) (n = 15) and with ethnically matched controls (n = 65-330). Results are described with reference to the high-producing genotype in each case. Susceptibility to aspergillosis (all patients compared with normal controls) was associated with higher frequency of the IL-15 +13689*A allele (OR = 2.37, P = 0.0028) and A/A genotype (chi(2) = 10.31, P < 0.001), with a lower frequency of the TNF-alpha-308*A/A genotype (chi(2) = 11.05, P < 0.01). Within the aspergillosis patients, CCPA is associated with lower frequency of the IL-10 -1082*G allele (OR = 0.38, P = 0.0006) and G/G genotype (chi(2) = 22.45, P < 0.001) and with a lower frequency of the TGF-beta1 +869 *T allele (OR +0.42, P < 0.0029) and T/T genotype (chi(2) = 17.82, P < 0.001) compared with non-CCPA patients and normal controls. Patients infected with Aspergillus appear to be higher producers of IL-15, a Th2-promoting cytokine, and lower producers of TNF-alpha, a cytokine central in protective responses. CCPA occurs in patients who are genetically lower producers of both IL-10 and TGF-beta1. As these cytokines are regulatory and anti-inflammatory, CCPA may be a consequence of poor inflammatory response control in the lung.

Topics: Adult; Aspergillosis; Aspergillosis, Allergic Bronchopulmonary; Aspergillus fumigatus; Case-Control Studies; Cytokines; England; Genetic Predisposition to Disease; Genotype; Humans; Interferon-gamma; Interleukin-10; Interleukin-15; Lung Diseases, Fungal; Middle Aged; Polymerase Chain Reaction; Sinusitis; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

In a recent study, we have shown that gelatinase-B (metalloproteinase [MMP]-9) in nasal secretions can have both monitoring and predictive value on the healing outcome after functional endoscopic sinus surgery (FESS) to treat chronic rhinosinusitis (CRS) and nasal polyposis (NP). In this work, we aimed to explore the source of MMP-9 and the influence of inflammation on MMP-9 expression and release in nasal tissue and secretions during airway remodelling after surgery.. Biopsies from 23 patients operated by FESS for CRS or NP were collected 1, 3, and 6 months after sinus surgery. MMP-9 expression in the paranasal mucosa was correlated with healing quality, with MMP-9 concentrations in nasal fluid, and with histomorphologic findings (edema, fibrosis, alphasmooth muscle actin, CD-68, myeloperoxidase, EG2, and transforming growth factor [TGF]-beta1 stainings).. MMP-9 concentrations in nasal fluid were paralleled by MMP-9 expression inside the extracellular matrix (ECM) after sinus surgery. MMP-9 expression in ECM was significantly correlated with healing quality (r = 0.378, P = .0181), and poor healers presented significantly more edema (P < .05). The amounts of MMP-9 in nasal fluid were significantly and independently predicted by the number of neutrophils (P = .0224) and macrophages (P = .0497) in the tissue. In contrast, MMP-9 expression was not related to fibrosis, number of myofibroblasts, or TGF-beta1 expression in ECM.. MMP-9 expression is increased in the ECM during wound healing and parallels concentrations of MMP-9 in nasal fluids. Inflammatory cells represent the major source of increased MMP-9 expression, which is linked to poor healing quality.

Topics: Adolescent; Adult; Chronic Disease; Endoscopy; Enzyme-Linked Immunosorbent Assay; Extracellular Matrix; Female; Humans; Immunohistochemistry; Inflammation; Male; Matrix Metalloproteinase 9; Middle Aged; Nasal Mucosa; Nasal Polyps; Neutrophils; Sinusitis; Transforming Growth Factor beta; Wound Healing

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).. 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.. 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).. 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.

Topics: Adult; Aged; Biomarkers; Cell Proliferation; Chronic Disease; Endoscopy; Female; Humans; Interleukin-11; Interleukin-4; Interleukin-6; Interleukin-8; Interleukins; Male; Middle Aged; Nasal Polyps; Receptors, Interleukin-4; Reverse Transcriptase Polymerase Chain Reaction; Rhinitis; Sinusitis; Transforming Growth Factor beta

Long-term, low-dose macrolide therapy is effective in the treatment of chronic rhinosinusitis. It is believed that macrolide antibiotics produce this benefit through an anti-inflammatory effect. In this study, the effect of clarithromycin treatment on the expression of transforming growth factor (TGF)-beta and the key pro-inflammatory nuclear transcription factor, NF-kappa B, was examined in vitro and in vivo.. In vitro: nasal mucosa was obtained from 10 patients with chronic sinusitis and was cultured for 24 hours in the presence of clarithromycin or control. Cellular expression of TGF-beta and NF-kappa B was determined by immunohistochemistry. In vivo: 10 patients with chronic rhinosinusitis were treated for 3 months with clarithromycin. Nasal mucosal biopsies were taken pre- and posttreatment. Cellular expression of TGF-beta and NF-kappa B was again determined by immunohistochemistry.. Clarithromycin, when applied to nasal biopsies in vitro, reduced cellular expression of TGF-beta and NF-kappa B. Nasal biopsies taken before and after clarithromycin treatment showed no differences in cellular expression of NF-kappa B or TGF-beta.. Clarithromycin can reduce cellular expression of TGF-beta and NF-kappa B when applied in vitro, but its action during clinical therapy is less clear. Clarithromycin is capable of inhibiting pro-inflammatory cytokines in vitro, and reductions of TGF-beta and NF-kappa B may represent additional mechanisms by which macrolides reduce inflammation in chronic airway disease. Discrepancies between the actions of clarithromycin on nasal biopsies in vitro and after clinical therapy warrant further investigation.

Topics: Adult; Anti-Inflammatory Agents; Biopsy; Cells, Cultured; Chronic Disease; Clarithromycin; Female; Humans; Immunohistochemistry; Male; Middle Aged; Nasal Mucosa; NF-kappa B; Paranasal Sinus Diseases; Sinusitis; Transforming Growth Factor beta