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Airway Remodelling (airway + remodelling)
Selected AbstractsAirway wall geometry in asthma and nonasthmatic eosinophilic bronchitisALLERGY, Issue 6 2009S. Siddiqui Background:, Variable airflow obstruction and airway hyperresponsiveness (AHR) are features of asthma, which are absent in nonasthmatic eosinophilic bronchitis (EB). Airway remodelling is characteristic of both conditions suggesting that remodelling and airway dysfunction are disassociated, but whether the airway geometry differs between asthma and nonasthmatic EB is uncertain. Methods:, We assessed airway geometry by computed tomography (CT) imaging in asthma vs EB. A total of 12 subjects with mild,moderate asthma, 14 subjects with refractory asthma, 10 subjects with EB and 11 healthy volunteers were recruited. Subjects had a narrow collimation (0.75 mm) CT scan from the aortic arch to the carina to capture the right upper lobe apical segmental bronchus (RB1). In subjects with asthma and EB, CT scans were performed before and after a 2-week course of oral prednisolone (0.5 mg/kg). Results:, Mild,moderate and refractory asthma were associated with RB1 wall thickening in contrast to subjects with nonasthmatic EB who had maintained RB1 patency without wall thickening [mean (SD) % wall area and luminal area mild-t0-moderate asthma 67.7 (7.3)% and 6.6 (2.8) mm2/m2, refractory asthma 67.3 (5.6)% and 6.7 (3.4) mm2/m2, healthy control group 59.7 (6.3)% and 8.7 (3.8) mm2/m2, EB 61.4 (7.8)% and 11.1 (4.6) mm2/m2 respectively; P < 0.05]. Airway wall thickening of non-RB1 airways generation three to six was a feature of asthma only. There was no change in airway geometry of RB1 after prednisolone. Proximal airway wall thickening was associated with AHR in asthma (r = ,0.56; P = 0.02). Conclusions:, Maintained airway patency in EB may protect against the development of AHR, whereas airway wall thickening may promote AHR in asthma. [source] Differential expression of peroxisome proliferator activated receptor , and cyclin D1 does not affect proliferation of asthma- and non-asthma-derived airway smooth muscle cellsRESPIROLOGY, Issue 2 2010Justine Y. LAU ABSTRACT Background and objective: Airway remodelling involves thickening of the airway smooth muscle (ASM) bulk. Proliferation of asthma-derived ASM cells is increased in vitro, but underlying mechanisms remain unknown. Peroxisome proliferators activated receptor-, (PPAR,) regulates the cell cycle. It is suggested that PPAR, agonists have anti-inflammatory effects, which may be valuable in the treatment of asthma, but information regarding their antiproliferative properties in ASM is lacking. Although corticosteroids reduce airway inflammation, in vitro they inhibit proliferation in only non-asthma ASM cells by reducing cyclin D1. We therefore investigated the effects of mitogenic stimulation (foetal bovine serum (FBS)), and a PPAR, ligand (ciglitazone), on PPAR, and cyclin D1 expression and proliferation of ASM cells. In addition, we examined the effects of ciglitazone on ASM cell proliferation. Methods: We assessed PPAR, and cyclin D1 mRNA and protein levels using quantitative PCR and immunoblotting. Cell proliferation was assessed using bromodeoxyuridine uptake. Results: In the presence of 5% FBS, PPAR, and cyclin D1 expression decreased over time in non-asthmatic cells but increased in asthmatic cells (compared with sub-confluent cells). FBS-induced proliferation of asthmatic cells increased at all time points, but occurred only at day 7 with non-asthmatic cells (compared with unstimulated time-matched control). Ciglitazone increased PPAR, expression in both groups, but did not alter cell proliferation, while fluticasone increased PPAR, protein only in asthmatic cells. Conclusions: Although in the presence of a mitogenic stimulus, PPAR, was differentially expressed in asthma- and non-asthma-derived ASM; its expression was not related to the increased proliferation observed in asthmatic ASM. [source] Pathological airway remodelling in inflammationTHE CLINICAL RESPIRATORY JOURNAL, Issue 2010Gunilla Westergren-Thorsson Abstract Introduction:, Airway remodelling refers to a wide pattern of patophysiological mechanisms involving smooth muscle cell hyperplasia, increase of activated fibroblasts and myofibroblasts with deposition of extracellular matrix. In asthma, it includes alterations of the epithelial cell layer with goblet cell hyperplasia, thickening of basement membranes, peri-bronchial and peri-broncheolar fibrosis. Moreover, airway remodelling occurs not only in asthma but also in several pulmonary disorders such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and systemic sclerosis. Asthma treatment with inhaled corticosteroids does not fully prevent airway remodelling and thus have restricted influence on the natural course of the disease. Objectives:, This review highlights the role of different fibroblast phenotypes and potential origins of these cells in airway remodelling. Results:, During inflammatory conditions, such as asthma, fibroblasts can differentiate into an active, more contractile phenotype termed myofibroblast, with expression of stress fibres and alpha-smooth muscle actin. The origin of myofibroblasts has lately been debated, and three sources have been identified: recruitment and differentiation of resident tissue fibroblasts; fibrocytes , circulating progenitor cells; and epithelial,mesenchymal transition. Conclusion:, It is clear that airway mesenchymal cells, including fibroblasts/myofibroblasts, are more dynamic in terms of differentiation and origin than has previously been recognised. Considering that these cells are key players in the remodelling process, it is of utmost importance to characterise specific markers for the various fibroblast phenotypes and to explore factors that drive the differentiation to develop future diagnostic and therapeutic tools for asthma patients. Please cite this paper as: Westergren-Thorsson G, Larsen K, Nihlberg K, Andersson-Sjöland A, Hallgren O, Marko-Varga G and Bjermer L. Pathological airway remodelling in inflammation. Clin Respir J 2010; 4 (Suppl. 1): 1,8. [source] Opposite effect of fluticasone and salmeterol on fibronectin and tenascin-C expression in primary human lung fibroblastsCLINICAL & EXPERIMENTAL ALLERGY, Issue 5 2009M. Degen Summary Background Airway remodelling is a key feature of asthma and chronic obstructive pulmonary disease (COPD). The remodelling process involves the deposition of extracellular matrix (ECM) proteins within the airways. Current therapies for asthma and COPD consist of inhaled corticosteroids and long-acting ,2 -agonists (LABA). However, their effect on airway remodelling is not well understood so far. Objective In this study we investigated the effect of fluticasone and salmeterol, either alone or in combination, on fibronectin and tenascin-C protein, isoform, and mRNA levels in primary human lung fibroblasts. Methods In our model, fibroblasts cultured in serum-free medium represented a non-inflammatory condition and stimulation with 5% fetal calf serum and/or TGF-,1 mimicked a pro-fibrotic environment with activation of tissue repair. Using these two different conditions, the effects of fluticasone and salmeterol on fibronectin and tenascin-C protein and mRNA levels were analysed by immunoblotting and semi-quantitative RT-PCR. Results In both conditions, fluticasone increased fibronectin transcript and protein levels, whereas it decreased those of tenascin-C. Salmeterol neither affected fibronectin and tenascin-C synthesis significantly nor did it influence the effect of fluticasone when applied in combination. Furthermore, we found that treatment with fluticasone had an opposite effect on extra domain A and B containing fibronectin isoforms generated by alternative splicing compared with total fibronectin transcript levels, whereas tenascin-C isoforms were not differently modulated by fluticasone. Conclusions Our results indicate that standard therapies for inflammatory lung disorders influence ECM protein composition and relative expression levels. In contrast to corticosteroids, LABA did not significantly alter the expression of tenascin-C and fibronectin in cultures of primary human lung fibroblasts. [source] Pathological airway remodelling in inflammationTHE CLINICAL RESPIRATORY JOURNAL, Issue 2010Gunilla Westergren-Thorsson Abstract Introduction:, Airway remodelling refers to a wide pattern of patophysiological mechanisms involving smooth muscle cell hyperplasia, increase of activated fibroblasts and myofibroblasts with deposition of extracellular matrix. In asthma, it includes alterations of the epithelial cell layer with goblet cell hyperplasia, thickening of basement membranes, peri-bronchial and peri-broncheolar fibrosis. Moreover, airway remodelling occurs not only in asthma but also in several pulmonary disorders such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and systemic sclerosis. Asthma treatment with inhaled corticosteroids does not fully prevent airway remodelling and thus have restricted influence on the natural course of the disease. Objectives:, This review highlights the role of different fibroblast phenotypes and potential origins of these cells in airway remodelling. Results:, During inflammatory conditions, such as asthma, fibroblasts can differentiate into an active, more contractile phenotype termed myofibroblast, with expression of stress fibres and alpha-smooth muscle actin. The origin of myofibroblasts has lately been debated, and three sources have been identified: recruitment and differentiation of resident tissue fibroblasts; fibrocytes , circulating progenitor cells; and epithelial,mesenchymal transition. Conclusion:, It is clear that airway mesenchymal cells, including fibroblasts/myofibroblasts, are more dynamic in terms of differentiation and origin than has previously been recognised. Considering that these cells are key players in the remodelling process, it is of utmost importance to characterise specific markers for the various fibroblast phenotypes and to explore factors that drive the differentiation to develop future diagnostic and therapeutic tools for asthma patients. Please cite this paper as: Westergren-Thorsson G, Larsen K, Nihlberg K, Andersson-Sjöland A, Hallgren O, Marko-Varga G and Bjermer L. Pathological airway remodelling in inflammation. Clin Respir J 2010; 4 (Suppl. 1): 1,8. [source] Airway proteoglycans are differentially altered in fatal asthmaTHE JOURNAL OF PATHOLOGY, Issue 1 2005Marcus de Medeiros Matsushita Abstract It has been suggested that airway remodelling is responsible for the persistent airway obstruction and decline in lung function observed in some asthmatic patients. The small airways are thought to contribute significantly to this functional impairment. Proteoglycans (PGs) are important components of the extracellular matrix (ECM) in the lungs. Besides controlling biophysical properties of the ECM, they play important roles in the regulation of some cytokines. Increased subepithelial PG deposition in the airways of mild asthmatics has been reported. However, there are no data on the PG content in small airways in asthma. This study has compared the content and distribution of PGs in large and small airways of patients who died of asthma with those in control lungs. Immunohistochemistry and image analysis were used to determine the content of lumican, decorin, biglycan, and versican in large (internal perimeter >6 mm) and small (internal perimeter ,6 mm) airways of 18 patients who had died of asthma (A) and ten controls (C). The results were expressed as PG area (µm2)/epithelial basement membrane length (µm). The main differences between asthmatics and controls were observed in the small airways. There was a significant decrease in decorin and lumican contents in the external area of small airways in asthmatics (decorin: A = 1.05 ± 0.27 µm, C = 3.97 ± 1.17 µm, p = 0.042; lumican: A = 1.97 ± 0.37 µm, C = 5.66 ± 0.99 µm, p = 0.002). A significant increase in versican content in the internal area of small and large airways in asthmatics was also observed (small: A = 7.48 ± 0.84 µm, C = 5.16 ± 0.61 µm, p = 0.045; large: A = 18.38 ± 1.94 µm, C = 11.90 ± 2.86 µm, p = 0.028). The results show that PGs are differentially expressed in the airways of fatal asthma and may contribute to airway remodelling. These data reinforce the importance of the small airways in airway remodelling in asthma. Copyright © 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Induction of insulin-like growth factor-I by interleukin-17F in bronchial epithelial cellsCLINICAL & EXPERIMENTAL ALLERGY, Issue 7 2010M. Kawaguchi Summary Cite this as: M. Kawaguchi, J. Fujita, F. Kokubu, G. Ohara, S-K Huang, S. Matsukura, Y. Ishii, M. Adachi, H. Satoh and N. Hizawa, Clinical & Experimental Allergy, 2010 (40) 1036,1043. Background Increased expression of IL-17F has been noted in the airway of asthmatic patients, but its role in asthma has not been fully elucidated. Insulin-like growth factor-I (IGF-I) is known to be involved in airway remodelling and inflammation, while its regulatory mechanisms remain to be defined. Objective To further clarify the biological function of IL-17F, we investigated whether IL-17F is able to regulate the expression of IGF-I in bronchial epithelial cells. Methods Bronchial epithelial cells were stimulated with IL-17F in the presence or absence of T-helper type 2 cytokines. Various kinase inhibitors were added to the culture to identify the key signalling events leading to the expression of IGF-I, in conjunction with the use of short interfering RNAs (siRNAs) targeting mitogen- and stress-activated protein kinase (MSK) 1, p90 ribosomal S6 kinase (p90RSK), and cyclic AMP response element-binding protein (CREB). Results IL-17F significantly induced IGF-I gene and protein expression, and co-stimulation with IL-4 and IL-13 augmented its production. MAP kinase kinase (MEK) inhibitors and the Raf1 kinase inhibitor significantly inhibited IGF-I production, and the combination of PD98059 and Raf1 kinase inhibitor showed further inhibition. Overexpression of Raf1 and Ras dominant-negative mutants inhibited its expression. MSK1 inhibitors significantly blocked IL17F-induced IGF-I expression. Moreover, transfection of the siRNAs targeting MSK1, p90RSK, and CREB blocked its expression. Conclusions In bronchial epithelial cells, IL-17F is able to induce the expression of IGF-I via the Raf1,MEK1/2,ERK1/2,MSK1/p90RSK,CREB pathway in vitro. [source] Plasminogen activator inhibitor-1 and asthma: role in the pathogenesis and molecular regulationCLINICAL & EXPERIMENTAL ALLERGY, Issue 8 2009Z. Ma Summary Plasminogen activator inhibitor (PAI)-1 is a major inhibitor of the fibrinolytic system. PAI-1 levels are markedly increased in asthmatic airways, and mast cells (MCs), a pivotal cell type in the pathogenesis of asthma, are one of the main sources of PAI-1 production. Recent studies suggest that PAI-1 may promote the development of asthma by regulating airway remodelling, airway hyperresponsiveness (AHR), and allergic inflammation. The single guanosine nucleotide deletion/insertion polymorphism (4G/5G) at ,675 bp of the PAI-1 gene is the major genetic determinant of PAI-1 expression. Plasma PAI-1 level is higher in people with the 4G/4G genotype than in those with the 5G/5G genotype. A strong association between the 4G/5G polymorphism and the risk and the severity of asthma has been suggested. Levels of plasma IgE and PAI-1 and severity of AHR are greater in asthmatic patients with the 4G/4G genotype than in those with the 5G/5G genotype. The PAI-1 promoter with the 4G allele renders higher transcription activity than the PAI-1 promoter with the 5G allele in stimulated MCs. The molecular mechanism for the 4G allele-mediated higher PAI-1 expression is associated with greater binding of upstream stimulatory factor-1 to the E-box adjacent to the 4G site (E-4G) than to the E-5G. In summary, PAI-1 may play an important role in the pathogenesis of asthma. Further studies evaluating the mechanisms of PAI-1 action and regulation may lead to the development of a novel prognostic factor and therapeutic target for the treatment and prevention of asthma and other PAI-1-associated diseases. [source] Opposite effect of fluticasone and salmeterol on fibronectin and tenascin-C expression in primary human lung fibroblastsCLINICAL & EXPERIMENTAL ALLERGY, Issue 5 2009M. Degen Summary Background Airway remodelling is a key feature of asthma and chronic obstructive pulmonary disease (COPD). The remodelling process involves the deposition of extracellular matrix (ECM) proteins within the airways. Current therapies for asthma and COPD consist of inhaled corticosteroids and long-acting ,2 -agonists (LABA). However, their effect on airway remodelling is not well understood so far. Objective In this study we investigated the effect of fluticasone and salmeterol, either alone or in combination, on fibronectin and tenascin-C protein, isoform, and mRNA levels in primary human lung fibroblasts. Methods In our model, fibroblasts cultured in serum-free medium represented a non-inflammatory condition and stimulation with 5% fetal calf serum and/or TGF-,1 mimicked a pro-fibrotic environment with activation of tissue repair. Using these two different conditions, the effects of fluticasone and salmeterol on fibronectin and tenascin-C protein and mRNA levels were analysed by immunoblotting and semi-quantitative RT-PCR. Results In both conditions, fluticasone increased fibronectin transcript and protein levels, whereas it decreased those of tenascin-C. Salmeterol neither affected fibronectin and tenascin-C synthesis significantly nor did it influence the effect of fluticasone when applied in combination. Furthermore, we found that treatment with fluticasone had an opposite effect on extra domain A and B containing fibronectin isoforms generated by alternative splicing compared with total fibronectin transcript levels, whereas tenascin-C isoforms were not differently modulated by fluticasone. Conclusions Our results indicate that standard therapies for inflammatory lung disorders influence ECM protein composition and relative expression levels. In contrast to corticosteroids, LABA did not significantly alter the expression of tenascin-C and fibronectin in cultures of primary human lung fibroblasts. [source] Role of STAT6 and SMAD2 in a model of chronic allergen exposure: a mouse strain comparison studyCLINICAL & EXPERIMENTAL ALLERGY, Issue 1 2009J. A. Hirota Summary Background Asthma is a disease characterized by variable and reversible airway obstruction and is associated with airway inflammation, airway remodelling (including goblet cell hyperplasia, increased collagen deposition and increased smooth muscle mass) and increased airway responsiveness. It is believed that airway inflammation plays a critical role in the development of airway remodelling, with IL-13 and TGF-,1 pathways being strongly associated with the disease progression. Mouse models of asthma are capable of recapitulating some components of asthma and have been used to look at both IL-13 and TGF-,1 pathways, which use STAT6 and SMAD2 signalling molecules, respectively. Objectives Using brief and chronic models of allergen exposure, we utilized BALB/c and C57Bl/6 to explore the hypothesis that observed differences in responses to allergen between these mouse strains will involve fundamental differences in IL-13 and TGF-,1 responses. Methods The following outcome measurements were performed: airway physiology, bronchoalveolar lavage cell counts/cytokine analysis, histology, immunoblots and gene expression assays. Results We demonstrate in BALB/c mice an IL-13-dependent phosphorylation of STAT6, nuclear localized in inflammatory cells, which is associated with indices of airway remodelling and development of airway dysfunction. In BALB/c mice, phosphorylation of SMAD2 is delayed relative to STAT6 activation and also involves an IL-13-dependent mechanism. In contrast, despite an allergen-induced increase in IL-4, IL-13 and eosinophils, C57Bl/6 demonstrates a reduced and distinct pattern of phosphorylated STAT6, no SMAD2 phosphorylation changes and fail to develop indices of remodelling or changes in airway function. Conclusion The activation of signalling pathways and nuclear translocation of signalling molecules downstream of IL-13 and TGF-,1 further support the central role of these molecules in the pathology and dysfunction in animal models of asthma. Activation of signalling pathways downstream from IL-13 and TGF-,1 may be more relevant in disease progression than elevations in airway inflammation alone. [source] Airway epithelium-derived transforming growth factor-, is a regulator of fibroblast proliferation in both fibrotic and normal subjectsCLINICAL & EXPERIMENTAL ALLERGY, Issue 8 2008K. E. Hostettler Summary Background In the healthy lung, airway epithelial cells (AEC) regulate fibroblast proliferation through release of soluble factors, such as prostaglandins and proteins. Fibroproliferative diseases and airway remodelling may result from an inadequate generation of suppressive factors by AEC or the inability of fibroblasts to respond to them appropriately. Objective The aim of this study was to study the effect of primary human AEC on the proliferation of fibroblasts obtained from healthy and fibrotic lungs in an interactive cell culture model. Results Conditioned medium (CM) from 14 out of 16 AEC lines significantly inhibited proliferation of normal human lung fibroblasts by 51.2±6.0%. The proliferation of fibroblasts derived from patients with lung fibrosis was equally inhibited by CM of AEC. The inhibitory effect of AEC-CM was completely reversed when fibroblasts were pre-incubated with 2.5 ,m indomethacin. Furthermore, primary human AEC, but not fibroblasts, secrete TGF-,, and the inhibitory effect of the AEC-CM was blocked by neutralizing anti-TGF-, antibodies. Conclusion These results demonstrate that AEC actively inhibit the proliferation of both normal and fibrotic fibroblasts via TGF-,, which induces the prostaglandin E2 synthesis in fibroblasts. The data indicate that proliferative lung diseases may be treated using the epithelial cell as the target of medication. [source] Interleukin-13 acts as an apoptotic effector on lung epithelial cells and induces pro-fibrotic gene expression in lung fibroblastsCLINICAL & EXPERIMENTAL ALLERGY, Issue 4 2008A. Borowski Summary Background IL-13 promotes acute allergic asthma and is discussed to play a role in late asthmatic features such as fibrotic processes and airway remodelling. The contributions of IL-13-mediated mechanisms to subepithelial events related to fibrosis are not yet settled. Objective We investigated the impact of IL-13 on lung epithelial cells as apoptotic effector and on lung fibroblasts as inducer of pro-fibrotic gene expression. Methods Using the two lung epithelial cell lines A549 and BEAS-2B as well as primary lung epithelial cells, we investigated the capability of IL-13 to induce apoptosis by both flow-cytometry and ELISA. The ability of IL-13 to increase the expression of pro-fibrotic genes and to exert influence on the expression of its own receptor was investigated by real-time quantitative PCR measurement of mRNAs encoding collagen I, collagen III, basic fibroblast growth factor (bFGF), ,-smooth muscle actin (,-SMA) and the IL-13 receptor ,1 (IL-13R,1) chain in human primary lung fibroblasts. The specificity of IL-13-mediated cellular responses was confirmed by means of an inhibitory monoclonal antibody directed to the IL-13 receptor. Results IL-13 induces apoptosis in lung epithelial cell lines as well as in primary lung epithelial cells. Furthermore, IL-13 increases the expression of mRNA for ,-SMA and collagen III, but not for bFGF in human primary lung fibroblasts. The susceptibility of lung fibroblasts to IL-13-induced up-regulation of pro-fibrotic genes is associated with the regulation of IL-13 receptor expression. IL-13-dependent fibrosis-associated effects could be inhibited by antibody-mediated blockade of the IL-13R,1 subunit. Conclusion Our findings indicate a function of IL-13 as a mediator in fibrotic processes leading to loss of functional airway tissue in asthma. They also highlight the therapeutic potential of specifically targeting the interaction between IL-13 and its receptor. [source] Modulation of the epithelial inflammatory response to rhinovirus in an atopic environmentCLINICAL & EXPERIMENTAL ALLERGY, Issue 3 2008M. Xatzipsalti Summary Background Immune responses to rhinovirus (RV) as well as direct effects of RV on respiratory epithelium may contribute to the induction of asthma exacerbations. Objective To evaluate the effect of the environment resulting from an atopic immune response on RV-induced epithelial inflammation, replication and cytotoxicity. Methods Peripheral blood mononuclear cells (PBMC) from atopic asthmatic subjects and matched controls (12 pairs) were isolated and stimulated by RVs. Human bronchial epithelial (BEAS-2B) cells were infected with RV in the presence of conditioned media from RV-stimulated PBMC cultures. IL-6, IL-8, RANTES and TGF-,1 levels were measured by ELISA, RV-induced cytotoxicity by a colorimetric method and RV titres on Ohio-HeLa cells. Results RV-induced epithelial production of IL-6, IL-8 and RANTES was significantly lower, while TGF-,1 was higher when cells were exposed to conditioned media from atopic asthmatic subjects compared with those from normal controls. Exposure to the ,atopic' environment also resulted in elevated RV titres and increased RV-induced cytotoxicity. Conclusions Under the influence of an atopic environment, the epithelial inflammatory response to RV is down-regulated, associated with increased viral proliferation and augmented cell damage, while TGF is up-regulated. These changes may help explain the propensity of atopic asthmatic individuals to develop lower airway symptoms after respiratory infections and indicate a mechanism through which viral infections may promote airway remodelling. [source] Suppressive activity of fexofenadine hydrochloride on metalloproteinase production from nasal fibroblasts in vitroCLINICAL & EXPERIMENTAL ALLERGY, Issue 12 2004K. Asano Summary Background Allergic rhinitis (AR) is an inflammatory disease characterized by nasal wall remodelling with intense infiltration of eosinophils and mast cells/basophils. Matrix metalloproteinases (MMPs), MMP-2 and MMP-9, are the major proteolytic enzymes that induce airway remodelling. These enzymes are also important in the migration of inflammatory cells through basement membrane components. Objective We evaluated whether fexofenadine hydrochloride (FEX), the carboxylic acid metabolite of terfenadine with selective H1 -receptor antagonist activity, could inhibit MMP production from nasal fibroblasts (NFs) in response to TNF-, stimulation in vitro. Methods NFs were established from nasal polyp-derived fibroblasts (PFs) taken from patients with AR. Nasal mucosal fibroblasts (MFs) were also induced from nasal mucosal tissues from septal deformity patients without allergy. PF and MF (2 × 105 cells/mL, each) were stimulated with TNF-, in the presence of various concentrations of FEX. After 24 h, culture supernatants were obtained and assayed for MMP-2, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 levels by ELISA. The influence of FEX on mRNA expression of MMPs and TIMPs in 4 h-cultured cells was also evaluated by real-time RT-PCR. Furthermore, nuclear factor-,B (NF-,B) activation in fibroblasts treated with FEX for 4 h was examined by ELISA. Results FEX at more than 350 ng/mL inhibited the production of MMP-2 and MMP-9 from both PF and MF in response to TNF-, stimulation, whereas TIMP-1 and TIMP-2 production was scarcely affected by FEX. FEX also inhibited MMP mRNA expression and NF-,B activation in PF and MF after TNF-, stimulation. Conclusion The present data suggest that the attenuating effect of FEX on MMP-2 and -9 production from NFs induced by inflammatory stimulation may underlie the therapeutic mode of action of the agent on allergic diseases, including AR. [source] Mast cell-mediated airway remodellingCLINICAL & EXPERIMENTAL ALLERGY REVIEWS, Issue 4 2006Y. Okayama Summary Airway structural changes (remodelling) in asthma include increased smooth muscle mass, mucus gland hypertrophy, deposition of extracellular matrix components, thickening of reticular basement membrane, and angiogenesis. The extent of remodelling correlates with severity of asthma, and since patients with extensive remodelling may be resistant to steroids therapy, prevention of airway remodelling is a promising therapeutic strategy for curing patients with severe asthma. Mast cells play a pivotal role in allergic inflammatory diseases including asthma and rhinitis. Both early-phase mediators such as tryptase and chymase and late-phase mediators such as cytokines released by mast cells are capable of modulating airway smooth muscle cell function and inducing goblet cell hyperplasia. Nasal remodelling in patients with rhinitis seems far less extensive than that which occurs in bronchi of asthmatic patients. Because cytokine production by smooth muscle cells may partly explain the differences in remodelling at these two sites, further investigation of the interaction between human mast cells and airway smooth muscle cells is required to identify new therapeutic strategies for reducing airway remodelling in asthma. [source] Histamine H1 -receptor-mediated release of preformed mediators and cytokines and airway remodellingCLINICAL & EXPERIMENTAL ALLERGY REVIEWS, Issue 3 2002M. Triggiani Summary Histamine is a chemical mediator synthesized and stored within secretory granules of human basophils and mast cells [1,2]. The central role of histamine as a mediator of allergic reactions is unchallenged and is also supported by the efficacy of antihistamines in relieving symptoms of the early-phase allergic response [3]. However, a recent hypothesis suggests that the role of histamine is not limited to the early-phase reaction, but may also have a role in the regulation of the late-phase response. This paper describes certain effects of histamine on human inflammatory cell activation, and in particular, its ability to directly activate human lung macrophages and the molecular mechanism for this interaction. These studies have important implications for the therapeutic potential of antihistamines in the treatment of patients with allergic disorders. [source] Interleukin-18-deficient mice exhibit diminished chronic inflammation and airway remodelling in ovalbumin-induced asthma modelCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 3 2008S. Yamagata Summary Interleukin (IL)-18, which is produced by activated monocytes/macrophages and airway epithelial cells, is suggested to contribute to the pathophysiology of asthma by modulating airway inflammation. However, the involvement of IL-18 on modulating chronic airway inflammation and airway remodelling, which are characterized in a refractory asthma model exposed to long-term antigen, has not been investigated sufficiently. We examined the role of IL-18 in chronic airway inflammation and airway remodelling by long-term antigen exposure. IL-18-deficient and C57BL/6-wild-type mice were sensitized by ovalbumin (OVA) and were then exposed to aerosolized OVA twice a week for 12 weeks. We assessed airway inflammation by assessing the infiltration of cells into the airspace and lung tissues, and airway remodelling by airway mucus expression, peribronchial fibrosis and smooth muscle thickness. In IL-18-deficient mice, when exposed to OVA, the total cells and neutrophils of the bronchoalveolar lavage fluid (BALF) were diminished, as were the number of infiltrated cells in the lung tissues. IL-18-deficient mice exposed to OVA after 12 weeks showed significantly decreased levels of interferon (IFN)-,, IL-13 and transforming growth factor (TGF)-,1 in the BALF. The airway hyperresponsiveness to acetyl-,-methacholine chloride was inhibited in IL-18-deficient mice in comparison with wild-type mice. In addition, IL-18-deficient mice exposed to OVA had fewer significant features of airway remodelling. These findings suggest that IL-18 may enhance chronic airway inflammation and airway remodelling through the production of IFN-,, IL-13 and TGF-,1 in the OVA-induced asthma mouse model. [source] Interactions of tachykinin receptor antagonists with lipopolysaccharide-induced airway inflammation in miceCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 9 2004M Veron Summary 1.,Several observations suggest that tachykinins are involved in the pathogenesis of bronchopulmonary alterations. We have investigated the effect of antagonists for tachykinin NK1 (SR 140333), NK2 (SR 48968) or NK3 (SR 142801) receptors on inflammatory cell recruitment, tumour necrosis factor (TNF)-, and interleukin (IL)-6 release and matrix metalloproteinase (MMP)-9 activity in the bronchoalveolar lavage fluid (BALF) of mice exposed to lipopolysaccharide (LPS; 100 µg/mL aerosol for 30 min). 2.,Treatment of mice with a combination of SR 140333 and SR 48968 (10,6 mol/L, aerosol) significantly reduced the increase in the number of total cells and neutrophils and MMP-9 activity in the BALF of mice 2.5 h after LPS exposure. Treatment with the NK3 antagonist SR 142801 (10,6 mol/L, aerosol) did not inhibit the influx of neutrophils, but markedly reduced the increase in TNF-, and IL-6 levels at 2.5 h and MMP-9 activity at 20 h. 3.,These results show that the three tachykinin receptor antagonists may interfere with the development of airway inflammation, namely neutrophilia, TNF-, release or MMP-9 activity in the BALF of mice exposed to LPS and suggest that not only NK1 and NK2 receptors, but also NK3 receptors are involved in the modulation of the inflammatory response and airway remodelling. [source] | |||||||||||||||||||||||||