共查询到20条相似文献,搜索用时 31 毫秒
1.
Inhibition of matrix metalloproteinases prevents allergen-induced airway inflammation in a murine model of asthma 总被引:19,自引:0,他引:19
Kumagai K Ohno I Okada S Ohkawara Y Suzuki K Shinya T Nagase H Iwata K Shirato K 《Journal of immunology (Baltimore, Md. : 1950)》1999,162(7):4212-4219
Although matrix metalloproteinases (MMPs) have been reported to play crucial roles in the migration of inflammatory cells through basement membrane components in vitro, the role of MMPs in the in vivo accumulation of the cells to the site of inflammation in bronchial asthma is still obscure. In this study, we investigated the role of MMPs in the pathogenesis of bronchial asthma, using a murine model of allergic asthma. In this model, we observed the increase of the release of MMP-2 and MMP-9 in bronchoalveolar lavage fluids after Ag inhalation in the mice sensitized with OVA, which was accompanied by the infiltration of lymphocytes and eosinophils. Administration of tissue inhibitor of metalloproteinase-2 to airways inhibited the Ag-induced infiltration of lymphocytes and eosinophils to airway wall and lumen, reduced Ag-induced airway hyperresponsiveness, and increased the numbers of eosinophils and lymphocytes in peripheral blood. The inhibition of cellular infiltration to airway lumen was observed also with tissue inhibitor of metalloproteinase-1 and a synthetic matrix metalloproteinase inhibitor. These data suggest that MMPs, especially MMP-2 and MMP-9, are crucial for the infiltration of inflammatory cells and the induction of airway hyperresponsiveness, which are pathophysiologic features of bronchial asthma, and further raise the possibility of the inhibition of MMPs as a therapeutic strategy of bronchial asthma. 相似文献
2.
Mouse monocyte-derived chemokine is involved in airway hyperreactivity and lung inflammation. 总被引:26,自引:0,他引:26
J A Gonzalo Y Pan C M Lloyd G Q Jia G Yu B Dussault C A Powers A E Proudfoot A J Coyle D Gearing J C Gutierrez-Ramos 《Journal of immunology (Baltimore, Md. : 1950)》1999,163(1):403-411
The cloning, expression, and function of the murine (m) homologue of human (h) monocyte-derived chemokine (MDC) is reported here. Like hMDC, mMDC is able to elicit the chemotactic migration in vitro of activated lymphocytes and monocytes. Among activated lymphocytes, Th2 cells were induced to migrate most efficiently. mMDC mRNA and protein expression is modulated during the course of an allergic reaction in the lung. Neutralization of mMDC with specific Abs in a model of lung inflammation resulted in prevention of airway hyperreactivity and significant reduction of eosinophils in the lung interstitium but not in the airway lumen. These data suggest that mMDC is essential in the transit/retention of leukocytes in the lung tissue rather than in their extravasation from the blood vessel or during their transepithelial migration into the airways. These results also highlight the relevance of factors, such as mMDC, that regulate the migration and accumulation of leukocytes within the tissue during the development of the key physiological endpoint of asthma, airway hyperreactivity. 相似文献
3.
Le'Negrate G Rostagno P Auberger P Rossi B Hofman P 《Cell death and differentiation》2003,10(2):153-162
During inflammatory bowel diseases, commitment of extravased polymorphonuclear leucocytes (PMN) to apoptosis is required for the resolution of inflammation. To investigate the effect of transepithelial migration on PMN apoptotic rates, PMN transepithelial migration was reproduced in vitro using T84 intestinal monolayers. Transepithelial migration was found to delay neutrophil apoptosis, and this survival effect correlated with a downregulation of the surface expression of Fas ligand (FasL) and with a decrease in both procaspases-3, and -8 mRNA and procaspases-3, -6, -7 and -8 protein levels. Moreover, neutrophil survival and FasL shedding mediated by transepithelial migration were abrogated by a broad-spectrum metalloproteinase inhibitor, BB-94. Although Erk1/2 and p38 MAPK were activated in transmigrated PMN, inhibition of these MAP kinases did not impair transmigration-induced PMN survival. Taken together, our results show that trans-epithelial migration induces the downregulation of proapoptotic proteins expression in transmigrated PMN, which results in their increased lifespan. 相似文献
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5.
Role of extracellular matrix and its regulators in human airway smooth muscle biology 总被引:3,自引:0,他引:3
Parameswaran K Willems-Widyastuti A Alagappan VK Radford K Kranenburg AR Sharma HS 《Cell biochemistry and biophysics》2006,44(1):139-146
Altered extracellular matrix (ECM) deposition contributing to airway wall remodeling is an important feature of asthma and
chronic obstructive pulmonary disease (COPD). The molecular mechanisms of this process are poorly understood. One of the key
pathological features of these diseases is thickening of airway walls. This thickening is largely to the result of airway
smooth muscle (ASM) cell hyperplasia and hypertrophy as well as increased deposition of ECM proteins such as collagens, elastin,
laminin, and proteoglycans around the smooth muscle. Many growth factors and cytokines, including fibroblast growth factor
(FGF)-1, FGF-2, and transforming growth factor (TGF)-α1, that are released from the airway wall have the potential to contribute to airway remodeling, revealed by enhanced ASM proliferation
and increased ECM protein deposition. TGF-α1 and FGF-1 stimulate mRNA expression of collagen I and III in ASM cells, suggesting their role in the deposition of extracellular
matrix proteins by ASM cells in the airways of patients with chronic lung diseases. Focus is now on the bidirectional relationship
between ASM cells and the ECM. In addition to increased synthesis of ECM proteins, ASM cells can be involved in downregulation
of matrix metalloproteinases (MMPs) and upregulation of tissue inhibitors of metalloproteinases (TIMPs), thus eventually contributing
to the alteration in ECM. In turn, ECM proteins promote the survival, proliferation, cytokine synthesis, migration, and contraction
of human airway smooth muscle cells. Thus, the intertwined relationship of ASM and ECM and their response to stimuli such
as chronic inflammation in diseases such as asthma and COPD contribute to the remodeling seen in airways of patients with
these diseases. 相似文献
6.
Inflammatory cells as source of tachykinin-induced mucus secretion in chronic bronchitis 总被引:3,自引:0,他引:3
Substance P and neurokinin A are regulatory peptides of the tachykinin family that influence many aspects of human airway function in health and diseases such as bronchial asthma or chronic obstructive pulmonary disease (COPD). Tachykinin-induced mucus secretion has been regarded as sensory nerve-dependent so far. We studied the distribution of tachykinin-mRNA and -peptide and its relation to NK-1 subtype-positive cells in human airway glands to assess if tachykinins may also be expressed in inflammatory cells. RT-PCR demonstrated the expression of tachykinin- and NK-1-mRNA in human airway tissues. In situ hybridisation resulted in preprotachykinin (PPT)-A mRNA-signal detection in inflammatory cells which were in close contact to myoepithelial cells of airway glands. NK-1 immunoreactivity was found in myoepithelial cells which were in direct contact to the PPT-A mRNA and tachykinin-positive cells. The present data directly demonstrate the presence of both PPT-A mRNA and tachykinin immunoreactivity in inflammatory airway cells which are in direct contact to NK-1 receptor positive glandular myoepithelium. Our findings indicate that besides neurally released tachykinins, also inflammatory cell-derived tachykinins may lead to glandular secretion via NK-1 receptor stimulation. This points to a major second source of these proinflammatory mediators in chronic inflammatory airway diseases such as COPD or asthma. 相似文献
7.
Immune responses are pathologically sustained in several common diseases, including asthma. To determine endogenous proresolving mechanisms for adaptive immune responses, we used a murine model of self-limited allergic airway inflammation. After cessation of allergen exposure, eosinophils and T cells were cleared concomitant with the appearance of increased numbers of NK cells in the lung and mediastinal lymph nodes. The mediastinal lymph node NK cells were activated, expressing CD27, CD11b, CD69, CD107a, and IFN-γ. NK cell depletion disrupted the endogenous resolution program, leading to delayed clearance of airway eosinophils and Ag-specific CD4(+) T cells. NK cell trafficking to inflamed tissues for resolution was dependent upon CXCR3 and CD62L. During resolution, eosinophils and Ag-specific CD4(+) T cells expressed NKG2D ligands, and a blocking Ab for the NKG2D receptor delayed clearance of these leukocytes. Of interest, NK cells expressed CMKLR1, a receptor for the proresolving mediator resolvin E1, and depletion of NK cells decreased resolvin E1-mediated resolution of allergic inflammation. Resolvin E1 regulated NK cell migration in vivo and NK cell cytotoxicity in vitro. Together, these findings indicate new functions in catabasis for NK cells that can also serve as targets for proresolving mediators in the resolution of adaptive immunity. 相似文献
8.
Chloride channels are involved in many different physiological processes such as cell migration, proliferation and apoptosis. The importance of the CLC family of chloride channels in these cellular functions has been recognized only recently. Infiltration of inflammatory cells, such as eosinophils, T cells, mast cells and neutrophils, is a hallmark of allergy and asthma. Indeed, chronic asthma is associated with widespread damage to the bronchial epithelium, due to excessive apoptosis, and with defective epithelial repair. However, the relationship between the immune cells of allergic airway diseases and chloride channels has not been clearly elucidated. In this review, characteristics of CLC channels are mainly discussed based on their function and presence in different immune cells in airway diseases. Not only are chloride channels involved in the recruitment of immune cells, they also play a role in the activation of these cells. Thus, understanding the role of CLC channels in the immune cells would provide unique insights to the pathophysiologic process of chronic asthma and the means to prevent or reverse the disease. 相似文献
9.
Role of IL-10 in the resolution of airway inflammation 总被引:1,自引:0,他引:1
IL-10 can be considered an important agent in the resolution of inflammation. Originally named "cytokine synthesis inhibitory factor" for its ability to inhibit IFN-gamma and IL-2 production in Th2 cells, it is secreted by monocytes, macrophages, mast cells, T and B lymphocytes, and dendritic cells (DCs). IL-10 production and release by monocytic cells in response to allergic challenge is upregulated by TNF-alpha, and by negative feedback regulation of itself. However, it is also secreted by T regulatory cells (Tregs), under the control of IL-2. Importantly in the context of asthma, IL-10 inhibits eosinophilia, by suppression of IL-5 and GM-CSF, by direct effects on eosinophil apoptosis, and effects on cell proliferation through down-regulation of IL-1. A number of its cytokine suppressive characteristics are now thought to occur through its upregulation of suppressor of cytokine signaling (SOCS)-3. IL-10 is also a suppressor of nitric oxide (NO) production, which may have ramifications for its role in airway inflammatory diseases. Initial clinical trials have demonstrated relative safety and few clinically adverse events at doses of recombinant human IL-10 below 50 microg/kg, with mixed success in treatment of patients with inflammatory bowel disease and psoriasis. However, both steroid therapy and allergen specific immunotherapy are known to elevate endogenous IL-10 levels, which may account for their efficacy, suggesting that further study of IL-10 as a target for treatment of airway inflammatory diseases such as asthma and COPD is warranted. 相似文献
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Matrix metalloproteinase-9-mediated dendritic cell recruitment into the airways is a critical step in a mouse model of asthma 总被引:12,自引:0,他引:12
Vermaelen KY Cataldo D Tournoy K Maes T Dhulst A Louis R Foidart JM Noël A Pauwels R 《Journal of immunology (Baltimore, Md. : 1950)》2003,171(2):1016-1022
Dendritic cells (DCs) appear to be strategically implicated in allergic diseases, including asthma. Matrix metalloproteinase (MMP)-9 mediates transmigration of inflammatory leukocytes across basement membranes. This study investigated the role of MMP-9 in airway DC trafficking during allergen-induced airway inflammation. MMP-9 gene deletion affected the trafficking of pulmonary DCs in a specific way: only the inflammatory transmigration of DCs into the airway lumen was impaired, whereas DC-mediated transport of airway Ag to the thoracic lymph nodes remained unaffected. In parallel, the local production of the Th2-attracting chemokine CC chemokine ligand 17/thymus and activation-regulated chemokine, which was highly concentrated in purified lung DCs, fell short in the airways of allergen-exposed MMP-9(-/-) mice. This was accompanied by markedly reduced peribronchial eosinophilic infiltrates and impaired allergen-specific IgE production. We conclude that the specific absence of MMP-9 activity inhibits the development of allergic airway inflammation by impairing the recruitment of DCs into the airways and the local production of DC-derived proallergic chemokines. 相似文献
13.
Woo CH Yoo MH You HJ Cho SH Mun YC Seong CM Kim JH 《Journal of immunology (Baltimore, Md. : 1950)》2003,170(12):6273-6279
The epithelial cells that form a barrier lining the lung airway are key regulators of neutrophil trafficking into the airway lumen in a variety of lung inflammatory diseases. Although the lipid mediator leukotriene B(4) (LTB(4)) is known to be a principal chemoattractant for recruiting neutrophils to inflamed sites across the airway epithelium, the precise signaling mechanism involved remains largely unknown. In the present study, therefore, we investigated the signaling pathway through which LTB(4) induces transepithelial migration of neutrophils. We found that LTB(4) induces concentration-dependent transmigration of DMSO-differentiated HL-60 neutrophils and human polymorphonuclear neutrophils across A549 human lung epithelium. This effect was mediated via specific LTB(4) receptors and was inhibited by pretreating the cells with N-acetylcysteine (NAC), an oxygen free radical scavenger, with diphenylene iodonium (DPI), an inhibitor of NADPH oxidase-like flavoproteins, or with PD98059, an extracellular signal-regulated kinase (ERK) inhibitor. Consistent with those findings, LTB(4)-induced ERK phosphorylation was completely blocked by pretreating cells with NAC or DPI. Taken together, our observations suggest LTB(4) signaling to transepithelial migration is mediated via generation of reactive oxygen species, which leads to downstream activation of ERK. The physiological relevance of this signaling pathway was demonstrated in BALB/c mice, in which intratracheal instillation of LTB(4) led to acute recruitment of neutrophils into the airway across the lung epithelium. Notably, the response to LTB(4) was blocked by NAC, DPI, PD98059, or CP105696, a specific LTB(4) receptor antagonist. 相似文献
14.
《Biochimica et Biophysica Acta (BBA)/General Subjects》2016,1860(6):1089-1097
BackgroundFungal infections develop in pulmonary chronic inflammatory diseases such as asthma, Chronic Obstructive Pulmonary Disease (COPD) and Cystic Fibrosis (CF). The available antifungal drugs may fail to eradicate fungal pathogens, that can invade the lungs and vessels and spread by systemic circulation taking advantage of defective lung immunity. An increased rate of sphingolipid de novo synthesis, leading to ceramide accumulation, was demonstrated in CF and COPD inflamed lungs. The inhibitor of sphingolipid synthesis myriocin reduces inflammation and ameliorates the response against bacterial airway infection in CF mice. Myriocin also inhibits sphingolipid synthesis in fungi and exerts a powerful fungistatic effect.MethodsWe treated Aspergillus fumigatus infected airway epithelial cells with myriocin and we administered myriocin-loaded nanocarriers to A. fumigatus infected mice lung.ResultsWe demonstrate here that de novo synthesized ceramide mediates the inflammatory response induced by A. fumigatus infection in airway epithelia. CF epithelial cells are chronically inflamed and defective in killing internalized conidia. Myriocin treatment reduced ceramide increase and inflammatory mediator release whereas it upregulated HO1 and NOD2, allowing the recovery of a functional killing of conidia in these cells. Myriocin-loaded nanocarriers, intratracheally administered to mice, significantly reduced both the inflammatory response induced by A. fumigatus pulmonary challenge and fungal lung invasion.ConclusionsWe conclude that inhibition of sphingolipid synthesis can be envisaged as a dual anti-inflammatory and anti-fungal therapy in patients suffering from chronic lung inflammation with compromised immunity.General significanceMyriocin represents a powerful agent for inflammatory diseases and fungal infection. 相似文献
15.
Hurley BP Siccardi D Mrsny RJ McCormick BA 《Journal of immunology (Baltimore, Md. : 1950)》2004,173(9):5712-5720
Lung inflammation resulting from bacterial infection of the respiratory mucosal surface in diseases such as cystic fibrosis and pneumonia contributes significantly to the pathology. A major consequence of the inflammatory response is the recruitment and accumulation of polymorphonuclear cells (PMNs) at the infection site. It is currently unclear what bacterial factors trigger this response and exactly how PMNs are directed across the epithelial barrier to the airway lumen. An in vitro model consisting of human PMNs and alveolar epithelial cells (A549) grown on inverted Transwell filters was used to determine whether bacteria are capable of inducing PMN migration across these epithelial barriers. A variety of lung pathogenic bacteria, including Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa are indeed capable of inducing PMN migration across A549 monolayers. This phenomenon is not mediated by LPS, but requires live bacteria infecting the apical surface. Bacterial interaction with the apical surface of A549 monolayers results in activation of epithelial responses, including the phosphorylation of ERK1/2 and secretion of the PMN chemokine IL-8. However, secretion of IL-8 in response to bacterial infection is neither necessary nor sufficient to mediate PMN transepithelial migration. Instead, PMN transepithelial migration is mediated by the eicosanoid hepoxilin A3, which is a PMN chemoattractant secreted by A549 cells in response to bacterial infection in a protein kinase C-dependent manner. These data suggest that bacterial-induced hepoxilin A3 secretion may represent a previously unrecognized inflammatory mechanism occurring within the lung epithelium during bacterial infections. 相似文献
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Patel HJ Belvisi MG Bishop-Bailey D Yacoub MH Mitchell JA 《Journal of immunology (Baltimore, Md. : 1950)》2003,170(5):2663-2669
Airway smooth muscle is actively involved in the inflammatory process in diseases such as chronic obstructive pulmonary disease and asthma by 1) contributing to airway narrowing through hyperplasia and hypertrophy and 2) the release of GM-CSF and G-CSF, which promotes the survival and activation of infiltrating leukocytes. Thus, the identification of novel anti-inflammatory pathways in airway smooth muscle will have important implications for the treatment of inflammatory airway disease. This study identifies such a pathway in the activation of peroxisome proliferator-activated receptors (PPARs). PPAR ligands are known therapeutic agents in the treatment of diabetes; however, their role in human airway disease is unknown. We demonstrate, for the first time, that human airway smooth muscle cells express PPAR alpha and -gamma subtypes. Activation of PPAR gamma by natural and synthetic ligands inhibits serum-induced cell growth more effectively than does the steroid dexamethasone, and induces apoptosis. Moreover, PPAR gamma activation, like dexamethasone, inhibits the release of GM-CSF. However, PPAR gamma ligands, but not dexamethasone, similarly inhibits G-CSF release. These results reveal a novel anti-inflammatory pathway in human airway smooth muscle, where PPAR gamma activation has additional anti-inflammatory effects to those of steroids. Hence, PPAR ligands might act as potential treatments in human respiratory diseases. 相似文献
18.
Choe MM Sporn PH Swartz MA 《American journal of physiology. Lung cellular and molecular physiology》2003,285(2):L427-L433
Recent studies have shown that mechanical forces on airway epithelial cells can induce upregulation of genes involved in airway remodeling in diseases such as asthma. However, the relevance of these responses to airway wall remodeling is still unclear since 1). mechanotransduction is highly dependent on environment (e.g., matrix and other cell types) and 2). inflammatory mediators, which strongly affect remodeling, are also present in asthma. To assess the effects of mechanical forces on the airway wall in a relevant three-dimensional inflammatory context, we have established a tissue culture model of the human airway wall that can be induced to undergo matrix remodeling. Our model contains differentiated human bronchial epithelial cells characterized by tight junctions, cilia formation, and mucus secretion atop a collagen gel embedded with human lung fibroblasts. We found that addition of activated eosinophils and the application of 50% strain to the same system increased the epithelial thickness compared with either condition alone, suggesting that mechanical strain affects airway wall remodeling synergistically with inflammation. This integrated model more closely mimics airway wall remodeling than single-cell, conditioned media, or even two-dimensional coculture systems and is relevant for examining the importance of mechanical strain on airway wall remodeling in an inflammatory environment, which may be crucial for understanding and treating pathologies such as asthma. 相似文献
19.
Identification of pendrin as a common mediator for mucus production in bronchial asthma and chronic obstructive pulmonary disease 总被引:2,自引:0,他引:2
Nakao I Kanaji S Ohta S Matsushita H Arima K Yuyama N Yamaya M Nakayama K Kubo H Watanabe M Sagara H Sugiyama K Tanaka H Toda S Hayashi H Inoue H Hoshino T Shiraki A Inoue M Suzuki K Aizawa H Okinami S Nagai H Hasegawa M Fukuda T Green ED Izuhara K 《Journal of immunology (Baltimore, Md. : 1950)》2008,180(9):6262-6269
Excessive production of airway mucus is a cardinal feature of bronchial asthma and chronic obstructive pulmonary disease (COPD) and contributes to morbidity and mortality in these diseases. IL-13, a Th2-type cytokine, is a central mediator in the pathogenesis of bronchial asthma, including mucus overproduction. Using a genome-wide search for genes induced in airway epithelial cells in response to IL-13, we identified pendrin encoded by the SLC26A4 (PDS) gene as a molecule responsible for airway mucus production. In both asthma and COPD mouse models, pendrin was up-regulated at the apical side of airway epithelial cells in association with mucus overproduction. Pendrin induced expression of MUC5AC, a major product of mucus in asthma and COPD, in airway epithelial cells. Finally, the enforced expression of pendrin in airway epithelial cells in vivo, using a Sendai virus vector, rapidly induced mucus overproduction in the lumens of the lungs together with neutrophilic infiltration in mice. These findings collectively suggest that pendrin can induce mucus production in airway epithelial cells and may be a therapeutic target candidate for bronchial asthma and COPD. 相似文献
20.
Yunee Kim Heba Atalla Bonnie Mallard Claude Robert Niel Karrow 《BMC veterinary research》2011,7(1):1-13