Home About us Contact
|
Home About us Contact | ||
|
|
||
Lung Inflammation (lung + inflammation)
Selected AbstractsConversion of Th17-type into Th2-type inflammation by acetyl salicylic acid via the adenosine and uric acid pathway in the lungALLERGY, Issue 9 2010H.-G. Moon To cite this article: Moon H-G, Tae Y-M, Kim Y-S, Gyu Jeon S, Oh S-Y, Song Gho Y, Zhu Z, Kim Y-K. Conversion of Th17-type into Th2-type inflammation by acetyl salicylic acid via the adenosine and uric acid pathway in the lung. Allergy 2010; 65: 1093,1103. Abstract Background:, Allergen-specific T-cell responses orchestrate airway inflammation, which is a characteristic of asthma. Recent evidence suggests that noneosinophilic asthma can be developed by mixed Th1 and Th17 cell responses when exposed to lipopolysaccharide (LPS)-containing allergens. Objective:, To evaluate the therapeutic or adverse effects of acetyl salicylic acid (ASA) on the expression of Th1-type and Th17-type inflammation induced by airway exposure to LPS-containing allergens. Methods:, Th1 + Th17 asthma and Th2 asthma mouse models were generated by intranasal sensitization with ovalbumin (OVA) and LPS and intraperitoneal sensitization with OVA and alum, respectively. Therapeutic or adverse effects were evaluated after allergen challenge using pharmacologic and transgenic approaches. Results:, Lung infiltration of eosinophils was enhanced in OVA/LPS-sensitized mice by ASA treatment, which was accompanied by the enhanced production of eotaxin. These changes were associated with the down-regulation of Th17 cell response, which was partly dependent on adenosine receptor A1 and A3 subtypes, but up-regulation of allergen-specific IL-13 production from T cells. Lung inflammation induced by LPS-containing allergen was markedly reduced in IL-13-deficient mice in the context of ASA treatment, but not without ASA. Meanwhile, adenosine levels in the lung were enhanced by ASA treatment. Moreover, lung infiltration of eosinophils induced by ASA treatment was reversed by co-treatment of a xanthine oxidase inhibitor (allopurinol). Conclusion:, These findings suggest that ASA changes Th17-type into Th2-type inflammation mainly via the adenosine and uric acid metabolic pathway in the lung. [source] Both Fc,RIV and Fc,RIII are essential receptors mediating type II and type III autoimmune responses via FcR,-LAT-dependent generation of C5aEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2009Shahzad N. Syed Abstract Fc,RIV is a relatively new IgG Fc receptor (Fc,R) that is reported to contribute to the pathogenesis of autoimmune diseases, although its specific role in relation to Fc,RIII, complement and IgG2 subclasses remains uncertain. Here we define Fc,RIV on macrophages as a receptor for soluble IgG2a/b complexes but not for cellular bound IgG2a and show that simultaneous activation of Fc,RIV and Fc,RIII is critical to mediate certain type II/III autoimmune responses. Fc,RIII-deficient mice display compensatory enhanced Fc,RIV expression, are protected from lung inflammation after deposition of IgG complexes, and show reduced sensitivity to IgG2a/b-mediated hemolytic anemia, indicating that increased Fc,RIV alone is not sufficient to trigger these diseases in the absence of Fc,RIII. Importantly, however, blockade of Fc,RIV is also effective in inhibiting phagocytosis and cytokine production in IgG2b-induced anemia and acute lung injury, processes that display a further dependence on C5a anaphylatoxin receptor. Using gene deletion and functional inhibition studies, we found that Fc,RIII and Fc,RIV are each essential to trigger an FcR,-linker for activation of T-cell-dependent signal that drives C5a production in the Arthus reaction. Together, the results demonstrate a combined requirement for Fc,RIII and Fc,RIV in autoimmune injury, and identify the linker for activation of T cells adaptor as an integral component of linked Fc,R and C5a anaphylatoxin receptor activation to generate inflammation. [source] Pulmonary stromal cells induce the generation of regulatory DC attenuating T-cell-mediated lung inflammationEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2008Qian Li Abstract The tissue microenvironment may affect the development and function of immune cells such as DC. Whether and how the pulmonary stromal microenvironment can affect the development and function of lung DC need to be investigated. Regulatory DC (DCreg) can regulate T-cell response. We wondered whether such regulatory DC exist in the lung and what is the effect of the pulmonary stromal microenvironment on the generation of DCreg. Here we demonstrate that murine pulmonary stromal cells can drive immature DC, which are regarded as being widely distributed in the lung, to proliferate and differentiate into a distinct subset of DCreg, which express high levels of CD11b but low levels of MHC class II (I-A), CD11c, secrete high amounts of IL-10, NO and prostaglandin E2 (PGE2) and suppress T-cell proliferation. The natural counterpart of DCreg in the lung with similar phenotype and regulatory function has been identified. Pulmonary stroma-derived TGF-, is responsible for the differentiation of immature DC to DCreg, and DCreg-derived PGE2 contributes to their suppression of T-cell proliferation. Moreover, DCreg can induce the generation of CD4+CD25+Foxp3+ Treg. Importantly, infusion with DCreg attenuates T-cell-mediated eosinophilic airway inflammation in vivo. Therefore, the pulmonary microenvironment may drive the generation of DCreg, thus contributing to the maintenance of immune homoeostasis and the control of inflammation in the lung. [source] Airway inflammation: chemokine-induced neutrophilia and the class,I phosphoinositide 3-kinasesEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2005Matthew Abstract Class,I phosphoinositide 3-kinases (PI3K) are known to play a significant role in neutrophil chemotaxis. However, the relative contributions of different PI3K isoforms, and how these impact on lung inflammation, have not been addressed. In vitro studies using wild-type and PI3K, knockout neutrophils demonstrated the major role of the ,,isoform in chemotactic but not chemokinetic events. This was confirmed by a model of direct chemokine instillation into the airways in vivo. Within all studies, a low yet significant degree of neutrophil movement in the absence of PI3K, could be observed. No role for the ,,isoform was demonstrated both in vitro and in vivo using PI3K, kinase-dead knock-in mice. Moreover, further studies using the broad-spectrum PI3K inhibitors wortmannin or LY294002 showed no other class,I PI3K isoforms to be involved in these chemotactic processes. Here, we identify a contributory PI3K-independent mechanism of neutrophil movement, yet demonstrate PI3K, as the pivotal mediator through which the majority of neutrophils migrate into the lung in response to chemokines. These data resolve the complexities of chemokine-induced neutrophilia and PI3K signaling and define the ,,isoform as a promising target for new therapeutics to treat airway inflammatory diseases. [source] Fas ligand-induced murine pulmonary inflammation is reduced by a stable decoy receptor 3 analogueIMMUNOLOGY, Issue 2 2003Mark A. Wortinger Summary Fas ligand (FasL)-induced lung inflammation has recently been suggested to play an important role in the pathogenesis of acute respiratory disease syndrome (ARDS). In order to further explore this connection, we established a FasL-induced murine model of pulmonary inflammation. Instillation of recombinant FasL (rFasL) into the lung induced neutrophil infiltration and increased pulmonary permeability, as evidenced by increased total protein in the airspace; both occur in patients with ARDS. These effects were accompanied with a rapid induction of proinflammatory mediators: cytokine granulocyte,macrophage colony-stimulating factor (GM-CSF) and the chemokines macrophage inflammatory protein-2 (MIP-2) and KC. Pretreatment with a FasL antagonist, a decoy receptor 3 analogue (DcR3 analogue), reduced neutrophil infiltration into the airspace and resulted in a highly significant reduction in the levels of GM-CSF, MIP-2 and KC in bronchoalveolar lavage (BAL) fluid. We postulate that rFasL may be responsible for induction of proinflammatory chemokines and cytokines in the lung, which in turn attract neutrophil infiltration into the airspace. This proinflammatory process and the associated pulmonary permeability may, in part, explain the association of FasL with severe pulmonary inflammation, such as ARDS, and shed new light on FasL and its role in lung injury. [source] Testing Nanomaterials of Unknown Toxicity: An Example Based on Platinum Nanoparticles of Different Shapes,ADVANCED MATERIALS, Issue 20 2007A. Elder Human endothelial and lung epithelial cells were exposed to nanosized Pt shapes following acellular analyses of their oxidant potential. Despite clear evidence of particle uptake by cells, the Pt nanoparticles were not found to induce cytotoxicity or oxidative stress in either cell type. Results from in vivo respiratory tract exposures suggest that the particles are retained by lung tissue and that minimal-mild lung inflammation results from exposure to the nanosized Pt particles. [source] Lack of Clinical Efficacy of a Phosphodiesterase-4 Inhibitor for Treatment of Heaves in HorsesJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 1 2006Jean-Pierre Lavoie Phosphodiesterase-4 (PDE 4) enzyme inhibitors have been shown to have anti-inflammatory properties in various animal disease processes and therefore could be effective drugs for the treatment of equine airway diseases. The purpose of this study was to evaluate the efficacy and adverse effects of the PDE 4 inhibitor L-826,141 in horses with heaves. In a blinded parallel design, horses with heaves exposed daily to moldy hay were given a placebo for 14 days and then administered either L-826,141 (n = 6; loading dose of 1 mg/kg IV followed by 0.5 mg/kg IV q48h) or dexamethasone (n = 6; 0.04 mg/kg IV q24h) from days 15 to 29 (study 1). Pulmonary function and bronchoalveolar (BAL) cytology were evaluated weekly from baseline (day 0) to 29 days. In study 2, horses were treated with L-826,141 (1.0 mg/kg IV q24h) for 8 days. Although ex vivo lipopolysaccharide-induced tumor necrosis factor (TNF)-, and LTB4 production by fresh blood were inhibited up to 90% after repeated administrations of L-826,141, this treatment failed to improve lung function. In contrast, dexamethasone (positive control) treatment resulted in significant improvement in lung mechanics and airway function in all horses. Neither drug had a significant effect on BAL total cell counts and differential cytology. Administration of the PDE 4 inhibitor L-826,141 for up to 14 days to horses with heaves was not associated with an improvement in airway function or inflammation. These findings suggest that the PDE 4 enzyme is not a key mediator of lung inflammation in heaves. [source] Targeting the allergen to oral dendritic cells with mucoadhesive chitosan particles enhances tolerance inductionALLERGY, Issue 7 2009N. Saint-Lu Background:, Sublingual immunotherapy (SLIT) efficacy could be improved by formulations facilitating allergen contact with the oral mucosa and uptake by antigen-presenting cells (APCs). Methods:, Two types of chitosan microparticles, differing in size and surface charge, were tested in vitro for their capacity to improve antigen uptake and presentation by murine bone marrow-derived dendritic cells (BMDCs) or purified oral APCs. T-cell priming in cervical lymph nodes (LNs) was assessed by intravenous transfer of carboxyfluorescein diacetate succinimidyl ester-labelled ovalbumin (OVA)-specific CD4+ T cells and flow cytometry analysis. Ovalbumin-sensitized BALB/c mice were treated sublingually with soluble or chitosan-formulated OVA twice a week for 2 months. Airway hyperresponsiveness (AHR), lung inflammation and T-cell responses in cervical and mediastinal LNs were assessed by whole-body plethysmography, lung histology and Cytometric Bead Array technology, respectively. Results:, Only a mucoadhesive (i.e. highly positively charged) and microparticulate form of chitosan enhances OVA uptake, processing and presentation by murine BMDCs and oral APCs. Targeting OVA to dendritic cells with this formulation increases specific T-cell proliferation and IFN-,/IL-10 secretion in vitro, as well as T-cell priming in cervical LNs in vivo. Sublingual administration of such chitosan-formulated OVA particles enhances tolerance induction in mice with established asthma, with a dramatic reduction of both AHR, lung inflammation, eosinophil numbers in bronchoalveolar lavages, as well as antigen-specific Th2 responses in mediastinal LNs. Conclusions:, Mucoadhesive chitosan microparticles represent a valid formulation for sublingual allergy vaccines. [source] Detecting early structural lung damage in cystic fibrosis,,PEDIATRIC PULMONOLOGY, Issue 3 2002Harm A.W.M. Tiddens MD In cystic fibrosis (CF) patients, both severe lung inflammation and severe lung damage occur early and persist throughout life. High-resolution computed tomography (HRCT), a more sensitive method of detecting structural abnormalities than chest X-ray, shows that airways undergo substantial thickening in early CF lung disease. Lung function tests, which are an indirect measure of structural integrity, are insensitive to localized or early damage. Thickening of the peripheral airways causes a reduction in maximal expiratory flow at 25% of forced vital capacity (MEF25) or other measurements of peripheral air flow. Reduced peripheral flows, even in the presence of normal forced expired volume in 1 sec (FEV1) and forced vital capacity (FVC), should be considered an early sign of substantial lung damage and should stimulate aggressive treatment to prevent further deterioration. Pediatr Pulmonol. 2002; 34:228,231. © 2002 Wiley-Liss, Inc. [source] Impact of oxidative stress on lung diseasesRESPIROLOGY, Issue 1 2009Hee Sun PARK ABSTRACT Reactive oxygen species (ROS) are products of normal cellular metabolism and are known to act as second messengers. Under physiological conditions, ROS participate in maintenance of cellular ,redox homeostasis' in order to protect cells against oxidative stress through various redox-regulatory mechanisms. Overproduction of ROS, most frequently due to excessive stimulation of either reduced nicotinamide adenine dinucleotide phosphate by cytokines or the mitochondrial electron transport chain and xanthine oxidase, results in oxidative stress. Oxidative stress is a deleterious process that leads to lung damage and consequently to various disease states. Knowledge of the mechanisms of ROS regulation could lead to the pharmacological manipulation of antioxidants in lung inflammation and injury. [source] Role of Protease Activated Receptor 2 in Experimental Acute Lung Injury and Lung FibrosisTHE ANATOMICAL RECORD : ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY, Issue 4 2009Xiao Su Abstract Protease activated receptor 2 (PAR2) is widely-distributed (lung, liver, kidney, etc.) and expressed by variety of cells (i.e. leukocytes, epithelial cells, endothelial cells, and fibroblast). PAR2 may participate in many pathological processes, such as, inflammation, injury, as well as fibrosis. Therefore, in this study, we tested whether PAR2 would exert a role in acid-induced acute lung injury, E. coli pneumonia, bleomycin-induced acute lung injury and fibrosis. Acid, E. coli, or bleomycin were intratracheally instilled into the lungs of both wildtype and PAR2 knockout mice to detect differences in pulmonary edema, lung vascular permeability, lung fibrosis, and other parameters. Knockout of PAR2 did not affect the extent of pulmonary edema and lung vascular permeability in acid-induced acute lung injury. Also, both activation of PAR2 in the airspaces of the lung and deletion of PAR2 did not alter the magnitude of pulmonary edema and lung vascular permeability in E. coli pneumonia. Finally, PAR2 deficiency did not affect the severity of lung inflammation and lung fibrosis in bleomycin-induced acute lung injury and lung fibrosis models. Thus, PAR2 does not appear to play a critical role in the pathogeneses of experimental acid-induced acute lung injury, E. coli pneumonia, and bleomycin-induced acute lung injury and pulmonary fibrosis in mice. Anat Rec, 2009. © 2009 Wiley-Liss, Inc. [source] C-C chemokine receptor 2 (CCR2) deficiency improves bleomycin-induced pulmonary fibrosis by attenuation of both macrophage infiltration and production of macrophage-derived matrix metalloproteinasesTHE JOURNAL OF PATHOLOGY, Issue 5 2004Toshiyuki Okuma Abstract Macrophage infiltration is implicated in various types of pulmonary fibrosis. One important pathogenetic process associated with pulmonary fibrosis is injury to basement membranes by matrix metalloproteinases (MMPs) that are produced mainly by macrophages. In this study, C-C chemokine receptor 2-deficient (CCR2,/,) mice were used to explore the relationship between macrophage infiltration and MMP activity in the pathogenesis of pulmonary fibrosis, using the bleomycin-induced model of this disease process. CCR2 is the main (if not only) receptor for monocyte chemoattractant protein-1/C-C chemokine ligand 2 (MCP-1/CCL2), which is a critical mediator of macrophage trafficking, and CCR2 ,/, mice demonstrate defective macrophage migration. Pulmonary fibrosis was induced in CCR2,/, and wild-type (CCR2+/+) mice by intratracheal instillation of bleomycin. No significant differences in the total protein concentration in bronchoalveolar lavage (BAL) fluid, or in the degree of histological lung inflammation, were observed in the two groups until day 7. Between days 3 and 21, however, BAL fluid from CCR2,/, mice contained fewer macrophages than BAL fluid from CCR2+/+ mice. Gelatin zymography of BAL fluid and in situ zymography revealed reduced gelatinolytic activity in CCR2,/, mice. Immunocytochemical staining showed weaker expression of MMP-2 and MMP-9 in macrophages in BAL fluid from CCR2,/, mice at day 3. Gelatin zymography of protein extracted from alveolar macrophages showed reduced gelatinolytic activity of MMP-2 and MMP-9 in CCR2,/, mice. At days 14 and 21, lung remodelling and the hydroxyproline content of lung tissues were significantly reduced in CCR2,/, mice. These results suggest that the CCL2/CCR2 functional pathway is involved in the pathogenesis of bleomycin-induced pulmonary fibrosis and that CCR2 deficiency may improve the outcome of this disease by regulating macrophage infiltration and macrophage-derived MMP-2 and MMP-9 production. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] The immune response to chronic Pseudomonas aeruginosa lung infection in cystic fibrosis patients is predominantly of the Th2 typeAPMIS, Issue 5 2000Claus Moser Most cystic fibrosis (CF) patients with chronic Pseudomonas aeruginosa lung infection have a persistent acute type lung inflammation dominated by polymorphonuclear neutrophils (PMN) and a pronounced antibody response against P. aeruginosa. We speculated whether this immune response in CF is of the Th2 type and whether a change to a Th1 type immune response could improve the prognosis. Therefore, we studied 14 CF patients with (CF +P) and 14 CF patients without (CF ,P) chronic P. aeruginosa lung infection. The specific production of interferon-gamma (IFN-,) and interleukin-4 (IL-4) by peripheral blood mononuclear cells was determined. Cells from CF +P patients had lower IFN-, (p<0.05) and higher IL-4 (p<0.005) production as compared to cells from CF -P patients. Furthermore, a positive correlation between IFN-, production and lung function was found (FVC: Rho=0.637; p<0.03; FEV1: Rho=0.524; p<0.07). We conclude that a Th2 type immune response is most frequent in CF patients with chronic P. aeruginosa lung infection, and the patients with a Th1-dominated immune response had the best lung function. The clinical implication is that a change to a Th1 type immune response might improve the prognosis in these patients. [source] Early-life co-administration of cockroach allergen and endotoxin augments pulmonary and systemic responsesCLINICAL & EXPERIMENTAL ALLERGY, Issue 7 2009K. Kulhankova Summary Background Environmental exposures to cockroach allergen and endotoxin are recognized epidemiological risk factors for the early development of allergies and asthma in children. Because of this, it is important to examine the role of early-life concurrent inhalation exposures to cockroach allergen and endotoxin in the pathogenesis of allergic airways disease. Objective We examined the effects of repeated concomitant endotoxin and cockroach allergen inhalation on the pulmonary and systemic immune responses of newborn and juvenile mice. Methods C3H/HeBFeJ mice were exposed to inhaled endotoxin and cockroach allergen via intranasal instillation from day 2 to 21 after birth, and systemic and pulmonary responses were examined in serum, bronchoalveolar lavage fluid, and lung tissue. Results Cockroach allergen exposures induced pulmonary eosinophilic inflammation, total and allergen-specific IgE, IgG1, and IgG2a production, and alveolar remodelling. Co-exposures with endotoxin and cockroach allergen significantly increased serum IgE and IgG1, lung inflammation, and alveolar wall thickness, and decreased airspace volume density. Importantly, compared with exposures with individual substances, the responses to co-exposures were more than additive. Conclusions Repeated inhalation exposures of neonatal and juvenile mice to endotoxin and cockroach allergen increased the pulmonary inflammatory and systemic immune responses in a synergistic manner and enhanced alveolar remodelling in the developing lung. These data underscore the importance of evaluating the effect of multiple, concurrent environmental exposures, and of using an experimental model that incorporates clinically relevant timing and route of exposures. [source] Inflammatory cell mapping of the respiratory tract in fatal asthmaCLINICAL & EXPERIMENTAL ALLERGY, Issue 5 2005S. De Magalhães Simões Summary Background The site and distribution of inflammation in the airways of asthmatic patients has been largely investigated. Inflammatory cells are distributed in both large and small airways in asthma. It has been demonstrated that distal lung inflammation in asthma may significantly contribute to the pathophysiology of the disease. The upper airways have also been implicated in the overall asthmatic inflammation. Although it is now accepted that lung inflammation is not restricted to the intrapulmonary airways in asthma, little is known about cell distribution in the other lung compartments and their relation to the intrapulmonary airways. Objective We aimed to map the inflammatory process in fatal asthma (FA), from the upper airways to the lung parenchyma. Methods Eosinophil, neutrophil, mast cell and lymphocyte content were determined in nasal mucosa, the trachea, intrapulmonary airways and parenchyma (peribronchiolar and distal) of 20 patients with FA and 10 controls. Results Eosinophil content was higher in all studied areas in FA compared with controls (P<0.02). Mast cell content was higher in the outer area of larger airways, small membranous bronchioles and in peribronchiolar parenchyma of FA compared with controls (P<0.04). CD3+, CD4+and CD20+cells showed increased content in FA intrapulmonary airways compared with controls (P<0.05). There was a positive correlation between CD4+cell content in nasal mucosa and larger airways in asthmatics. Increased neutrophil content was observed only in peribronchiolar parenchyma of FA (P=0.028). Conclusion Eosinophils present a widespread distribution within the respiratory tract in FA, from the nasal mucosa to the distal lung. The outer wall of small membranous bronchioles is the main site of inflammatory changes in FA. There is a localized distribution of alveolar inflammation at the peribronchiolar region for mast cells and neutrophils. Our findings provide further evidence of the importance of the lung periphery in the pathophysiology of FA. [source] Intranasal exposure to a damp building mould, Stachybotrys chartarum, induces lung inflammation in mice by satratoxin-independent mechanismsCLINICAL & EXPERIMENTAL ALLERGY, Issue 11 2003M. Leino Summary Background Stachybotrys chartarum is a damp building mould and a potent toxin producer that has been related to serious cases of respiratory health problems. However, the direct link between exposure and health symptoms has not been established. Objective To examine the mechanism by which exposure to spores of satratoxin producing and non-producing S. chartarum strains induce inflammatory responses in murine lungs. Methods BALB/c mice were intranasally exposed for 3 weeks to spores of a satratoxin-producing and a non-producing S. chartarum strain. Inflammatory cell infiltration was characterized from bronchoalveolar lavage (BAL) fluid. Cytokine and chemokine mRNA expression in lung tissue was measured with real-time PCR. Bronchial responsiveness to methacholine (MCh) was determined by whole-body plethysmography and serum antibody levels by ELISA. Results A dose-dependent increase in monocytes, neutrophils and lymphocytes was observed in BAL fluid after intranasal (i.n.) instillation of S. chartarum spores. There was no difference in the BAL between exposure to the satratoxin-producing and the non-producing strains. Infiltration of inflammatory cells was associated with an induction of pro-inflammatory cytokine (IL-1,, IL-6 and TNF-,) and chemokine (CCL3/MIP-1,, CCL4/MIP-1, and CCL2/MCP-1) mRNA levels in the lungs. Interestingly, CXCL5/LIX was the only chemokine that showed significantly higher mRNA levels after exposure to the satratoxin-producing strain compared with the non-producing strain. MCh-induced bronchial responsiveness was not altered significantly after mould instillation. Moreover, no significant increase in total or specific IgE, IgG2a and IgG1 antibody levels were found after S. chartarum exposure. Conclusion These results indicate that lung inflammation induced by i.n. instillations of S. chartarum spores is regulated by the induction of pro-inflammatory cytokines and leucocyte-attracting chemokines. The data also imply that S. chartarum -derived components, other than satratoxins, are mediating the development of this inflammatory response. [source] | |||||||||||||||||||||||||