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ABSTRACT: IL-33 and its receptor ST2 are over-expressed in clinical colitis tissue. However, the significance of these observations is at present unknown. Significantly, we demonstrate here that IL33 and ST2 are the primary early genes induced in the inflamed colon of BALB/c mice following dextran sulphate sodium (DSS)-induced experimental ulcerative colitis. Accordingly diarrhoea and DSS induced colon inflammation were impaired in ST2(-/-) BALB/c mice and exacerbated in WT mice by treatment with exogenous recombinant IL-33, associated respectively with reduced and enhanced expression of chemokines (CXCL9 and CXCL10), inflammatory (IL-4, IL-13, IL-1, IL-6, IL-17), and angiogenic (VEGF) cytokines in vivo. The exacerbation effect of treatment with recombinant IL-33 on DSS-induced acute colitis was abolished in IL-4(-/-) BALB/c mice. Thus, IL-33 signalling via ST2, by inducing an IL-4-dependent immune response may be a major pathogenic factor in the exacerbation of ulcerative colitis. This article is protected by copyright. All rights reserved.
Immunology 04/2013; · 3.32 Impact Factor
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ABSTRACT: BACKGROUND: Clinical outcomes are worse in current smokers and exsmokers with mild-to-moderate asthma compared with never smokers, but little is known about the influence of smoking status in patients with severe asthma. OBJECTIVES: We sought to examine the association of current or previous cigarette smoking with clinical and inflammatory variables in patients with severe asthma. METHODS: We compared patients' demographics, disease characteristics, and biomarkers of inflammation in current smokers (n = 69 [9%]), exsmokers (n = 210 [28%]), and never smokers (n = 461 [62%]) with severe asthma (n = 760) recruited to the British Thoracic Society Severe Asthma Registry. RESULTS: Current smokers had poorer asthma control, more unscheduled health care visits, more rescue courses of oral steroids, and higher anxiety and depression scale scores than exsmokers or never smokers. Current smokers had a reduced proportion of sputum eosinophils compared with never smokers (1% and 4%, respectively) and lower fraction of expired nitric oxide (50 mL/s; 14 ppb and 35 ppb, respectively). Exsmokers compared with never smokers had an increased proportion of sputum neutrophils (59% and 43%, respectively) but a similar proportion of sputum eosinophils (3%) and fraction of expired nitric oxide (50 mL/s; 35 ppb). Both current smokers and exsmokers had reduced serum specific IgE levels to several common environmental allergens. CONCLUSION: Current smokers with severe asthma exhibit worse clinical and health care outcomes compared with exsmokers and never smokers with severe asthma. Their inflammatory profiles in sputum and blood differ.
The Journal of allergy and clinical immunology 02/2013; · 9.17 Impact Factor
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Rekha Chaudhuri, Charles McSharry,
Jeffrey Brady,
Iona Donnelly,
Christal Grierson,
Stephen McGuinness,
Lisa Jolly,
Christopher J Weir,
C Martina Messow,
Mark Spears, [......],
Maureen Brannigan,
Jane Lafferty,
Michael Sproule,
William Macnee,
Martin Connell,
John T Murchison,
Malcolm C Shepherd,
Giora Feuerstein,
Douglas K Miller,
Neil C Thomson
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ABSTRACT: Matrix metalloproteinase (MMP)-12 has been implicated in the pathogenesis of both chronic obstructive pulmonary disease (COPD) and asthma. The influence of disease severity on sputum MMP-12 concentrations and activity is not known.
We sought to examine the relationship between disease severity assessed by means of lung function and computed tomography (CT) and induced sputum MMP-12 concentrations and activity in patients with asthma and COPD.
In 208 subjects (109 asthmatic patients, smokers and never smokers, mild, moderate, and severe; 53 patients with COPD, smokers and exsmokers, mild, moderate, and severe; and 46 healthy control subjects, smokers and never smokers), we measured induced sputum MMP-12 concentrations (ELISA) and enzyme activity (fluorescence resonance energy transfer), sputum cell MMP12 mRNA expression (quantitative PCR [qPCR]), diffusing capacity for carbon monoxide (Dlco), and CT assessment of emphysema (percentage of low-attenuation areas at less -950 Hounsfield units).
Sputum MMP-12 concentrations are greater in patients with COPD and smokers with asthma than in healthy nonsmokers (P = .003 and P = .035, respectively) but similar to those seen in healthy smokers. In patients with COPD, disease severity, when measured by means of CT-assessed emphysema, but not by means of spirometry or Dlco values, is directly associated with sputum MMP-12 concentrations and activity. In the asthma groups there is no significant association between disease severity and sputum MMP-12 concentrations or activity.
Sputum MMP-12 concentrations and activity in patients with COPD are directly associated with the extent of emphysema measured by means of CT. This finding supports a role for MMP-12 in the pathogenesis of COPD and might suggest that blocking MMP-12 activity in patients with COPD could prevent the further development of emphysema.
The Journal of allergy and clinical immunology 03/2012; 129(3):655-663.e8. · 9.17 Impact Factor
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Jeffrey T J Huang,
Rekha Chaudhuri,
Osama Albarbarawi,
Alun Barton,
Christal Grierson,
Petra Rauchhaus,
Christopher J Weir,
Martina Messow,
Nicola Stevens, Charles McSharry,
Giora Feuerstein,
Somnath Mukhopadhyay,
Jeffrey Brady,
Colin N A Palmer,
Douglas Miller,
Neil C Thomson
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ABSTRACT: Although an increased concentration of degraded elastin products in patients with chronic obstructive pulmonary disease (COPD) has been reported for many years, its clinical validity and utility remain uncertain due to technical difficulties, small study groups and the unknown relationship between exacerbation and elastin degradation. The objectives of this study were to determine the validity of urinary and blood total desmosine/isodesmosine in patients with COPD and asthma and to evaluate their relationship to exacerbation status and lung function.
Urinary and blood desmosine levels were measured using validated isotopic dilution liquid chromatography-tandem mass spectrometry methods.
390 study participants were recruited from the following groups: healthy volunteers, stable asthma, stable and 'during an exacerbation' COPD. Compared with healthy non-smokers, we found increased urinary or blood desmosine levels in patients with COPD, but no differences in patients with asthma or healthy smokers. The elevation of urinary desmosine levels was associated with the exacerbation status in patients with COPD. Approximately 40% of patients with stable and 'during an exacerbation' COPD showed elevated blood desmosine levels. Blood desmosine levels were strongly associated with age and were negatively correlated with lung diffusing capacity for carbon monoxide.
The results suggest that urinary desmosine levels are raised by exacerbations of COPD whereas blood desmosine levels are elevated in a subgroup of patients with stable COPD and reduced lung diffusing capacity. The authors speculate that a raised blood desmosine level may identify patients with increased elastin degradation suitable for targeted therapy. Future prospective studies are required to investigate this hypothesis.
Thorax 02/2012; 67(6):502-8. · 6.84 Impact Factor
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ABSTRACT: Alcohol intake is inversely related to rheumatoid arthritis (RA) disease incidence and severity. Resveratrol, a safe, well-described plant-derived compound, possesses anti-inflammation and immune-regulatory properties and is present in red wine. As such, it could mediate anti-inflammatory properties of the latter and offer novel therapeutic utility in is own right.
To evaluate the therapeutic effect of resveratrol on collagen-induced arthritis (CIA) and its putative immune modulation in mice.
CIA was induced in DBA1 mice by immunisation with collagen II. Different doses of resveratrol were administered before or after the development of CIA. The levels of antibody and cytokines in serum or in draining lymph node (DLN) lymphocyte culture supernatants were measured by ELISA and Th17 cell development in DLN was monitored by flow cytometry.
Either prophylactic or therapeutic administration of resveratrol attenuated clinical parameters and bone erosion in CIA mice. The arthritis-protective effects were associated with markedly reduced serum levels of pro-inflammatory cytokines and collagen-specific, but not total, IgG, and with reduced numbers of Th17 cells and the production of IL-17 in DLN.
Resveratrol modulates inflammatory arthritis in rodents by selectively suppressing key cellular and humoral responses necessary for disease development. This may partly explain the protective effects of red wine but importantly may offer a novel, effective and safe pathway whereby novel agents could be developed to treat RA.
Annals of the rheumatic diseases 09/2011; 71(1):129-35. · 8.11 Impact Factor
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ABSTRACT: Exhaled nitric oxide provides a convenient, non-invasive insight into airway inflammation. However it is suppressed by current smoking, reducing its potential as an endpoint in studies of smokers with asthma, a group with increased symptoms and poor clinical responses to corticosteroids. We examined extended nitric oxide analysis as some derived variables are thought to be unaffected. Therefore this approach could reveal hidden inflammation and enable its use as an exploratory endpoint in this group.
Smokers (n = 22) and never smokers (n = 21) with asthma performed exhaled nitric oxide measurements and spirometry before and after two weeks of oral dexamethasone (6 mg/1.74 m(2)/day). Linear and non-linear nitric oxide analysis was performed to derive estimates for alveolar nitric oxide (C(alv)) and nitric oxide flux (J'(aw)) for each subject.
FE(NO50) was significantly lower in smokers with asthma and did not change significantly in response to dexamethasone. C(alv) derived by linear modelling was lower in smokers with asthma and did not change significantly in response in either group. J'(aw) was substantially lower in smokers with asthma (smokers (median (IQR)); 573 pl/s (217, 734), non-smoker; 1535 pl/s (785, 3496), p = 0.001) and was reduced in both groups following dexamethasone (non-smokers change (mean (95% CI)); -743.3 pl/s (-1710, -163), p = 0.005, smokers; -293 pl/s (-572, -60), p = 0.016). Correction for axial flow did not substantially change the derived results.
Bronchial NO flux appears to be sensitive to oral dexamethasone and may provide a useful exploratory endpoint for the analysis of novel anti-inflammatory therapies in smokers with asthma.
Respiratory medicine 08/2011; 105(12):1823-30. · 2.33 Impact Factor
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Mariola Kurowska-Stolarska,
Stefano Alivernini,
Lucy E Ballantine,
Darren L Asquith,
Neal L Millar,
Derek S Gilchrist,
James Reilly,
Michelle Ierna,
Alasdair R Fraser,
Bartosz Stolarski, Charles McSharry,
Axel J Hueber,
Derek Baxter,
John Hunter,
Steffen Gay,
Foo Y Liew,
Iain B McInnes
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ABSTRACT: MicroRNA (miRNA) species (miR) regulate mRNA translation and are implicated as mediators of disease pathology via coordinated regulation of molecular effector pathways. Unraveling miR disease-related activities will facilitate future therapeutic interventions. miR-155 recently has been identified with critical immune regulatory functions. Although detected in articular tissues, the functional role of miR-155 in inflammatory arthritis has not been defined. We report here that miR-155 is up-regulated in synovial membrane and synovial fluid (SF) macrophages from patients with rheumatoid arthritis (RA). The increased expression of miR-155 in SF CD14(+) cells was associated with lower expression of the miR-155 target, Src homology 2-containing inositol phosphatase-1 (SHIP-1), an inhibitor of inflammation. Similarly, SHIP-1 expression was decreased in CD68(+) cells in the synovial lining layer in RA patients as compared with osteoarthritis patients. Overexpression of miR-155 in PB CD14(+) cells led to down-regulation of SHIP-1 and an increase in the production of proinflammatory cytokines. Conversely, inhibition of miR-155 in RA synovial CD14(+) cells reduced TNF-α production. Finally, miR-155-deficient mice are resistant to collagen-induced arthritis, with profound suppression of antigen-specific Th17 cell and autoantibody responses and markedly reduced articular inflammation. Our data therefore identify a role of miR-155 in clinical and experimental arthritis and suggest that miR-155 may be an intriguing therapeutic target.
Proceedings of the National Academy of Sciences 06/2011; 108(27):11193-8. · 9.68 Impact Factor
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Georgina Braganza,
Rekha Chaudhuri, Charles McSharry,
Christopher J Weir,
Iona Donnelly,
Lisa Jolly,
Jane Lafferty,
Suzanne M Lloyd,
Mark Spears,
Frances Mair,
Neil C Thomson
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ABSTRACT: The immune modulating properties of statins may benefit smokers with asthma. We tested the hypothesis that short-term treatment with atorvastatin improves lung function or indices of asthma control in smokers with asthma.
Seventy one smokers with mild to moderate asthma were recruited to a randomized double-blind parallel group trial comparing treatment with atorvastatin (40 mg per day) versus placebo for 4 weeks. After 4 weeks treatment inhaled beclometasone (400 μg per day) was added to both treatment arms for a further 4 weeks. The primary outcome was morning peak expiratory flow after 4 weeks treatment. Secondary outcome measures included indices of asthma control and airway inflammation.
At 4 weeks, there was no improvement in the atorvastatin group compared to the placebo group in morning peak expiratory flow [-10.67 L/min, 95% CI -38.70 to 17.37, p = 0.449], but there was an improvement with atorvastatin in asthma quality of life score [0.52, 95% CI 0.17 to 0.87 p = 0.005]. There was no significant improvement with atorvastatin and inhaled beclometasone compared to inhaled beclometasone alone in outcome measures at 8 weeks.
Short-term treatment with atorvastatin does not alter lung function but may improve asthma quality of life in smokers with mild to moderate asthma.
Clinicaltrials.gov identifier: NCT00463827.
BMC Pulmonary Medicine 01/2011; 11:16. · 1.33 Impact Factor
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ABSTRACT: Chronic obstructive pulmonary disease (COPD) has been identified as a risk factor for ischaemic heart disease, independent of smoking history, and inflammation is thought to play a role.
We sought to ascertain whether occult myocardial infarction (MI) was present in the COPD population, and to assess its relationship with inflammation and natriuretic peptides.
We recruited 25 patients with moderate/severe COPD and 17 control smokers without lung disease. All participants had no known cardiac disease. Contrast-enhanced cardiac magnetic resonance imaging was performed and analysed for delayed contrast enhancement (DE), indicative of previous MI. All participants had venous blood samples taken for assessment of NT-proBNP and inflammatory markers.
DE was not found in any participant. Right ventricular ejection fraction was lower in COPD patients. Other cardiac measurements and NT-proBNP levels were similar in the 2 groups. C-reactive protein, IL-8, GM-CSF, IL-1 beta and TNF-alpha were all significantly higher in the COPD group.
DE, indicating previous MI, was not found in patients with moderate/severe COPD. Occult MI does not appear to be common in this population, but a larger study would be needed to conclusively test this.
Respiration 03/2009; 78(3):263-9. · 2.26 Impact Factor
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E J Hothersall,
R Chaudhuri, C McSharry,
I Donnelly,
J Lafferty,
A D McMahon,
C J Weir,
J Meiklejohn,
N Sattar,
I McInnes,
S Wood,
N C Thomson
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ABSTRACT: Statins have anti-inflammatory properties that may be beneficial in the treatment of asthma. A study was undertaken to test the hypothesis that atorvastatin added to inhaled corticosteroids improves lung function and airway inflammation in atopic adults with asthma.
54 adults with atopic asthma were recruited to a double-blind randomised controlled crossover trial comparing the effect of oral atorvastatin 40 mg daily with that of a matched placebo on asthma control and airway inflammation. Each treatment was administered for 8 weeks separated by a 6-week washout period. The primary outcome was morning peak expiratory flow (PEF). Secondary outcomes included forced expiratory volume in 1 s, asthma control questionnaire score, airway hyper-responsiveness to methacholine, induced sputum cytology and inflammatory biomarkers.
At 8 weeks the change in mean morning PEF compared with baseline did not differ substantially between the atorvastatin and placebo treatment periods (mean difference -0.5 l/min, 95% CI -10.6 to 9.6, p = 0.921). Values for other clinical outcomes were similar between the atorvastatin and placebo treatment periods. The absolute sputum macrophage count was reduced after atorvastatin compared with placebo (mean difference -45.0 x 10(4) cells, 95% CI -80.1 to -9.7, p = 0.029), as was the sputum fluid leucotriene B4 (mean difference -88.1 pg/ml, 95% CI -156.4 to -19.9, p = 0.014).
The addition of atorvastatin to inhaled corticosteroids results in no short-term improvement in asthma control but reduces sputum macrophage counts in mild to moderate atopic asthma. The change in sputum macrophage count suggests potential areas for investigation of statins in other chronic lung diseases.
Thorax 09/2008; 63(12):1070-5. · 6.84 Impact Factor
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ABSTRACT: Sensitization to the house dust mite (Dermataphagoides pteronyssinus) (HDM) is the most common risk factor associated with the development of asthma in adults and children. The effectiveness of HDM control measures in the treatment of asthma is not yet proven. The strategies for control for avoidance depend on our understanding of the biology of the HDM. The evidence suggests a favorable effect of transferring allergic asthmatic children to naturally low dust mite environments, such as at altitude or in hospital, but little to suggest that this can be replicated in general practice by simple practical measures such as mattress covers. However, a recent multi-allergen reduction approach has suggested benefits may be achievable. HDM densities tend to be high in warm, humid conditions in the home, which may be modified by external factors, such as ventilation. However, ventilation control to reduce indoor humidity has had inconsistent effects on dust mite levels and asthma. The challenge is to further refine the interventions in large placebo-controlled trials such that clinical outcomes may be more easily demonstrated.
Therapeutics and Clinical Risk Management 01/2007; 2(4):347-54.
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ABSTRACT: Extrinsic allergic alveolitis (also known as hypersensitivity pneumonitis) is caused by repeated inhalation of mainly organic antigens by sensitized subjects. This induces a hypersensitivity response in the distal bronchioles and alveoli and subjects may present clinically with a variety of symptoms. The aims of this review are to describe the current concepts of the immunological response, the diverse clinical presentation of this disease, the relevant investigations and management, and areas for future studies.
Respirology 06/2006; 11(3):262-8. · 2.42 Impact Factor
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ABSTRACT: Detecting serum antibody against inhaled antigens is an important diagnostic adjunct for hypersensitivity pneumonitis (HP). We sought to validate a quantitative fluorimetric assay testing serum from bird fanciers.
Antibody activity was assessed in bird fanciers and control subjects using various avian antigens and serological methods, and the titer was compared with symptoms of HP.
IgG antibody against pigeon serum antigens, quantified by fluorimetry, provided a good discriminator of disease. Levels below 10 mg/L were insignificant, and increasing titers were associated with disease. The assay was unaffected by total IgG, autoantibodies and antibody to dietary hen's egg antigens. Antigens from pigeon serum seem sufficient to recognize immune sensitivity to most common pet avian species. Decreasing antibody titers confirmed antigen avoidance.
Increasing antibody titer reflected the likelihood of HP, and decreasing titers confirmed antigen avoidance. Quantifying antibody was rapid and the increased sensitivity will improve the rate of false-negative reporting and obviate the need for invasive diagnostic procedures. Automated fluorimetry provides a method for the international standardization of HP serology thereby improving quality control and improving its suitability as a diagnostic adjunct.
BMC Pulmonary Medicine 02/2006; 6:16. · 1.33 Impact Factor
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ABSTRACT: Glucocorticoid-induced TNFR family-related protein (GITR) is expressed at low levels on resting T cells, B cells and macrophages but at high levels on regulatory T cells (Treg). Although GITR expression is up-regulated on CD4+ effector cells upon activation, the role of GITR in Th1 and Th2 cell development is unclear. We report here that activation of GITR signalling by anti-GITR antibody markedly enhanced the induction of both Th1 and Th2 cytokine production by naive CD4+CD25- T cells. Consistent with this observation, anti-GITR antibody significantly enhanced the expression of the key Th1 (T-bet) and Th2 (GATA3) transcription factors in vitro. Administration of anti-GITR mAb in a murine model of arthritis significantly exacerbated the severity and onset of joint inflammation with elevated production of TNF-alpha, IFN-gamma, IL-5, and collagen-specific IgG1. Administration of anti-GITR mAb also significantly exacerbated murine allergic airways inflammation with elevated production of OVA-specific IFN-gamma, IL-2, IL-4, IL-5, and IgE. Finally, we demonstrated that adoptive transfer of CD4+GITR+ T cells effectively abolished airway inflammation induced in SCID mice reconstituted with CD4+GITR- T cells. Our results therefore provide direct evidence that GITR can modulate both Th1- and Th2-mediated inflammatory diseases, and may be a potential target for therapeutic intervention.
European Journal of Immunology 01/2006; 35(12):3581-90. · 5.10 Impact Factor
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ABSTRACT: Abstract
Background
Detecting serum antibody against inhaled antigens is an important diagnostic adjunct for hypersensitivity pneumonitis (HP). We sought to validate a quantitative fluorimetric assay testing serum from bird fanciers.
Methods
Antibody activity was assessed in bird fanciers and control subjects using various avian antigens and serological methods, and the titer was compared with symptoms of HP.
Results
IgG antibody against pigeon serum antigens, quantified by fluorimetry, provided a good discriminator of disease. Levels below 10 mg/L were insignificant, and increasing titers were associated with disease. The assay was unaffected by total IgG, autoantibodies and antibody to dietary hen's egg antigens. Antigens from pigeon serum seem sufficient to recognize immune sensitivity to most common pet avian species. Decreasing antibody titers confirmed antigen avoidance.
Conclusion
Increasing antibody titer reflected the likelihood of HP, and decreasing titers confirmed antigen avoidance. Quantifying antibody was rapid and the increased sensitivity will improve the rate of false-negative reporting and obviate the need for invasive diagnostic procedures. Automated fluorimetry provides a method for the international standardization of HP serology thereby improving quality control and improving its suitability as a diagnostic adjunct.
BMC Pulmonary Medicine. 01/2006;
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ABSTRACT: TLRs are primary sensors of both innate and adaptive immune systems, where they play a pivotal role in the response directed against structurally conserved components of pathogens. Synthetic bacterial lipopeptide Pam3CSK4 is a TLR2 agonist capable of modulating Th1 and Th2 responses. This study examines the therapeutic effect of Pam3CSK4 in established airway inflammation in a murine model of asthma. In mice previously sensitized and challenged with OVA, Pam3CSK4 given i.p. markedly reduced the total inflammatory cell infiltrate and eosinophilia in bronchoalveolar lavage fluid. Pam3CSK4 therapy was associated with a reduction in OVA-induced IL-4 and IL-5 secretion from thoracic lymph node culture, airways inflammation, bronchial hyperresponsiveness, and serum levels of IgE. Pam3CSK4 therapy was also associated with an increase in OVA-induced IFN-gamma, IL-12, and IL-10 production. However, the anti-inflammatory effect of Pam3CSK4 was independent of IL-10 or TGF-beta, but was critically dependent on IL-12, the production of which by dendritic cells was enhanced by Pam3CSK4 in vitro. Our results provide direct evidence that Pam3CSK4 could represent a novel therapeutic agent in allergic airways disease.
The Journal of Immunology 07/2005; 174(12):7558-63. · 5.79 Impact Factor
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ABSTRACT: Some patients with chronic asthma develop irreversible airflow obstruction. Our aim was to assess whether reported duration of asthma and induced sputum cell counts were associated with pulmonary function in patients with asthma who did not smoke. Maximal forced expiratory volume in the first second (FEV(1)) was determined following a steroid trial (oral prednisolone, 30 mg/d [n = 92 patients]; or inhaled fluticasone, 2000 microg/d [n = 5]; for 2 weeks) and 2.5 mg of nebulized albuterol. Asthma history was recorded with duration from first diagnosis. All subjects were nonsmokers, or were to have stopped smoking > or =5 years previously and smoked < or =5 pack-years (n = 12). Induced sputum was obtained from 59 subjects for analysis of airway cell counts. Maximal FEV(1) was inversely associated with asthma duration (r = -0.47, P <0.0001), age (r = -0.40, P <0.0001), and the proportion of sputum neutrophils (r(s) = -0.50, P = 0.00004). After adjusting for age, both duration of disease and sputum neutrophils were independently associated with maximal FEV(1). Neutrophil activation, as measured by sputum myeloperoxidase levels, was positively associated with the proportion of sputum neutrophils (r(s) = 0.45, P = 0.0004) and inversely associated with maximal FEV(1) (r(s) = -0.59, P <0.0001). Long disease duration may be a predisposing factor for the development of irreversible airflow obstruction in patients with chronic asthma. The negative associations of sputum neutrophil count and activation with maximal FEV(1) suggest that neutrophils may be involved in the pathophysiology of irreversible airflow obstruction in asthma.
The American Journal of Medicine 04/2002; 112(6):446-52. · 5.43 Impact Factor
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ABSTRACT: The development of lung disorders of environmental origin depends on a host response and the circumstances of exposure to noxious inhalable material. Climate, geography, culture, level of physical activity and the quality of indoor and outdoor air are important extrinsic variables. Host susceptibility is influenced by variable mechanisms which comprise plumonary defence. Few of these mechanisms are fully understood and most require more precise definition.
International Journal of Environmental Health Research 06/1991; 1(2):63-75. · 0.86 Impact Factor
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