Suzanne Traves - Academia.edu (original) (raw)

Papers by Suzanne Traves

Research paper thumbnail of Rhinovirus infection interferes with induction of tolerance to aeroantigens through OX40 ligand, thymic stromal lymphopoietin, and IL-33

The Journal of allergy and clinical immunology, Jan 19, 2015

Rhinovirus infection at an early age has been associated with development of asthma, but how rhin... more Rhinovirus infection at an early age has been associated with development of asthma, but how rhinovirus influences the immune response is not clear. Tolerance to inhaled antigen is mediated through induction of regulatory T (Treg) cells, and we examined whether rhinovirus infection of the respiratory tract can block airway tolerance by modulating Treg cells. The immune response to intranasal ovalbumin in mice was assessed with concomitant infection with RV1B, and the factors induced in vivo were compared with those made by human lung epithelial cells infected in vitro with RV16. RV1B infection of mice abrogated tolerance induced by inhalation of soluble ovalbumin, suppressing the normal generation of forkhead box protein 3-positive Treg cells while promoting TH2 cells. Furthermore, RV1B infection led to susceptibility to asthmatic lung disease when mice subsequently re-encountered aeroantigen. RV1B promoted early in vivo expression of the TNF family protein OX40 ligand on lung dendr...

Research paper thumbnail of Su1218 Cigarette Smoke Extract Differentially Affects Expression of CD11c in Monocyte-Derived Dendritic Cells in Crohn's Disease Patients With Active Versus Inactive Disease

Research paper thumbnail of Specific CXC but not CC chemokines cause elevated monocyte migration in COPD: a role for CXCR2

Journal of Leukocyte Biology, 2004

Leukocyte migration is critical to maintaining host defense, but uncontrolled cellular infiltrati... more Leukocyte migration is critical to maintaining host defense, but uncontrolled cellular infiltration into tissues can lead to chronic inflammation. In the lung, such diseases include chronic obstructive pulmonary disease (COPD), a debilitating, respiratory condition characterized by progressive and largely irreversible airflow limitation for which cigarette smoking is the major risk factor. COPD is associated with an increased inflammatory cell influx including increased macrophage numbers in the airways and tissue. Alveolar macrophages develop from immigrating blood monocytes and have the capacity to cause the pathological changes associated with COPD. This study addressed the hypothesis that increased macrophage numbers in COPD are a result of increased recruitment of monocytes from the circulation. Chemotaxis assays of peripheral blood mononuclear cells (PBMC)/monocytes from nonsmokers, smokers, and COPD patients demonstrated increased chemotactic responses for cells from COPD patients when compared with controls toward growth-related oncogene (GRO)␣ and neutrophil-activating peptide (NAP)-2 but not toward monocyte chemoattractant protein, interleukin-8, or epithelialderived NAP(ENA)-78. The enhanced chemotactic response toward GRO␣ and NAP-2 was not mediated by differences in expression of their cellular receptors, CXCR 1 or CXCR 2 . Receptor expression studies using flow cytometry indicated that in COPD, monocyte expression of CXCR 2 is regulated differently from nonsmokers and smokers, which may account for the enhanced migration toward GRO␣ and NAP-2. The results highlight the potential of CXCR 2 antagonists as therapy for COPD and demonstrate that an enhanced PBMC/ monocyte response to specific CXC chemokines in these patients may contribute to increased recruitment and activation of macrophages in the lungs. J. Leukoc. Biol. 76: 441-450; 2004.

Research paper thumbnail of Viral-associated exacerbations of asthma and COPD

Current Opinion in Pharmacology, 2007

Exacerbations of asthma and chronic obstructive pulmonary disease are major burdens on the health... more Exacerbations of asthma and chronic obstructive pulmonary disease are major burdens on the healthcare system, and contribute significantly to the mortality and morbidity associated with these diseases. Upper respiratory viral infections are associated with the majority of such disease exacerbations. The past few years have seen advances in the mechanisms by which viral infections induce pro-inflammatory chemokine production, and in our understanding of host antiviral and anti-inflammatory defence pathways that might regulate responses to infection. A more comprehensive understanding of the molecular basis of these processes could elucidate new therapeutic approaches to reduce the devastating impact that these exacerbations have on quality of life and healthcare costs.

Research paper thumbnail of Mo1729 Differential Effect of Cigarette Smoke Extract Modifies CD103 and CXCR3 Expressions of Monocyte-Derived Dendritic Cells From Crohn's Disease and Ulcerative Colitis Patients

Gastroenterology, 2014

INTRODUCTION: Smoking has a paradoxical influence upon two types of Inflammatory Bowel Disease (I... more INTRODUCTION: Smoking has a paradoxical influence upon two types of Inflammatory Bowel Disease (IBD), it is protective in ulcerative colitis (UC) but adversely affects Crohn's disease (CD). Dendritic cells (DC) play a critical role in modulating and orchestrating T cell-mediated inflammation such as IBD. DC surface markers, which are responsible for guthoming, enable the categorization of these cells into inflammatory and regulatory phenotypes. CXCR3 is an inflammatory marker that induces Th-1 polarization, whereas CD103 and CCR9 are considered regulatory markers. We hypothesized that smoking differentially modifies the immune response of DC in CD and UC patients. Our aim is to compare the in vitro effects of cigarette smoke extract (CSE) on cell surface marker expression by monocyte-derived DC (Mo-DC) from patients with CD and UC. METHODS: Blood monocytes (CD14+ leukocytes) from 6 CD and 7 UC patients with diagnosed IBD and no history of smoking were cultured with GM-CSF and IL-4 for 7 days to differentiate into DC. CSE was prepared fresh each time by bubbling cigarette smoke into the culture media and the concentration was adjusted to an absorbance of 0.15 at 320 nm (considered as 100%) using a spectrophotometer. Mo-DC were then exposed to 50% CSE for 24 hours. Cell surface expressions of CD103, CCR9, and CXCR3 were assessed by flow cytometry and secretion of CXCL10 (IP-10, a ligand for CXCR3) from Mo-DC were assessed by Luminex. Data from un-treated and CSEexposed cells were analyzed using Mann-Whitney U test to compare between CD and UC samples. RESULTS: Baseline CD103 and CCR9 expression showed no significant differences between CD and UC patients. CSE exposure increased CD103 expression in UC but decreased it in CD, and this difference was statistically significant (p=0.008, . CSE decreased CCR9 expression in both CD and UC samples but no significant difference was seen between CD and UC . UC samples showed significantly higher CXCR3 at baseline level than CD (p=0.041). CSE exposure increased CXCR3 expression in CD samples but decreased it in UC, causing a significant difference in CSE-driven CXCR3 expression between CD and UC (p=0.012, ). This was accompanied by CSE-driven decreases in CXCL10 secretion in UC samples compared to CD (p=0.008). CONCLUSION: CSE exposure differentially affected Mo-DC expression of CD103 and CXCR3 in CD and UC. CSE skewed Mo-DC into a more pro-inflammatory type in CD but induced a regulatory phenotype in UC patients. These differences may be relevant in part to the contrasting effects of cigarette smoking on the inflammation in CD and UC. CSE-driven modulation of DC gut-homing receptor expression may be considered a therapeutic target in future.

Research paper thumbnail of Role of nuclear receptor signaling in platelets: antithrombotic effects of PPAR

Faseb Journal, 2005

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that heterodimerize wit... more Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that heterodimerize with the retinoid X receptor and then modulate at the transcriptional level the function of many target genes. Three PPARs are known: α, β (sometimes called δ), and γ. The better studied are PPARα and PPARγ, which are activated by fibrates and thiazolidinediones/glitazones, respectively. It is now believed that activation of the PPARs could be associated with the prevention of heart attack and stroke in humans. Here we report, for the first time, that human platelets contain PPARβ and that its selective activation inhibits platelet aggregation. PPARβ is a putative receptor for prostacyclin. Prostacyclin is an important antithrombotic hormone that synergizes with nitric oxide to inhibit platelet aggregation. In the current study, we show that PPARβ ligands similarly synergize with nitric oxide to inhibit platelet aggregation. These observations challenge our view of a nuclear receptor because PPARβ is present and active in nonnucleated platelets. Furthermore, these data suggest that some of the antithrombotic actions of prostacyclin may be mediated via activation of PPARs. Thus, our results identify PPARβ as a novel antiplatelet target that may mediate some of the effects of prostacyclin in blood.

Research paper thumbnail of CXCR3 and CCR5 Chemokines in Induced Sputum From Patients With COPD

Chest, 2008

COPD is associated with increased numbers of CD4(+) and CD8(+) lymphocytes and macrophages in the... more COPD is associated with increased numbers of CD4(+) and CD8(+) lymphocytes and macrophages in the small airways and lung parenchyma. The chemokines regulating T-cell recruitment into the lung are unknown but may involve CXCR3 and CCR5 chemoattractants. The aims of this study were to determine the concentrations of CXCR3 chemokines CXCL9, CXCL10, CXCL11, and the CCR5 chemokine CCL5 in induced sputum from patients with COPD, smokers, and nonsmokers, and to examine the relationship between chemokine expression, inflammatory cells, and airway obstruction. Differential cell counts were performed and concentrations of CXCL9, CXCL10, CXCL11, and CCL5 were measured in induced sputum from nonsmokers (n = 18), smokers (n = 20), and COPD patients (n = 35) using an enzyme-linked immunosorbent assay. Concentrations of CXCL9, CXCL10, CXCL11, and CCL5 were significantly increased in the sputum of patients with COPD when compared with nonsmokers but not smokers without obstruction: CXCL9 (median, 14.3 pg/mL; interquartile range [IQR], 6.5 to 99.3; vs median, 1.4 pg/mL; IQR, 0 to 10.4 [p < 0.001]; vs 8.5 pg/mL; IQR, 0 to 16.0, respectively); CXCL10 (16.9 pg/mL; IQR, 6.2 to 148.8; vs 3.7 pg/mL; IQR, 0 to 18.8 [p < 0.05]; vs 11.3 pg/mL; IQR, 3.7 to 46.7); CXCL11 (58.1 pg/mL; IQR, 34.5 to 85.3; vs 33.5 pg/mL; IQR, 23.2 to 49.7 [p < 0.05]; vs 49.8 pg/mL; IQR, 32.6 to 105.6); and CCL5 (59.9 pg/mL; IQR, 57.1 to 67.8; vs 33.5 pg/mL; IQR, 31.6 to 36.9 [p < 0.001]). CCL5 in sputum from smokers was also significantly increased compared with that from nonsmokers (median, 63.0 pg/mL; IQR, 60.8 to70.2; p < 0.001). There was a negative correlation between FEV(1) percentage of predicted, FEV(1)/FVC ratio, and percentage of macrophages, and all the chemokines analyzed. Neutrophil numbers correlated positively with the concentrations of chemokines. CXCR3 chemokines and CCL5 are increased in sputum from COPD patients compared with nonsmokers, and may be important in COPD pathogenesis.

Research paper thumbnail of Sputum matrix metalloproteases: comparison between chronic obstructive pulmonary disease and asthma

Respiratory Medicine, 2005

Asthma and chronic obstructive pulmonary disease (COPD) are different conditions with contrasting... more Asthma and chronic obstructive pulmonary disease (COPD) are different conditions with contrasting airway inflammation and parenchymal disease patterns. A number of matrix metalloproteases (MMPs) are implicated in the pathophysiology of COPD and asthma. Different profiles of airway MMPs may, therefore, be expected in asthma and COPD. The present study compared MMP profiles in the airways of non-smokers, non-symptomatic cigarette smokers, and patients with COPD or asthma (n=15n=15 subjects per group). Induced sputum was assessed for MMP-1, -2, -3, -8 and -9, and tissue inhibitor of metalloproteases (TIMP)-1 by ELISA. Gelatinase activity was determined by zymography. Sputum from COPD patients contained increased levels of MMP-1, -8 and -9 compared with the other groups (2–7-fold, depending upon group). MMP-9 activity was elevated in COPD sputum by 3–12-fold above the other groups. Sputum from COPD patients had 3-fold higher levels of TIMP-1 than samples from asthmatics or controls, but was not different to smokers. FEV1 correlated negatively with MMP-1, -8, -9, MMP-9 activity and TIMP-1, whereas percent neutrophils in sputum correlated positively with MMP-1, -8, -9, TIMP-1 and MMP-9 activity. The MMP profile in COPD differs to that in asthma and cigarette smokers. This may contribute to, or be a marker of, different pathophysiologies of asthma and COPD.

Research paper thumbnail of Increased levels of the chemokines GROα and MCP-1 in sputum samples from patients with COPD

Thorax, 2002

Background: Patients with chronic obstructive pulmonary disease (COPD) have increased numbers of ... more Background: Patients with chronic obstructive pulmonary disease (COPD) have increased numbers of neutrophils and macrophages in their lungs. Growth related oncogene-α (GROα) attracts neutrophils, whereas monocyte chemoattractant protein-1 (MCP-1) attracts monocytes that can differentiate into macrophages. The aim of this study was to determine the concentration of GROα and MCP-1 in bronchoalveolar lavage (BAL) fluid and sputum from non-smokers, healthy smokers and patients with COPD, and to see if there was a correlation between the concentrations of these chemokines, lung function, and numbers of inflammatory cells. Methods: BAL fluid and sputum from non-smokers (n=32), healthy smokers (n=36), and patients with COPD (n=40) were analysed for the presence of GROα and MCP-1 using ELISA. Cells counts were performed on the samples and correlations between the concentrations of these chemokines, lung function, and inflammatory cells observed. Results: Median (SE) GROα and MCP-1 levels were significantly increased in sputum from patients with COPD compared with non-smokers and healthy smokers (GROα: 31 (11) v 2 (2) v 3 (0.8) ng/ml; MCP-1: 0.8 (0.4) v 0.2 (0.1) v 0.1 (0.04) ng/ml, p<0.05), but not in BAL fluid. There were significant negative correlations between both GROα and MCP-1 levels in sputum and forced expiratory volume in 1 second (FEV 1 ) % predicted (GROα: r=-0.5, p<0.001; MCP-1: r=-0.5, p<0.001), together with significant positive correlations between GROα and MCP-1 and neutrophil numbers in sputum (GROα: r=0.6, p<0.001; MCP-1: r=0.4, p<0.01). Conclusion: These results suggest that GROα and MCP-1 are involved in the migration of inflammatory cells, thus contributing to the inflammatory load associated with COPD.

Research paper thumbnail of Cytokines and Chemokines in Airway Inflammation

Analysis of Exhaled Breath Condensate, 2004

Research paper thumbnail of Chemokines and their Receptors as Targets for the Treatment of COPD

Current Respiratory Medicine Reviews, 2005

Chronic obstructive pulmonary disease (COPD) is a debilitating respiratory condition, characteris... more Chronic obstructive pulmonary disease (COPD) is a debilitating respiratory condition, characterised by progressive, irreversible airflow obstruction. The major risk factor for development of COPD is cigarette smoking, and the disease is predicted to become the 3 rd leading cause of death by 2020. Currently, there are no pharmacological interventions that halt the progression of COPD; however one strategy is to reduce the chronic lung inflammation associated with this disease. An increased inflammatory infiltrate comprising macrophages, neutrophils and T-lymphocytes is a major hallmark of COPD. Furthermore, both macrophages and neutrophils have the ability to cause all the pathological changes associated with COPD. Chemokines that are elevated in sputum from COPD patients have the capacity to recruit neutrophils, the macrophage precursor cells, monocytes, and T-lymphocytes. Chemokines are considered predominantly chemotactic cytokines however; there is a growing body of evidence demonstrating that chemokines can also act as functional antagonists thus leading to selective recruitment of inflammatory cells. Whilst inhibition of chemokine dependent recruitment of inflammatory cells via small molecule antagonists gives rise to potential treatments for COPD, the discovery that chemokines are also natural antagonists could also be exploited in the ongoing search for treatment of this currently fatal disease.

Research paper thumbnail of Th17 Cells in Airway Diseases

Current Molecular Medicine, 2008

Chronic inflammation is a key feature of many airway diseases. Leukocyte accumulation in the lung... more Chronic inflammation is a key feature of many airway diseases. Leukocyte accumulation in the lung has the capacity to mediate many aspects of the pathophysiology of such diseases including asthma and chronic obstructive pulmonary disease (COPD). Until recently, the CD4+ lymphocyte component of these inflammatory influxes was thought to consist of Th1 or Th2 type cells, however a third group of cells termed Th17 have been identified. These cells follow a distinct differentiation profile requiring TGFbeta and IL-6 leading to the expression of the Th17 selective transcription factor, RORgammat. Differentiation of these cells is restricted by Th1 and Th2 cytokines including IFNgamma and IL-4 which attenuate Th17 cell differentiation. The presence of Th17 cells in the airway has yet to be confirmed, yet IL-17 is expressed in both asthma and COPD. Many of the inflammatory effects of Th17 cells are attributed to the expression of this cytokine. For example, IL-17 up-regulates the expression of a number of CXCR2 chemokines including CXCL1, CXCL6 and CXCL8 together with neutrophil survival factors GM-CSF and G-CSF from the airway epithelium. This would suggest that Th17 cells are important in promoting and sustaining neutrophilic inflammation as observed in severe asthma and COPD. In addition, IL-17 can act synergistically with viral infection or other inflammatory mediators including TNF-alpha to potentiate these responses. Confirmation of the presence of Th17 cells in the airways in disease warrants further investigation since these cells would present a novel therapeutic opportunity to reduce neutrophilic inflammation in the lung.

Research paper thumbnail of Cytokines and Chemokines in Airway Inflammation

Analysis of Exhaled Breath Condensate, 2004

Research paper thumbnail of Chemokines and their Receptors as Targets for the Treatment of COPD

Current Respiratory Medicine Reviews, 2005

Chronic obstructive pulmonary disease (COPD) is a debilitating respiratory condition, characteris... more Chronic obstructive pulmonary disease (COPD) is a debilitating respiratory condition, characterised by progressive, irreversible airflow obstruction. The major risk factor for development of COPD is cigarette smoking, and the disease is predicted to become the 3 rd leading cause of death by 2020. Currently, there are no pharmacological interventions that halt the progression of COPD; however one strategy is to reduce the chronic lung inflammation associated with this disease. An increased inflammatory infiltrate comprising macrophages, neutrophils and T-lymphocytes is a major hallmark of COPD. Furthermore, both macrophages and neutrophils have the ability to cause all the pathological changes associated with COPD. Chemokines that are elevated in sputum from COPD patients have the capacity to recruit neutrophils, the macrophage precursor cells, monocytes, and T-lymphocytes. Chemokines are considered predominantly chemotactic cytokines however; there is a growing body of evidence demonstrating that chemokines can also act as functional antagonists thus leading to selective recruitment of inflammatory cells. Whilst inhibition of chemokine dependent recruitment of inflammatory cells via small molecule antagonists gives rise to potential treatments for COPD, the discovery that chemokines are also natural antagonists could also be exploited in the ongoing search for treatment of this currently fatal disease.

Research paper thumbnail of Th17 Cells in Airway Diseases

Current Molecular Medicine, 2008

Chronic inflammation is a key feature of many airway diseases. Leukocyte accumulation in the lung... more Chronic inflammation is a key feature of many airway diseases. Leukocyte accumulation in the lung has the capacity to mediate many aspects of the pathophysiology of such diseases including asthma and chronic obstructive pulmonary disease (COPD). Until recently, the CD4+ lymphocyte component of these inflammatory influxes was thought to consist of Th1 or Th2 type cells, however a third group of cells termed Th17 have been identified. These cells follow a distinct differentiation profile requiring TGFbeta and IL-6 leading to the expression of the Th17 selective transcription factor, RORgammat. Differentiation of these cells is restricted by Th1 and Th2 cytokines including IFNgamma and IL-4 which attenuate Th17 cell differentiation. The presence of Th17 cells in the airway has yet to be confirmed, yet IL-17 is expressed in both asthma and COPD. Many of the inflammatory effects of Th17 cells are attributed to the expression of this cytokine. For example, IL-17 up-regulates the expression of a number of CXCR2 chemokines including CXCL1, CXCL6 and CXCL8 together with neutrophil survival factors GM-CSF and G-CSF from the airway epithelium. This would suggest that Th17 cells are important in promoting and sustaining neutrophilic inflammation as observed in severe asthma and COPD. In addition, IL-17 can act synergistically with viral infection or other inflammatory mediators including TNF-alpha to potentiate these responses. Confirmation of the presence of Th17 cells in the airways in disease warrants further investigation since these cells would present a novel therapeutic opportunity to reduce neutrophilic inflammation in the lung.

Research paper thumbnail of Asthma In Older Adults; Potential Factors To Explain Increased Mortality Rates

B92. ASTHMA PHENOTYPES: BETTER UNDERSTANDING OF ASTHMA AND RATIONALE FOR THERAPY, 2012

Research paper thumbnail of Cigarette smoke modulates rhinovirus-induced airway epithelial cell chemokine production

European Respiratory Journal, 2010

Human rhinovirus (HRV) infections induce epithelial cell production of chemokines that may contri... more Human rhinovirus (HRV) infections induce epithelial cell production of chemokines that may contribute to the pathogenesis of exacerbations of chronic obstructive pulmonary disease (COPD) and asthma. Cigarette smoking is the predominant risk factor for the development of COPD and also aggravates asthma symptoms. We examined whether cigarette smoke extract (CSE) modulates viral inflammation by altering the profile of HRV-induced epithelial chemokine production.

Research paper thumbnail of A Method To Allow Preservation And Delayed Examination Of Induced Unselected Sputum

C34. NON-INVASIVE ASSESSMENT OF AIRWAYS DISEASE, 2010

Research paper thumbnail of Modulation Of Human Rhinovirus (HRV)-Induced Airway Epithelial Cell Responses By Cigarette Smoke Extract (CSE)

C32. RHINOVIRUS AND THE AIRWAYS, 2010

Research paper thumbnail of The Effect Of Exercise Intensity On Airway And Systemic Inflammation In Patients With COPD

C109. REVISITING EXERCISE FOR CHILDREN AND ADULTS, 2010

Research paper thumbnail of Rhinovirus infection interferes with induction of tolerance to aeroantigens through OX40 ligand, thymic stromal lymphopoietin, and IL-33

The Journal of allergy and clinical immunology, Jan 19, 2015

Rhinovirus infection at an early age has been associated with development of asthma, but how rhin... more Rhinovirus infection at an early age has been associated with development of asthma, but how rhinovirus influences the immune response is not clear. Tolerance to inhaled antigen is mediated through induction of regulatory T (Treg) cells, and we examined whether rhinovirus infection of the respiratory tract can block airway tolerance by modulating Treg cells. The immune response to intranasal ovalbumin in mice was assessed with concomitant infection with RV1B, and the factors induced in vivo were compared with those made by human lung epithelial cells infected in vitro with RV16. RV1B infection of mice abrogated tolerance induced by inhalation of soluble ovalbumin, suppressing the normal generation of forkhead box protein 3-positive Treg cells while promoting TH2 cells. Furthermore, RV1B infection led to susceptibility to asthmatic lung disease when mice subsequently re-encountered aeroantigen. RV1B promoted early in vivo expression of the TNF family protein OX40 ligand on lung dendr...

Research paper thumbnail of Su1218 Cigarette Smoke Extract Differentially Affects Expression of CD11c in Monocyte-Derived Dendritic Cells in Crohn's Disease Patients With Active Versus Inactive Disease

Research paper thumbnail of Specific CXC but not CC chemokines cause elevated monocyte migration in COPD: a role for CXCR2

Journal of Leukocyte Biology, 2004

Leukocyte migration is critical to maintaining host defense, but uncontrolled cellular infiltrati... more Leukocyte migration is critical to maintaining host defense, but uncontrolled cellular infiltration into tissues can lead to chronic inflammation. In the lung, such diseases include chronic obstructive pulmonary disease (COPD), a debilitating, respiratory condition characterized by progressive and largely irreversible airflow limitation for which cigarette smoking is the major risk factor. COPD is associated with an increased inflammatory cell influx including increased macrophage numbers in the airways and tissue. Alveolar macrophages develop from immigrating blood monocytes and have the capacity to cause the pathological changes associated with COPD. This study addressed the hypothesis that increased macrophage numbers in COPD are a result of increased recruitment of monocytes from the circulation. Chemotaxis assays of peripheral blood mononuclear cells (PBMC)/monocytes from nonsmokers, smokers, and COPD patients demonstrated increased chemotactic responses for cells from COPD patients when compared with controls toward growth-related oncogene (GRO)␣ and neutrophil-activating peptide (NAP)-2 but not toward monocyte chemoattractant protein, interleukin-8, or epithelialderived NAP(ENA)-78. The enhanced chemotactic response toward GRO␣ and NAP-2 was not mediated by differences in expression of their cellular receptors, CXCR 1 or CXCR 2 . Receptor expression studies using flow cytometry indicated that in COPD, monocyte expression of CXCR 2 is regulated differently from nonsmokers and smokers, which may account for the enhanced migration toward GRO␣ and NAP-2. The results highlight the potential of CXCR 2 antagonists as therapy for COPD and demonstrate that an enhanced PBMC/ monocyte response to specific CXC chemokines in these patients may contribute to increased recruitment and activation of macrophages in the lungs. J. Leukoc. Biol. 76: 441-450; 2004.

Research paper thumbnail of Viral-associated exacerbations of asthma and COPD

Current Opinion in Pharmacology, 2007

Exacerbations of asthma and chronic obstructive pulmonary disease are major burdens on the health... more Exacerbations of asthma and chronic obstructive pulmonary disease are major burdens on the healthcare system, and contribute significantly to the mortality and morbidity associated with these diseases. Upper respiratory viral infections are associated with the majority of such disease exacerbations. The past few years have seen advances in the mechanisms by which viral infections induce pro-inflammatory chemokine production, and in our understanding of host antiviral and anti-inflammatory defence pathways that might regulate responses to infection. A more comprehensive understanding of the molecular basis of these processes could elucidate new therapeutic approaches to reduce the devastating impact that these exacerbations have on quality of life and healthcare costs.

Research paper thumbnail of Mo1729 Differential Effect of Cigarette Smoke Extract Modifies CD103 and CXCR3 Expressions of Monocyte-Derived Dendritic Cells From Crohn's Disease and Ulcerative Colitis Patients

Gastroenterology, 2014

INTRODUCTION: Smoking has a paradoxical influence upon two types of Inflammatory Bowel Disease (I... more INTRODUCTION: Smoking has a paradoxical influence upon two types of Inflammatory Bowel Disease (IBD), it is protective in ulcerative colitis (UC) but adversely affects Crohn's disease (CD). Dendritic cells (DC) play a critical role in modulating and orchestrating T cell-mediated inflammation such as IBD. DC surface markers, which are responsible for guthoming, enable the categorization of these cells into inflammatory and regulatory phenotypes. CXCR3 is an inflammatory marker that induces Th-1 polarization, whereas CD103 and CCR9 are considered regulatory markers. We hypothesized that smoking differentially modifies the immune response of DC in CD and UC patients. Our aim is to compare the in vitro effects of cigarette smoke extract (CSE) on cell surface marker expression by monocyte-derived DC (Mo-DC) from patients with CD and UC. METHODS: Blood monocytes (CD14+ leukocytes) from 6 CD and 7 UC patients with diagnosed IBD and no history of smoking were cultured with GM-CSF and IL-4 for 7 days to differentiate into DC. CSE was prepared fresh each time by bubbling cigarette smoke into the culture media and the concentration was adjusted to an absorbance of 0.15 at 320 nm (considered as 100%) using a spectrophotometer. Mo-DC were then exposed to 50% CSE for 24 hours. Cell surface expressions of CD103, CCR9, and CXCR3 were assessed by flow cytometry and secretion of CXCL10 (IP-10, a ligand for CXCR3) from Mo-DC were assessed by Luminex. Data from un-treated and CSEexposed cells were analyzed using Mann-Whitney U test to compare between CD and UC samples. RESULTS: Baseline CD103 and CCR9 expression showed no significant differences between CD and UC patients. CSE exposure increased CD103 expression in UC but decreased it in CD, and this difference was statistically significant (p=0.008, . CSE decreased CCR9 expression in both CD and UC samples but no significant difference was seen between CD and UC . UC samples showed significantly higher CXCR3 at baseline level than CD (p=0.041). CSE exposure increased CXCR3 expression in CD samples but decreased it in UC, causing a significant difference in CSE-driven CXCR3 expression between CD and UC (p=0.012, ). This was accompanied by CSE-driven decreases in CXCL10 secretion in UC samples compared to CD (p=0.008). CONCLUSION: CSE exposure differentially affected Mo-DC expression of CD103 and CXCR3 in CD and UC. CSE skewed Mo-DC into a more pro-inflammatory type in CD but induced a regulatory phenotype in UC patients. These differences may be relevant in part to the contrasting effects of cigarette smoking on the inflammation in CD and UC. CSE-driven modulation of DC gut-homing receptor expression may be considered a therapeutic target in future.

Research paper thumbnail of Role of nuclear receptor signaling in platelets: antithrombotic effects of PPAR

Faseb Journal, 2005

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that heterodimerize wit... more Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that heterodimerize with the retinoid X receptor and then modulate at the transcriptional level the function of many target genes. Three PPARs are known: α, β (sometimes called δ), and γ. The better studied are PPARα and PPARγ, which are activated by fibrates and thiazolidinediones/glitazones, respectively. It is now believed that activation of the PPARs could be associated with the prevention of heart attack and stroke in humans. Here we report, for the first time, that human platelets contain PPARβ and that its selective activation inhibits platelet aggregation. PPARβ is a putative receptor for prostacyclin. Prostacyclin is an important antithrombotic hormone that synergizes with nitric oxide to inhibit platelet aggregation. In the current study, we show that PPARβ ligands similarly synergize with nitric oxide to inhibit platelet aggregation. These observations challenge our view of a nuclear receptor because PPARβ is present and active in nonnucleated platelets. Furthermore, these data suggest that some of the antithrombotic actions of prostacyclin may be mediated via activation of PPARs. Thus, our results identify PPARβ as a novel antiplatelet target that may mediate some of the effects of prostacyclin in blood.

Research paper thumbnail of CXCR3 and CCR5 Chemokines in Induced Sputum From Patients With COPD

Chest, 2008

COPD is associated with increased numbers of CD4(+) and CD8(+) lymphocytes and macrophages in the... more COPD is associated with increased numbers of CD4(+) and CD8(+) lymphocytes and macrophages in the small airways and lung parenchyma. The chemokines regulating T-cell recruitment into the lung are unknown but may involve CXCR3 and CCR5 chemoattractants. The aims of this study were to determine the concentrations of CXCR3 chemokines CXCL9, CXCL10, CXCL11, and the CCR5 chemokine CCL5 in induced sputum from patients with COPD, smokers, and nonsmokers, and to examine the relationship between chemokine expression, inflammatory cells, and airway obstruction. Differential cell counts were performed and concentrations of CXCL9, CXCL10, CXCL11, and CCL5 were measured in induced sputum from nonsmokers (n = 18), smokers (n = 20), and COPD patients (n = 35) using an enzyme-linked immunosorbent assay. Concentrations of CXCL9, CXCL10, CXCL11, and CCL5 were significantly increased in the sputum of patients with COPD when compared with nonsmokers but not smokers without obstruction: CXCL9 (median, 14.3 pg/mL; interquartile range [IQR], 6.5 to 99.3; vs median, 1.4 pg/mL; IQR, 0 to 10.4 [p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001]; vs 8.5 pg/mL; IQR, 0 to 16.0, respectively); CXCL10 (16.9 pg/mL; IQR, 6.2 to 148.8; vs 3.7 pg/mL; IQR, 0 to 18.8 [p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05]; vs 11.3 pg/mL; IQR, 3.7 to 46.7); CXCL11 (58.1 pg/mL; IQR, 34.5 to 85.3; vs 33.5 pg/mL; IQR, 23.2 to 49.7 [p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05]; vs 49.8 pg/mL; IQR, 32.6 to 105.6); and CCL5 (59.9 pg/mL; IQR, 57.1 to 67.8; vs 33.5 pg/mL; IQR, 31.6 to 36.9 [p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001]). CCL5 in sputum from smokers was also significantly increased compared with that from nonsmokers (median, 63.0 pg/mL; IQR, 60.8 to70.2; p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001). There was a negative correlation between FEV(1) percentage of predicted, FEV(1)/FVC ratio, and percentage of macrophages, and all the chemokines analyzed. Neutrophil numbers correlated positively with the concentrations of chemokines. CXCR3 chemokines and CCL5 are increased in sputum from COPD patients compared with nonsmokers, and may be important in COPD pathogenesis.

Research paper thumbnail of Sputum matrix metalloproteases: comparison between chronic obstructive pulmonary disease and asthma

Respiratory Medicine, 2005

Asthma and chronic obstructive pulmonary disease (COPD) are different conditions with contrasting... more Asthma and chronic obstructive pulmonary disease (COPD) are different conditions with contrasting airway inflammation and parenchymal disease patterns. A number of matrix metalloproteases (MMPs) are implicated in the pathophysiology of COPD and asthma. Different profiles of airway MMPs may, therefore, be expected in asthma and COPD. The present study compared MMP profiles in the airways of non-smokers, non-symptomatic cigarette smokers, and patients with COPD or asthma (n=15n=15 subjects per group). Induced sputum was assessed for MMP-1, -2, -3, -8 and -9, and tissue inhibitor of metalloproteases (TIMP)-1 by ELISA. Gelatinase activity was determined by zymography. Sputum from COPD patients contained increased levels of MMP-1, -8 and -9 compared with the other groups (2–7-fold, depending upon group). MMP-9 activity was elevated in COPD sputum by 3–12-fold above the other groups. Sputum from COPD patients had 3-fold higher levels of TIMP-1 than samples from asthmatics or controls, but was not different to smokers. FEV1 correlated negatively with MMP-1, -8, -9, MMP-9 activity and TIMP-1, whereas percent neutrophils in sputum correlated positively with MMP-1, -8, -9, TIMP-1 and MMP-9 activity. The MMP profile in COPD differs to that in asthma and cigarette smokers. This may contribute to, or be a marker of, different pathophysiologies of asthma and COPD.

Research paper thumbnail of Increased levels of the chemokines GROα and MCP-1 in sputum samples from patients with COPD

Thorax, 2002

Background: Patients with chronic obstructive pulmonary disease (COPD) have increased numbers of ... more Background: Patients with chronic obstructive pulmonary disease (COPD) have increased numbers of neutrophils and macrophages in their lungs. Growth related oncogene-α (GROα) attracts neutrophils, whereas monocyte chemoattractant protein-1 (MCP-1) attracts monocytes that can differentiate into macrophages. The aim of this study was to determine the concentration of GROα and MCP-1 in bronchoalveolar lavage (BAL) fluid and sputum from non-smokers, healthy smokers and patients with COPD, and to see if there was a correlation between the concentrations of these chemokines, lung function, and numbers of inflammatory cells. Methods: BAL fluid and sputum from non-smokers (n=32), healthy smokers (n=36), and patients with COPD (n=40) were analysed for the presence of GROα and MCP-1 using ELISA. Cells counts were performed on the samples and correlations between the concentrations of these chemokines, lung function, and inflammatory cells observed. Results: Median (SE) GROα and MCP-1 levels were significantly increased in sputum from patients with COPD compared with non-smokers and healthy smokers (GROα: 31 (11) v 2 (2) v 3 (0.8) ng/ml; MCP-1: 0.8 (0.4) v 0.2 (0.1) v 0.1 (0.04) ng/ml, p<0.05), but not in BAL fluid. There were significant negative correlations between both GROα and MCP-1 levels in sputum and forced expiratory volume in 1 second (FEV 1 ) % predicted (GROα: r=-0.5, p<0.001; MCP-1: r=-0.5, p<0.001), together with significant positive correlations between GROα and MCP-1 and neutrophil numbers in sputum (GROα: r=0.6, p<0.001; MCP-1: r=0.4, p<0.01). Conclusion: These results suggest that GROα and MCP-1 are involved in the migration of inflammatory cells, thus contributing to the inflammatory load associated with COPD.

Research paper thumbnail of Cytokines and Chemokines in Airway Inflammation

Analysis of Exhaled Breath Condensate, 2004

Research paper thumbnail of Chemokines and their Receptors as Targets for the Treatment of COPD

Current Respiratory Medicine Reviews, 2005

Chronic obstructive pulmonary disease (COPD) is a debilitating respiratory condition, characteris... more Chronic obstructive pulmonary disease (COPD) is a debilitating respiratory condition, characterised by progressive, irreversible airflow obstruction. The major risk factor for development of COPD is cigarette smoking, and the disease is predicted to become the 3 rd leading cause of death by 2020. Currently, there are no pharmacological interventions that halt the progression of COPD; however one strategy is to reduce the chronic lung inflammation associated with this disease. An increased inflammatory infiltrate comprising macrophages, neutrophils and T-lymphocytes is a major hallmark of COPD. Furthermore, both macrophages and neutrophils have the ability to cause all the pathological changes associated with COPD. Chemokines that are elevated in sputum from COPD patients have the capacity to recruit neutrophils, the macrophage precursor cells, monocytes, and T-lymphocytes. Chemokines are considered predominantly chemotactic cytokines however; there is a growing body of evidence demonstrating that chemokines can also act as functional antagonists thus leading to selective recruitment of inflammatory cells. Whilst inhibition of chemokine dependent recruitment of inflammatory cells via small molecule antagonists gives rise to potential treatments for COPD, the discovery that chemokines are also natural antagonists could also be exploited in the ongoing search for treatment of this currently fatal disease.

Research paper thumbnail of Th17 Cells in Airway Diseases

Current Molecular Medicine, 2008

Chronic inflammation is a key feature of many airway diseases. Leukocyte accumulation in the lung... more Chronic inflammation is a key feature of many airway diseases. Leukocyte accumulation in the lung has the capacity to mediate many aspects of the pathophysiology of such diseases including asthma and chronic obstructive pulmonary disease (COPD). Until recently, the CD4+ lymphocyte component of these inflammatory influxes was thought to consist of Th1 or Th2 type cells, however a third group of cells termed Th17 have been identified. These cells follow a distinct differentiation profile requiring TGFbeta and IL-6 leading to the expression of the Th17 selective transcription factor, RORgammat. Differentiation of these cells is restricted by Th1 and Th2 cytokines including IFNgamma and IL-4 which attenuate Th17 cell differentiation. The presence of Th17 cells in the airway has yet to be confirmed, yet IL-17 is expressed in both asthma and COPD. Many of the inflammatory effects of Th17 cells are attributed to the expression of this cytokine. For example, IL-17 up-regulates the expression of a number of CXCR2 chemokines including CXCL1, CXCL6 and CXCL8 together with neutrophil survival factors GM-CSF and G-CSF from the airway epithelium. This would suggest that Th17 cells are important in promoting and sustaining neutrophilic inflammation as observed in severe asthma and COPD. In addition, IL-17 can act synergistically with viral infection or other inflammatory mediators including TNF-alpha to potentiate these responses. Confirmation of the presence of Th17 cells in the airways in disease warrants further investigation since these cells would present a novel therapeutic opportunity to reduce neutrophilic inflammation in the lung.

Research paper thumbnail of Cytokines and Chemokines in Airway Inflammation

Analysis of Exhaled Breath Condensate, 2004

Research paper thumbnail of Chemokines and their Receptors as Targets for the Treatment of COPD

Current Respiratory Medicine Reviews, 2005

Chronic obstructive pulmonary disease (COPD) is a debilitating respiratory condition, characteris... more Chronic obstructive pulmonary disease (COPD) is a debilitating respiratory condition, characterised by progressive, irreversible airflow obstruction. The major risk factor for development of COPD is cigarette smoking, and the disease is predicted to become the 3 rd leading cause of death by 2020. Currently, there are no pharmacological interventions that halt the progression of COPD; however one strategy is to reduce the chronic lung inflammation associated with this disease. An increased inflammatory infiltrate comprising macrophages, neutrophils and T-lymphocytes is a major hallmark of COPD. Furthermore, both macrophages and neutrophils have the ability to cause all the pathological changes associated with COPD. Chemokines that are elevated in sputum from COPD patients have the capacity to recruit neutrophils, the macrophage precursor cells, monocytes, and T-lymphocytes. Chemokines are considered predominantly chemotactic cytokines however; there is a growing body of evidence demonstrating that chemokines can also act as functional antagonists thus leading to selective recruitment of inflammatory cells. Whilst inhibition of chemokine dependent recruitment of inflammatory cells via small molecule antagonists gives rise to potential treatments for COPD, the discovery that chemokines are also natural antagonists could also be exploited in the ongoing search for treatment of this currently fatal disease.

Research paper thumbnail of Th17 Cells in Airway Diseases

Current Molecular Medicine, 2008

Chronic inflammation is a key feature of many airway diseases. Leukocyte accumulation in the lung... more Chronic inflammation is a key feature of many airway diseases. Leukocyte accumulation in the lung has the capacity to mediate many aspects of the pathophysiology of such diseases including asthma and chronic obstructive pulmonary disease (COPD). Until recently, the CD4+ lymphocyte component of these inflammatory influxes was thought to consist of Th1 or Th2 type cells, however a third group of cells termed Th17 have been identified. These cells follow a distinct differentiation profile requiring TGFbeta and IL-6 leading to the expression of the Th17 selective transcription factor, RORgammat. Differentiation of these cells is restricted by Th1 and Th2 cytokines including IFNgamma and IL-4 which attenuate Th17 cell differentiation. The presence of Th17 cells in the airway has yet to be confirmed, yet IL-17 is expressed in both asthma and COPD. Many of the inflammatory effects of Th17 cells are attributed to the expression of this cytokine. For example, IL-17 up-regulates the expression of a number of CXCR2 chemokines including CXCL1, CXCL6 and CXCL8 together with neutrophil survival factors GM-CSF and G-CSF from the airway epithelium. This would suggest that Th17 cells are important in promoting and sustaining neutrophilic inflammation as observed in severe asthma and COPD. In addition, IL-17 can act synergistically with viral infection or other inflammatory mediators including TNF-alpha to potentiate these responses. Confirmation of the presence of Th17 cells in the airways in disease warrants further investigation since these cells would present a novel therapeutic opportunity to reduce neutrophilic inflammation in the lung.

Research paper thumbnail of Asthma In Older Adults; Potential Factors To Explain Increased Mortality Rates

B92. ASTHMA PHENOTYPES: BETTER UNDERSTANDING OF ASTHMA AND RATIONALE FOR THERAPY, 2012

Research paper thumbnail of Cigarette smoke modulates rhinovirus-induced airway epithelial cell chemokine production

European Respiratory Journal, 2010

Human rhinovirus (HRV) infections induce epithelial cell production of chemokines that may contri... more Human rhinovirus (HRV) infections induce epithelial cell production of chemokines that may contribute to the pathogenesis of exacerbations of chronic obstructive pulmonary disease (COPD) and asthma. Cigarette smoking is the predominant risk factor for the development of COPD and also aggravates asthma symptoms. We examined whether cigarette smoke extract (CSE) modulates viral inflammation by altering the profile of HRV-induced epithelial chemokine production.

Research paper thumbnail of A Method To Allow Preservation And Delayed Examination Of Induced Unselected Sputum

C34. NON-INVASIVE ASSESSMENT OF AIRWAYS DISEASE, 2010

Research paper thumbnail of Modulation Of Human Rhinovirus (HRV)-Induced Airway Epithelial Cell Responses By Cigarette Smoke Extract (CSE)

C32. RHINOVIRUS AND THE AIRWAYS, 2010

Research paper thumbnail of The Effect Of Exercise Intensity On Airway And Systemic Inflammation In Patients With COPD

C109. REVISITING EXERCISE FOR CHILDREN AND ADULTS, 2010