A respiratory physician with a long standing academic career with an emphasis on airways disease, rare diseases, pharmacology, clinical trials and genetics. Winner of many national grants and previous President of the Thoracic Society of Australia and New Zealand and founding Director of the Lung Institute of Western Australia.
β2 adrenergic receptor (ADRβ2) polymorphisms including ADRβ2+46G>A have been reported to cause... more β2 adrenergic receptor (ADRβ2) polymorphisms including ADRβ2+46G>A have been reported to cause adverse outcomes in mild asthmatics. The extent to which ADRβ2 polymorphisms and in particular their haplotypes contribute to severe asthma is unknown. To determine the association of ADRβ2 polymorphisms and haplotypes with asthma severity. Caucasians (n = 2979) were genotyped for 11 ADRβ2 polymorphisms. The cohort (mean age 39.6, 60% female) included 2296 non-asthmatics, 386 mild asthmatics, 172 moderate asthmatics and 125 severe asthmatics. Haplotype frequency and haplotype pair for each subject was determined using the PHASE algorithm. The three asthmatic cohorts were comparable in age and gender but were distinguishable from each other in terms of symptoms, spirometry, medication use and health care utilisation (p <0.001). None of the polymorphisms showed a genotypic or allelic association with asthma diagnosis or severity. Nine haplotypes were identified and no association was f...
In cystic fibrosis (CF) very few studies have assessed sputum 8-iso-PGF2alpha levels during pulmo... more In cystic fibrosis (CF) very few studies have assessed sputum 8-iso-PGF2alpha levels during pulmonary exacerbations as a direct measure of airway oxidative stress. The role of other lipid-derived inflammatory mediators, such as the cysteinyl leukotrienes (cys-LTs) and prostaglandin (PG)-E2, during exacerbations is also poorly defined and the effect of conventional antibiotic therapy on these components of the inflammatory process is unclear. Sputum 8-iso-PGF2alpha, total cys-LT and PGE2 levels were measured in 17 CF patients experiencing a pulmonary exacerbation and repeated analysis were performed in 15 of these patients after antibiotic treatment. Eight stable CF and nine healthy subjects provided control data. Sputum 8-iso-PGF2alpha was significantly elevated in acute, but not stable CF patients versus healthy controls (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;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;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). Similarly, sputum cys-LT and PGE2 levels were increased in acute compared with stable CF patients and healthy controls (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;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;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;or= 0.001). Although substantially lower than in acute patients, sputum cys-LT levels in stable patients were also significantly higher than in normal controls (P = 0.01). There were strong associations between cys-LT levels and sputum total cell counts, and blood neutrophils in acute patients (r2 = 0.53, P = 0.001 and r2 = 0.33, 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;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;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, respectively). Overall in the CF patients, FEV1% predicted was strongly and negatively correlated with sputum 8-iso-PGF2alpha (r2 = 0.34, P = 0.006), cys-LT (r2 = 0.40, P = 0.002) and PGE2 (r2 = 0.52, 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;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;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) levels. Antibiotic treatment reduced sputum total cell count (P = 0.03), but did not affect 8-iso-PGF2alpha, cys-LT or PGE2 levels. CF exacerbations are characterized by increased oxidative stress and sputum concentrations of bioactive lipid mediators. Treatment does not modulate these aspects of inflammation and more…
Kinins have been implicated in the pathophysiology of asthma and activation of kinin receptors st... more Kinins have been implicated in the pathophysiology of asthma and activation of kinin receptors stimulates neutrophil chemotaxis. However, the expression of kinin receptors on neutrophils of asthmatic subjects has not been assessed. The aim of this study was to compare the expression of kinin B(1) and B(2) receptor mRNA and proteins in neutrophils of asthmatic and non-asthmatic subjects, and to assess whether inhaled corticosteroid treatment may influence expression of the kinin receptors. Neutrophils were isolated from peripheral blood of asthmatic (n=27) and non-asthmatic subjects (n=14). The presence of kinin B(1) and B(2) receptor protein on neutrophils was confirmed by immunolabeling with specific antibodies followed by immunoperoxidase, immunofluorescence and FACS detection. Kinin B(1) and B(2) receptor mRNA expression was assessed by RT-PCR. Quantitative image analysis of fluorescence immunolabeled neutrophils showed no differences in kinin B(1) or B(2) receptor protein expression between asthmatic and non-asthmatic subjects. Similarly, quantitative real time RT-PCR analysis demonstrated no differences in expression of mRNA for the kinin B(1) or B(2) receptors between asthmatic and non-asthmatic subjects. However, B(1) receptor mRNA expression was significantly lower in asthmatic subjects using &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or =2000 microg of inhaled corticosteroid per day (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;lt;0.05) and B(1) receptor protein levels also tended to be lower in these subjects. Corticosteroids may have a beneficial anti-inflammatory effect in asthma by down-regulating B(1) receptor expression on neutrophils, thereby decreasing the migration of these inflammatory cells into the airways.
In this study the effects of different in vitro conditioning with transforming growth factor (TGF... more In this study the effects of different in vitro conditioning with transforming growth factor (TGF) beta1 on human monocyte-derived DC maturation (hMo-DC) were investigated. hMo-DC differentiated in the presence of physiologically relevant concentrations of TGFbeta1 (2 ng/ml) failed to undergo complete maturation despite adequate stimulation with LPS or LPS+IFNgamma. These hMo-DC did not produce IL-12p70 or PGE2, and showed decreased IL-10 and IL-18 production and HLA-DR expression. However, the expression of these molecules, except for IL-12p70, was not significantly affected in hMo-DC differentiated in the presence of lower concentrations of TGFbeta1 (0.2 and 0.02 ng/ml). Exposure of hMo-DC to TGFbeta1 (2 ng/ml) after they had completed differentiation had minimal effects. Thus, the functional response of hMo-DC to LPS or LPS+IFNgamma depended on the stage of hMo-DC differentiation at which cells were first exposed to TGFbeta1 and on the concentration of TGFbeta1. These results suggest that in the in vivo micro-environment, the concentrations and the timing of monocyte exposure to TGFbeta1 may be crucial in the differentiation of DC toward more or less mature phenotypes, and this may have important implications for DC functions. The decrease in T-cell proliferation and a small increase in IL-5 production by T cells co-cultured with hMo-DC that had been treated with TGFbeta1, suggest the possibility that in vivo such DC may provide chronic, but incomplete signals to T cells, and this could be a potential mechanism underlying polarisation of T cells towards anergy.
The interleukin (IL)-6 family of cytokines and exaggerated signal transducer and activator of tra... more The interleukin (IL)-6 family of cytokines and exaggerated signal transducer and activator of transcription (STAT)3 signaling is implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis, but the mechanisms regulating STAT3 expression and function are unknown. Suppressor of cytokine signaling (SOCS)1 and SOCS3 block STAT3, and low SOCS1 levels have been reported in IPF fibroblasts and shown to facilitate collagen production. Fibroblasts and lung tissue from IPF patients and controls were used to examine the mechanisms underlying SOCS1 down-regulation in IPF. A significant reduction in basal SOCS1 mRNA in IPF fibroblasts was confirmed. However, there was no difference in the kinetics of activation, and methylation of SOCS1 in control and IPF lung fibroblasts was low and unaffected by 5′-aza-2′-deoxycytidine’ treatment. SOCS1 is a target of microRNA-155 and although microRNA-155 levels were increased in IPF tissue, they were reduced in IPF fibroblasts. Therefore, SOCS1 is not reg...
In experimental studies viral infections have been shown to induce type 2 inflammation in asthmat... more In experimental studies viral infections have been shown to induce type 2 inflammation in asthmatics, but whether this is a feature of naturally occurring virus-induced asthma exacerbations is unknown. Thymic stromal lymphopoietin (TSLP) released from the airway epithelium in response to damage, has been suggested as a link between viral infection and type 2 inflammation, but the role of TSLP in asthma exacerbations is unknown. To assess whether type 2 inflammation, as measured by sputum eosinophils and fractional exhaled nitric oxide (FeNO), is a feature of naturally occurring virus-induced exacerbations of asthma and whether TSLP is associated with this type 2 inflammation. Patients presenting to hospital with acute asthma were examined during the exacerbation, and after 4 weeks recovery. The assessments included spirometry, FeNO and induced sputum for differential counts and TSLP mRNA levels. Nasal swabs were collected for viral detection. Sputum eosinophils and FeNO were similar...
The Journal of the Association of Physicians of India, 2015
Despite a better understanding of the pathophysiology of asthma, presence of reliable diagnostic ... more Despite a better understanding of the pathophysiology of asthma, presence of reliable diagnostic tools, availability of a wide array of effective and affordable inhaled drugs and simplified national and international asthma management guidelines, asthma remains poorly managed in India. The Asia-Pacific Asthma Insight and Management (AP-AIM) study was aimed at understanding the characteristics of asthma, current management, level of asthma control and its impact on quality of life across Australia, China, Hong Kong, India, Malaysia, Singapore, South Korea, Taiwan and Thailand. This paper describes the results of asthma management issues in India in detail and provides a unique insight into asthma in India. The AP-AIM India study was conducted in eight urban cities in India, viz: Ajmer, Delhi, Kolkata, Rourkela, Chennai, Mangalore, Mumbai and Rajkot from February to July 2011. Face-to-face interviews were conducted in adult asthmatics and parents of asthmatic children between the ages...
Purified α1 proteinase inhibitor (A1PI) slowed emphysema progression in patients with severe α1 a... more Purified α1 proteinase inhibitor (A1PI) slowed emphysema progression in patients with severe α1 antitrypsin deficiency in a randomised controlled trial (RAPID-RCT), which was followed by an open-label extension trial (RAPID-OLE). The aim was to investigate the prolonged treatment effect of A1PI on the progression of emphysema as assessed by the loss of lung density in relation to RAPID-RCT. Patients who had received either A1PI treatment (Zemaira or Respreeza; early-start group) or placebo (delayed-start group) in the RAPID-RCT trial were included in this 2-year open-label extension trial (RAPID-OLE). Patients from 22 hospitals in 11 countries outside of the USA received 60 mg/kg per week A1PI. The primary endpoint was annual rate of adjusted 15th percentile lung density loss measured using CT in the intention-to-treat population with a mixed-effects regression model. This trial is registered with ClinicalTrials.gov, number NCT00670007. Between March 1, 2006, and Oct 13, 2010, 140 p...
Several animal studies, and one inoculation study in adult asthmatics have shown that interleukin... more Several animal studies, and one inoculation study in adult asthmatics have shown that interleukin-33 (IL-33) is a major contributor to type-2 inflammation in acute asthma. However, the link between IL-33 and type-2 inflammation has not been shown in naturally occurring asthma exacerbations. To determine if airway IL-33 is associated with type-2 inflammation measured by type-2 cytokines, FeNO and sputum eosinophils in patients presenting to the Emergency Department with an asthma exacerbations. Adult patients hospitalized due to acute asthma were enrolled. Upper airways were sampled with nasal swabs and lower airways with induced sputum. Cytokines were measured at protein level using a Luminex assay and mRNA expression level using droplet-digital-PCR. Airway sampling was repeated four weeks after exacerbation. At the time of exacerbation, upper airway IL-33 correlated with upper airway IL-5 and IL-13 (R = 0.84, p < 0.01 and R = 0.76, p < 0.01, respectively) and with lower airwa...
Treatment with mepolizumab, a humanized monoclonal antibody to interleukin-5, reduces the rate of... more Treatment with mepolizumab, a humanized monoclonal antibody to interleukin-5, reduces the rate of asthma exacerbations and the requirement for systemic glucocorticoids while maintaining asthma control. Treatment decisions are guided by predictors of response, including blood eosinophil thresholds in patients with frequent exacerbations despite intensive anti-inflammatory and controller treatment. Identification of additional predictors of response could aid treatment decisions. We investigated genetic associations that may predict response to mepolizumab-treatment. In this post hoc analysis of DREAM and MENSA, association of genetic markers was tested in patients with severe asthma treated with mepolizumab who provided consent for pharmacogenetic research. Association was tested in a tiered approach with alpha spend differing for candidate genetic markers selected for prior history of association with relevant traits or pathways and in a genome-wide analyses (p < 4.7 × 10-4 and p...
β2 adrenergic receptor (ADRβ2) polymorphisms including ADRβ2+46G>A have been reported to cause... more β2 adrenergic receptor (ADRβ2) polymorphisms including ADRβ2+46G>A have been reported to cause adverse outcomes in mild asthmatics. The extent to which ADRβ2 polymorphisms and in particular their haplotypes contribute to severe asthma is unknown. To determine the association of ADRβ2 polymorphisms and haplotypes with asthma severity. Caucasians (n = 2979) were genotyped for 11 ADRβ2 polymorphisms. The cohort (mean age 39.6, 60% female) included 2296 non-asthmatics, 386 mild asthmatics, 172 moderate asthmatics and 125 severe asthmatics. Haplotype frequency and haplotype pair for each subject was determined using the PHASE algorithm. The three asthmatic cohorts were comparable in age and gender but were distinguishable from each other in terms of symptoms, spirometry, medication use and health care utilisation (p <0.001). None of the polymorphisms showed a genotypic or allelic association with asthma diagnosis or severity. Nine haplotypes were identified and no association was f...
In cystic fibrosis (CF) very few studies have assessed sputum 8-iso-PGF2alpha levels during pulmo... more In cystic fibrosis (CF) very few studies have assessed sputum 8-iso-PGF2alpha levels during pulmonary exacerbations as a direct measure of airway oxidative stress. The role of other lipid-derived inflammatory mediators, such as the cysteinyl leukotrienes (cys-LTs) and prostaglandin (PG)-E2, during exacerbations is also poorly defined and the effect of conventional antibiotic therapy on these components of the inflammatory process is unclear. Sputum 8-iso-PGF2alpha, total cys-LT and PGE2 levels were measured in 17 CF patients experiencing a pulmonary exacerbation and repeated analysis were performed in 15 of these patients after antibiotic treatment. Eight stable CF and nine healthy subjects provided control data. Sputum 8-iso-PGF2alpha was significantly elevated in acute, but not stable CF patients versus healthy controls (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;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;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). Similarly, sputum cys-LT and PGE2 levels were increased in acute compared with stable CF patients and healthy controls (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;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;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;or= 0.001). Although substantially lower than in acute patients, sputum cys-LT levels in stable patients were also significantly higher than in normal controls (P = 0.01). There were strong associations between cys-LT levels and sputum total cell counts, and blood neutrophils in acute patients (r2 = 0.53, P = 0.001 and r2 = 0.33, 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;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;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, respectively). Overall in the CF patients, FEV1% predicted was strongly and negatively correlated with sputum 8-iso-PGF2alpha (r2 = 0.34, P = 0.006), cys-LT (r2 = 0.40, P = 0.002) and PGE2 (r2 = 0.52, 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;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;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) levels. Antibiotic treatment reduced sputum total cell count (P = 0.03), but did not affect 8-iso-PGF2alpha, cys-LT or PGE2 levels. CF exacerbations are characterized by increased oxidative stress and sputum concentrations of bioactive lipid mediators. Treatment does not modulate these aspects of inflammation and more…
Kinins have been implicated in the pathophysiology of asthma and activation of kinin receptors st... more Kinins have been implicated in the pathophysiology of asthma and activation of kinin receptors stimulates neutrophil chemotaxis. However, the expression of kinin receptors on neutrophils of asthmatic subjects has not been assessed. The aim of this study was to compare the expression of kinin B(1) and B(2) receptor mRNA and proteins in neutrophils of asthmatic and non-asthmatic subjects, and to assess whether inhaled corticosteroid treatment may influence expression of the kinin receptors. Neutrophils were isolated from peripheral blood of asthmatic (n=27) and non-asthmatic subjects (n=14). The presence of kinin B(1) and B(2) receptor protein on neutrophils was confirmed by immunolabeling with specific antibodies followed by immunoperoxidase, immunofluorescence and FACS detection. Kinin B(1) and B(2) receptor mRNA expression was assessed by RT-PCR. Quantitative image analysis of fluorescence immunolabeled neutrophils showed no differences in kinin B(1) or B(2) receptor protein expression between asthmatic and non-asthmatic subjects. Similarly, quantitative real time RT-PCR analysis demonstrated no differences in expression of mRNA for the kinin B(1) or B(2) receptors between asthmatic and non-asthmatic subjects. However, B(1) receptor mRNA expression was significantly lower in asthmatic subjects using &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or =2000 microg of inhaled corticosteroid per day (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;lt;0.05) and B(1) receptor protein levels also tended to be lower in these subjects. Corticosteroids may have a beneficial anti-inflammatory effect in asthma by down-regulating B(1) receptor expression on neutrophils, thereby decreasing the migration of these inflammatory cells into the airways.
In this study the effects of different in vitro conditioning with transforming growth factor (TGF... more In this study the effects of different in vitro conditioning with transforming growth factor (TGF) beta1 on human monocyte-derived DC maturation (hMo-DC) were investigated. hMo-DC differentiated in the presence of physiologically relevant concentrations of TGFbeta1 (2 ng/ml) failed to undergo complete maturation despite adequate stimulation with LPS or LPS+IFNgamma. These hMo-DC did not produce IL-12p70 or PGE2, and showed decreased IL-10 and IL-18 production and HLA-DR expression. However, the expression of these molecules, except for IL-12p70, was not significantly affected in hMo-DC differentiated in the presence of lower concentrations of TGFbeta1 (0.2 and 0.02 ng/ml). Exposure of hMo-DC to TGFbeta1 (2 ng/ml) after they had completed differentiation had minimal effects. Thus, the functional response of hMo-DC to LPS or LPS+IFNgamma depended on the stage of hMo-DC differentiation at which cells were first exposed to TGFbeta1 and on the concentration of TGFbeta1. These results suggest that in the in vivo micro-environment, the concentrations and the timing of monocyte exposure to TGFbeta1 may be crucial in the differentiation of DC toward more or less mature phenotypes, and this may have important implications for DC functions. The decrease in T-cell proliferation and a small increase in IL-5 production by T cells co-cultured with hMo-DC that had been treated with TGFbeta1, suggest the possibility that in vivo such DC may provide chronic, but incomplete signals to T cells, and this could be a potential mechanism underlying polarisation of T cells towards anergy.
The interleukin (IL)-6 family of cytokines and exaggerated signal transducer and activator of tra... more The interleukin (IL)-6 family of cytokines and exaggerated signal transducer and activator of transcription (STAT)3 signaling is implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis, but the mechanisms regulating STAT3 expression and function are unknown. Suppressor of cytokine signaling (SOCS)1 and SOCS3 block STAT3, and low SOCS1 levels have been reported in IPF fibroblasts and shown to facilitate collagen production. Fibroblasts and lung tissue from IPF patients and controls were used to examine the mechanisms underlying SOCS1 down-regulation in IPF. A significant reduction in basal SOCS1 mRNA in IPF fibroblasts was confirmed. However, there was no difference in the kinetics of activation, and methylation of SOCS1 in control and IPF lung fibroblasts was low and unaffected by 5′-aza-2′-deoxycytidine’ treatment. SOCS1 is a target of microRNA-155 and although microRNA-155 levels were increased in IPF tissue, they were reduced in IPF fibroblasts. Therefore, SOCS1 is not reg...
In experimental studies viral infections have been shown to induce type 2 inflammation in asthmat... more In experimental studies viral infections have been shown to induce type 2 inflammation in asthmatics, but whether this is a feature of naturally occurring virus-induced asthma exacerbations is unknown. Thymic stromal lymphopoietin (TSLP) released from the airway epithelium in response to damage, has been suggested as a link between viral infection and type 2 inflammation, but the role of TSLP in asthma exacerbations is unknown. To assess whether type 2 inflammation, as measured by sputum eosinophils and fractional exhaled nitric oxide (FeNO), is a feature of naturally occurring virus-induced exacerbations of asthma and whether TSLP is associated with this type 2 inflammation. Patients presenting to hospital with acute asthma were examined during the exacerbation, and after 4 weeks recovery. The assessments included spirometry, FeNO and induced sputum for differential counts and TSLP mRNA levels. Nasal swabs were collected for viral detection. Sputum eosinophils and FeNO were similar...
The Journal of the Association of Physicians of India, 2015
Despite a better understanding of the pathophysiology of asthma, presence of reliable diagnostic ... more Despite a better understanding of the pathophysiology of asthma, presence of reliable diagnostic tools, availability of a wide array of effective and affordable inhaled drugs and simplified national and international asthma management guidelines, asthma remains poorly managed in India. The Asia-Pacific Asthma Insight and Management (AP-AIM) study was aimed at understanding the characteristics of asthma, current management, level of asthma control and its impact on quality of life across Australia, China, Hong Kong, India, Malaysia, Singapore, South Korea, Taiwan and Thailand. This paper describes the results of asthma management issues in India in detail and provides a unique insight into asthma in India. The AP-AIM India study was conducted in eight urban cities in India, viz: Ajmer, Delhi, Kolkata, Rourkela, Chennai, Mangalore, Mumbai and Rajkot from February to July 2011. Face-to-face interviews were conducted in adult asthmatics and parents of asthmatic children between the ages...
Purified α1 proteinase inhibitor (A1PI) slowed emphysema progression in patients with severe α1 a... more Purified α1 proteinase inhibitor (A1PI) slowed emphysema progression in patients with severe α1 antitrypsin deficiency in a randomised controlled trial (RAPID-RCT), which was followed by an open-label extension trial (RAPID-OLE). The aim was to investigate the prolonged treatment effect of A1PI on the progression of emphysema as assessed by the loss of lung density in relation to RAPID-RCT. Patients who had received either A1PI treatment (Zemaira or Respreeza; early-start group) or placebo (delayed-start group) in the RAPID-RCT trial were included in this 2-year open-label extension trial (RAPID-OLE). Patients from 22 hospitals in 11 countries outside of the USA received 60 mg/kg per week A1PI. The primary endpoint was annual rate of adjusted 15th percentile lung density loss measured using CT in the intention-to-treat population with a mixed-effects regression model. This trial is registered with ClinicalTrials.gov, number NCT00670007. Between March 1, 2006, and Oct 13, 2010, 140 p...
Several animal studies, and one inoculation study in adult asthmatics have shown that interleukin... more Several animal studies, and one inoculation study in adult asthmatics have shown that interleukin-33 (IL-33) is a major contributor to type-2 inflammation in acute asthma. However, the link between IL-33 and type-2 inflammation has not been shown in naturally occurring asthma exacerbations. To determine if airway IL-33 is associated with type-2 inflammation measured by type-2 cytokines, FeNO and sputum eosinophils in patients presenting to the Emergency Department with an asthma exacerbations. Adult patients hospitalized due to acute asthma were enrolled. Upper airways were sampled with nasal swabs and lower airways with induced sputum. Cytokines were measured at protein level using a Luminex assay and mRNA expression level using droplet-digital-PCR. Airway sampling was repeated four weeks after exacerbation. At the time of exacerbation, upper airway IL-33 correlated with upper airway IL-5 and IL-13 (R = 0.84, p < 0.01 and R = 0.76, p < 0.01, respectively) and with lower airwa...
Treatment with mepolizumab, a humanized monoclonal antibody to interleukin-5, reduces the rate of... more Treatment with mepolizumab, a humanized monoclonal antibody to interleukin-5, reduces the rate of asthma exacerbations and the requirement for systemic glucocorticoids while maintaining asthma control. Treatment decisions are guided by predictors of response, including blood eosinophil thresholds in patients with frequent exacerbations despite intensive anti-inflammatory and controller treatment. Identification of additional predictors of response could aid treatment decisions. We investigated genetic associations that may predict response to mepolizumab-treatment. In this post hoc analysis of DREAM and MENSA, association of genetic markers was tested in patients with severe asthma treated with mepolizumab who provided consent for pharmacogenetic research. Association was tested in a tiered approach with alpha spend differing for candidate genetic markers selected for prior history of association with relevant traits or pathways and in a genome-wide analyses (p < 4.7 × 10-4 and p...
Uploads
Papers by Philip Thompson