Biomedical subjects

Peter A B Wark

Publications and source records attributed to Peter A B Wark.

7 recordsLinked to original sources

PubMed2006

Role of deficient type III interferon-lambda production in asthma exacerbations.

Rhinoviruses are the major cause of asthma exacerbations, and asthmatics have increased susceptibility to rhinovirus and risk of invasive bacterial infections. Here we show deficient induction of interferon-lambdas by rhinovirus in asthmatic primary bronchial epithelial cells and alveolar macrophages, which was highly correlated with severity of rhinovirus-induced asthma exacerbation and virus load in experimentally infected human volunteers. Induction by lipopolysaccharide in asthmatic macrophages was also deficient and correlated with exacerbation severity. These results identify previously unknown mechanisms of susceptibility to infection in asthma and suggest new approaches to prevention and/or treatment of asthma exacerbations.

Asthma↗

PubMed2005

Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus.

Rhinoviruses are the major trigger of acute asthma exacerbations and asthmatic subjects are more susceptible to these infections. To investigate the underlying mechanisms of this increased susceptibility, we examined virus replication and innate responses to rhinovirus (RV)-16 infection of primary bronchial epithelial cells from asthmatic and healthy control subjects. Viral RNA expression and late virus release into supernatant was increased 50- and 7-fold, respectively in asthmatic cells compared with healthy controls. Virus infection induced late cell lysis in asthmatic cells but not in normal cells. Examination of the early cellular response to infection revealed impairment of virus induced caspase 3/7 activity and of apoptotic responses in the asthmatic cultures. Inhibition of apoptosis in normal cultures resulted in enhanced viral yield, comparable to that seen in infected asthmatic cultures. Examination of early innate immune responses revealed profound impairment of virus-induced interferon-beta mRNA expression in asthmatic cultures and they produced >2.5 times less interferon-beta protein. In infected asthmatic cells, exogenous interferon-beta induced apoptosis and reduced virus replication, demonstrating a causal link between deficient interferon-beta, impaired apoptosis and increased virus replication. These data suggest a novel use for type I interferons in the treatment or prevention of virus-induced asthma exacerbations.

Adult↗

PubMed2004

Induced sputum 8-isoprostane concentrations in inflammatory airway diseases.

Induced sputum 8-iso-prostaglandin F(2alpha) (PGF(2alpha)) concentrations may be a useful marker of oxidative stress in airways disease. This study examines oxidative stress (measured by 8-iso-PGF(2alpha)) in airway disease according to disease type (asthma and bronchiectasis), disease activity (stable and acute asthma), and disease pattern (intermittent, mild, moderate, and severe persistent asthma). We compared subjects with stable asthma (n = 71) and bronchiectasis (n = 23) with healthy control subjects (n = 29). Another group of patients with asthma (n = 39) were assessed during and after acute exacerbation. Induced sputum 8-iso-PGF(2alpha) concentrations were validated and found to be elevated in subjects with stable asthma and bronchiectasis versus control subjects (median [interquartile range] 216 [103-389] and 698 [264-1,613] ng/L vs. 123 [41-290] ng/L, p < 0.001) and increased as clinical asthma pattern worsened (intermittent 115 [42-153], mild persistent 116 [89-229] ng/L, moderate persistent 183 [110-317] ng/L, severe persistent 387 [102-587] ng/L; p = 0.010). Sputum 8-iso-PGF(2alpha) concentrations were elevated during acute asthma and decreased with recovery (458 [227-950] ng/L vs. 214 [148-304] ng/L, p = 0.0002). We conclude that 8-iso-PGF(2alpha) is involved in the pathophysiology of inflammatory airway diseases, being related to disease type, pattern, and activity. Analysis of 8-iso-PGF(2alpha) concentrations in induced sputum provides a useful tool for monitoring oxidative stress and investigating strategies aimed at reducing oxidative stress in airways disease.

Adult↗

PubMed2003

Clinical usefulness of inflammatory markers in asthma.

Asthma is a significant and increasing health problem. Airway inflammation and hyperresponsiveness are key pathophysiological mechanisms underlying asthma. Currently, effective treatments target these two processes and can lead to clinically important improvements in disease control. At present, decisions to initiate or modify therapy are based on symptoms and measures of airway caliber, with no direct assessment of airway inflammation or hyperresponsiveness. It is now possible to measure airway inflammation using noninvasive markers such as exhaled gases, induced sputum and serum measurements. Exhaled nitric oxide (eNO) and induced sputum eosinophils show the greatest promise as clinically useful markers of airway inflammation in asthma. Induced sputum can now be applied to the diagnosis of airway diseases, based on its ability to detect eosinophilic bronchitis in cough, and to differentiate between eosinophilic and non-eosinophilic asthma. The place of induced sputum and eNO in the ongoing monitoring of patients with asthma are now being investigated in controlled trials.

Asthma↗

PubMed2003

Use of induced sputum for the diagnosis of influenza and infections in asthma: a comparison of diagnostic techniques.

BACKGROUND: Influenza (Flu) and respiratory syncytial virus (RSV) are important viral pathogens that cause lower respiratory tract infections and severe exacerbations of asthma. Molecular biological techniques are permitting a rapid and accurate diagnosis of infections caused by respiratory pathogens, and have typically been applied to upper respiratory samples. Sputum induction provides an opportunity to directly sample secretions from the lower respiratory tract. OBJECTIVES/STUDY DESIGN: To determine the role of induced sputum reverse-transcription polymerase chain reaction (RT-PCR) in the detection of respiratory pathogens and compare this with detection using serology and immunofluorescent antigen (IFA) testing, we recruited 49 adults from emergency room with exacerbations of asthma. After a medical assessment and spirometry, sputum was induced using ultrasonically nebulised normal saline. Sputum was assayed using IFA and RT-PCR for flu and RSV. Flu serology was performed acutely and at convalescence, 4-5 weeks later. RESULTS: Influenza A or B was detected in 24% of the samples by PCR, significantly more than the nine cases detected using serology and the one case using IFA (P<0.05). RSV was detected in 37% of samples using PCR and 20% by IFA (P<0.05). CONCLUSION: The combination of induced sputum and RT-PCR provides a useful means of detecting respiratory infection. The technique is safe in both adults and children, and RT-PCR is more sensitive than conventional serology and IFA. The improved sensitivity of induced sputum RT-PCR also permits a more rapid diagnosis and the opportunity of early administration of effective treatments.

Acute Disease↗

PubMed2002

Optimization of sputum-processing methods for the measurement of interleukin-5: effects of protease inhibition.

BACKGROUND: Interleukin (IL)-5 measurement in sputum samples has produced variable results that appear to be due to methodological problems. The aim of the present study was to investigate the effects of dithiothreitol (DTT), sputum protease inhibition and sample storage on IL-5 recovery in order to develop a method to accurately measure IL-5 in dispersed sputum supernatant. METHODOLOGY: Measurement of IL-5 in sputum was performed in 22 subjects with airway disease. Interleukin-5 recovery was measured in samples spiked with recombinant human IL-5 using a commercial ELISA. A mix of four protease inhibitors (PI) was added to sputum processed using the selection method with dispersion using DTT and stored with and without inhibitors. RESULTS: The addition of PI to sputum resulted in a 24% increase in IL-5 recovery. Recovery was not further increased with the addition of a blocking protein. Storage of IL-5-spiked sputum gave significantly less recovery. The addition of PI to sputum processed with DTT had no effect on total cell count, viability or cell differential. CONCLUSION: Interleukin-5 recovery is increased by the addition of PI to samples processed using the selected portion method with DTT dispersion. A protease inhibitor cocktail should be added to sputum for IL-5 assay.

Adult↗

PubMed2002

DX-890 (Dyax).

Dyax (formerly Protein Engineering Corp) and Debiopharm are developing DX-890, an inhibitor of human neutrophil elastase (HNE), for the potential treatment of pulmonary diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) [242806]. In December 1999, Debiopharm initiated phase I trials with an aerosol formulation of DX-890; studies were completed by October 2000 [350718], [352554], [387155]. By August 2000, DX-890 was in phase II evaluation for the potential treatment of CF [378625], and in May 2002, Dyax planned to initiate a further study, in children with CF, within the year [451044]. By June 2002, phase II trials in CF were ongoing in France and Spain, with results expected soon after this date [454485]. In September 2000, JP Morgan predicted a 2005 launch for this drug, with estimated sales in that year of 23 US dollars million rising to 63 million US dollars in 2007 [397766].

Journal Article↗