Robert A Stockley

..Recent advances in the understanding of the molecular pathology provide opportunities for development of new therapeutic targets for this genetic disorder...

..In this review, we will present a synopsis of current Wnt research with particular attention paid to the role of Wnt signals in lung development and in pulmonary diseases...

....

..We performed a prospective longitudinal study of subjects with COPD that related markers of sputum inflammation at baseline to subsequent disease progression...

..However, emphysema is frequently localised to sub-regions of the lung and targeted densitometric sampling may be more informative than whole lung assessment...

..In summary, short-term therapy with AAT increased lung secretion concentrations and was associated with a fall in leukotriene B(4), which is thought to be central to the airway inflammation of AAT deficiency...

..The success related to the convergence of national registries into a common database creating a unique registry beyond geographic boundaries and encompassing alpha1-antitrypsin deficiency from various ethnic groups...

....

..Two randomised, double-blind, placebo-controlled trials have investigated the efficacy of IV alpha-1 antitrypsin (AAT) augmentation therapy on emphysema progression using CT densitometry...

..We hypothesised that gradations of sputum colour would correlate directly with the myeloperoxidase content of sputum and with various other indicators of the activity and consequences of bronchial diseases...

..This review examines evidence linking inflammation, disease progression and comorbidities in COPD, and the potential role of anti-inflammatory therapies...

..This study investigated the addition of salmeterol to existing treatment for exacerbations in patients with poorly reversible chronic obstructive pulmonary disease (COPD)...

..The presence of chronic expectoration in some patients will clearly complicate interpretation of studies employing sputum induction where this feature has not been identified...

..This study investigated subjects with AATD to determine the relationship between specific phenotypes and TNFalpha polymorphisms...

..01). Our results show that clinical differences in families with alpha-1-antitrypsin deficiency are not solely explained by smoking or ascertainment bias and may be due to variation within genes involved in inflammatory pathways...

..We investigated differences in emphysema distribution and health status in alpha(1)-antitrypsin deficient subjects (PiZ) with discordant lung function...

..This is reflected in an inferior health status, which is also influenced independently by an increased exacerbation frequency in those with CSE...

..Further studies are needed to establish the role of GGT in oxidative lung injury, and its use as a potential biomarker in chronic inflammatory lung disease...

....

..This is critical, because inaccurate or excessive neutrophil chemotaxis could drive pathological accumulation and tissue damage...

..Specific treatments for the disorder based on this knowledge will be reviewed, including alpha1-antitrypsin replacement, gene therapy and possible future therapies, such as those based on stem cells...

..002). Progression of emphysema in alpha(1)-ATD is dependent on baseline physiology and exacerbation frequency and may be detected by several different measurements of which HRCT density mask analysis and DL(CO) appear most sensitive...

....

..409, p < 0.001). The use of single physiologic parameters as a surrogate measure of emphysema severity may introduce systematic bias in the staging of subjects with emphysema...

..Internal air calibration is therefore critical in longitudinal and multicenter lung densitometry studies of emphysema and incorporation of a correction factor is essential for quantitative image analysis...

....

..To avoid this problem we recommend that an untreated aliquot of sputum be retained for cytokine analysis, unless the assay has been specifically validated...

..A study was undertaken to examine the intra- and inter-patient variability in spontaneous sputum samples from patients in the stable state and to describe the relationship between biomarkers, cell counts and markers of disease...

..Matrix metalloproteinases [MMPs] are believed to be important in the pathophysiology of COPD, and may therefore confer susceptibility to this phenotype in patients with AATD...

..This article describes the mechanisms involved and proposes a common inflammatory TNF-alpha phenotype that may, in part, account for the associations...

..Patients with alpha-1-antitrypsin deficiency (AATD) typically exhibit faster decline of lung function than subjects with usual COPD and thus represent a group in whom studies of factors influencing decline may be more easily clarified...

..It is unclear if concentrations relate to disease severity. The study aimed to investigate these relationships and to assess the potential activity of each cytokine in the context of their antagonists...

..Lung transplantation activity is frustrated by donor lung availability. We sought to examine the effect of active donor management and hormone administration on pulmonary function and yield in cadaveric heart-beating potential lung donors...

..Although both HRCT and lung function relate to health status, exercise capacity is the best predictor of patients disability in these patients with predominantly lower zone emphysema...

..Important aetiologies, with their potential underlying mechanisms, are discussed and the significance of each aetiology is considered...

..The aim of this study was to investigate the predictive potential of several parameters, including CT scanning, for mortality in patients with severe alpha(1)-antitrypsin deficiency...

..However, both methods are valid for use in longitudinal and interventional studies in which emphysema is the major outcome target...

..Increased chemotactic activity, together with inhibitor deficiency, may contribute to the more rapid disease progression seen in alpha(1)-AT deficiency via increased neutrophil recruitment and release of neutrophil elastase...

..Despite lung function decline, patients do not show a progressive loss in health status...

..This paper considers the concept of 'overspill' in depth, reviews the current evidence and highlights problems in generating direct evidence to support or refute this concept...

....

..Future studies of systemic and local GGT function and genotypes in well characterised patients may lead to a better understanding of the processes involved and hence the development of new treatment strategies...

..The development of this methodology to repair the gene defect in hepatocytes should have beneficial effects on secretion, thereby protecting both the lung and liver...

..The development of strategies to inactivate these IgA1 proteases has become the subject of recent research, as this has the potential to reduce bacterial colonisation at mucosal surfaces...

..In PiZ alpha(1)-AT-deficient patients, FEV(1) decline was greatest in moderate disease, unlike K(CO) decline, which was greatest in severe disease. The FEV(1) decline showed associations with BDR, BMI, sex and exacerbation rate...

..DBP has an indirect role in macrophage activation; thus it was hypothesised that DBP is present in the airway and contributes to lung disease by this mechanism...

..Wegener granulomatosis (WG) has previously been associated with increased nasal carriage of Staphylococcus aureus, but no studies have investigated the occurrence of pathogen growth in the lower airways...

..Smoke exposure is the main determinant of anti-elastin antibody levels, which fall after 10 pack-yrs. Local antibody complexes may be a better measure of elastin directed autoimmunity than circulating levels...

..This simple clinical observation enables decision making about the need for antibiotic therapy to be as much a part of patient self-management as physician directed management in the integrated care pathway for COPD...

..Purulent exacerbations are related to bacterial infection, and are associated with increased neutrophilic inflammation and increased leukotriene B4 concentrations...

..Higher exposures to ozone may be associated with worse respiratory status in alpha(1)-antitrypsin deficiency, identifying a group susceptible to ambient air pollution...

....

..A fall in SLPI concentration is also seen in culture supernatants of respiratory cells exposed to NE, for unknown reasons. We investigated the hypothesis that SLPI complexed with NE associates with cell membranes in vitro...

..These strategies may have benefits beyond A1AT deficiency...

..However, exacerbations characterized by increased breathlessness are associated with increases in airflow obstruction that may be influenced by sputum characteristics and/or changes in airway reactivity...

..The role of pulmonary rehabilitation (PR) and inspiratory muscle training (IMT) has not been investigated in this group of patients...

....

..Molecular studies provide new insights that may lead to specific therapies to halt progression...

..Finally, controlled clinical trials will be required to demonstrate that modifying inflammation influences long-term progression...

....

..A small phase II trial was conducted to assess the effects of a leukotriene synthesis inhibitor on bronchial inflammation in patients with stable COPD...

..Larger numbers may be required to demonstrate a statistically (if not clinically) significant difference...

....

..2 ± 0.01) to that of "M" (20.2 ± 0.02). The data support the concept that the murine "Z" gene is a potential model for the study of ?(1)ATD and that mice expressing this gene would be relevant for testing treatments in vivo...

..However, measurement of SFC is technically difficult and calculated SFC may offer a more practical alternative...

..The main methods of genomic research for complex disease traits are described, together with the genes implicated in COPD thus far, their roles in disease causation and the future for this area of investigation...

..Further work will be required in order to design specific inhibitors to this important class of proteolytic enzymes...

..A review of the clinical manifestations of alpha(1)-antitrypsin (AAT) deficiency, including lung disease and liver disease, and risk factors affecting the rate of decline in lung function in AAT deficient patients...

....

..Future studies need to define populations clearly, stratify for known confounding factors, and should aim to identify clinical correlates so that clinical practice can be modified appropriately...

..The aims of the study were to compare bacterial recovery following storage of sputum samples at 20 degrees C room temperature and 4 degrees C (refrigerated) for 24 h, and to determine the effect of postage on viable bacterial numbers...

..Those in whom bacteria continue to be cultured in their sputum have partial resolution of inflammation which may reflect continued stimulation by the reduced bacterial load...

..The results raise the possibility that other deficiency alleles are more common than has previously been suspected...

..The migration into and activation of neutrophils in the lung is likely to be a major determinant of the development of COPD. Understanding the processes has important implications for the design of new therapeutic strategies...

..This article reviews the evidence of the role VDBP and its gene (GC) in a range of lung diseases, including asthma, COPD and tuberculosis...

..Impairment of the cortisol response to stimulation is associated with poorer health status...

..Resolution occurred with conservative management. The histopathology and management of this unusual condition are discussed, with a review of the literature...

..Exacerbations are key drivers of morbidity and mortality in chronic obstructive pulmonary disease (COPD)...

..5-fold more sensitive using lung densitometry than by using currently recommended lung function parameters. Our results support CT scan as an efficacious test for novel drugs for emphysema...

..alpha(1)-Antitrypsin (AAT) deficiency is associated with increased risk of chronic obstructive pulmonary disease (COPD), in particular emphysema, but airway disease is less well described...

....