Neutrophil migration and inflammation in chronic obstructive pulmonary disease

COPD is a leading cause of morbidity and mortality worldwide and it is believed that the neutrophil is key to the pathology. Evidence to date suggests that neutrophils migrate less accurately in patients with COPD, although the precise mechanisms by which this occurs have not been defined. We have shown that COPD neutrophils migrate faster (chemokinesis) but less accurately (chemotaxis) in various chemokine gradients. It appears to be an intrinsic cell defect, as incubation of healthy neutrophils in COPD plasma did not alter migratory dynamics. This phenomenon does not occur in other respiratory diseases and is unrelated to age, disease severity, smoking status or the presence of emphysema. Furthermore, there were no differences in markers of neutrophil activation or maturity, although degranulation markers were higher in COPD. Expression of certain chemokine receptors was lower on quiescent COPD neutrophils, but these differences were abolished after stimulation. Receptors localised to the leading edge effectively in COPD neutrophils and there were no differences in receptor shedding. PI3K phosphorylation was increased in COPD and inhibition of γ and δ isoforms improved chemotaxis. Neither Akt phosphorylation nor intracellular calcium signalling was altered. Simvastatin also improved chemotaxis of COPD neutrophils but CXCR1/2 inhibitors did not

Small airways dysfunction:The importance of utilising Z-scores to define MMEF abnormalities in clinical practice

BACKGROUND: The small airways comprise the largest cross-sectional area of the lungs, however, assessing and reporting abnormalities for this region of the bronchial tree has been practically and scientifically uncertain.METHODS: Using routinely collected spirometry data for patients with either asthma or COPD, the accuracy of % predicted values for defining small airways dysfunction was assessed. A z-score of ≤ -1.645 of the maximal-mid expiratory flow (MMEF) was used as the gold standard for defining abnormality in the small airways.RESULTS: Records of 3396 patients were included in the analysis. The false positive (FP) rates were 24.6 %, 16.1 %, 11.5 %, or 7.9 % when the % predicted value of 80 %, 70 %, 65 %, or 60 % were used, respectively. Sex, age, and BMI were associated with FP rates. Males were more likely to be categorised as FP with odds ratio (OR) between 1.10 and 1.49 across % predicted groups. Age was associated with FP rates with an OR between 1.01 and 1.08. The BMI was also associated with FP rates with an OR of 1.03 across all % predicted groups. Assessing the association of age groups with FP rate showed that those above 60 years old were more likely to be categorised as FP with an OR between 1.23 and 73.2 compared to those less than 30 years old.CONCLUSION: When assessing the small airways in clinical practice or for scientific purposes, the % predicted values overestimate the actual impairment leading to FP interpretation. Utilising z-score values are recommended to assess the small airways using the spirometric index, MMEF.</p

The prevalence of bronchodilator responsiveness of the small airway (using mid-maximal expiratory flow) in COPD - a retrospective study

Abstract Background Bronchodilator responsiveness (BDR) using FEV1 is often utilised to separate COPD patients from asthmatics, although it can be present in some COPD patients. With the advent of treatments with distal airway deposition, BDR in the small airways (SA) may be of value in the management of COPD. We aimed to identify the prevalence of BDR in the SA, utilizing maximal mid-expiratory flow (MMEF) as a measure of SA. We further evaluated the prevalence of BDR in MMEF with and without BDR in FEV1 and its association with baseline demographics, including conventional airflow obstruction severity and smoking history. Methods Lung function data of ever-smoking COPD patients were retrospectively analysed. BDR was evaluated 20 min after administering 2.5 mg of salbutamol via jet nebulizer. Increase in percent change of ≥ 12% and absolute change of ≥ 200 ml was used to define a BDR in FEV1, whereas an increase percent change of MMEF ≥ 30% was used to define a BDR in MMEF. Patients were classified as one of three groups according to BDR levels: group 1 (BDR in MMEF and FEV1), group 2 (BDR in MMEF alone) and group 3 (no BDR in either measure). Result BDR in MMEF was present in 59.2% of the patients. Of note, BDR in MMEF was present in all patients with BDR in FEV1 (group 1) but also in 37.9% of the patients without BDR in FEV1 (group 2). Patients in group 1 were younger than in groups 2 and 3. BMI was higher in group 1 than in group 3. Baseline FEV1% predicted and FVC % predicted were also higher in groups 1 and 2 than in group 3. Conclusion BDR in the SA (evaluated by MMEF) is common in COPD, and it is also feature seen in all patients with BDR in FEV1. Even in the absence of BDR in FEV1, BDR in MMEF is detected in some patients with COPD, potentially identifying a subgroup of patients who may benefit from different treatment strategies

Small airways disease:time for a revisit?

James A Stockley,1 Brendan G Cooper,1 Robert A Stockley,2 Elizabeth Sapey3 1Department of Lung Function and Sleep, 2Department of Respiratory Medicine, University Hospital Birmingham, 3Institute of Inflammation and Ageing, Centre for Translational Inflammation Research, University of Birmingham, Edgbaston, Birmingham, UK Abstract: It is increasingly acknowledged that delays in the diagnosis of chronic inflammatory lung conditions have hampered our understanding of pathogenesis and thus our ability to design efficacious therapies. This is particularly true for COPD, where most patients are diagnosed with moderate-to-severe airflow obstruction and little is known about the inflammatory processes present in early disease. There is great interest in developing screening tests that can identify those most at risk of developing COPD before airflow obstruction has developed for the purpose of research and clinical care. Landmark pathology studies have suggested that damage to the small airways precedes the development of airflow obstruction and emphysema and, thus, presents an opportunity to identify those at risk of COPD. However, despite a number of physiological tests being available to assess small airways function, none have been adopted into routine care in COPD. The reasons that tests of small airways have not been utilized widely include variability in test results and a lack of validated reference ranges from which to compare results for some methodologies. Furthermore, population studies have not consistently demonstrated their ability to diagnose disease. However, the landscape may be changing. As the equipment that delivers tests of small airways become more widely available, reference ranges are emerging and newer methodologies specifically seek to address variability and difficulty in test performance. Moreover, there is evidence that while tests of small airways may not be helpful across the full range of established disease severity, there may be specific groups (particularly those with early disease) where they might be informative. In this review, commonly utilized tests of small airways are critically appraised to highlight why these tests may be important, how they can be used and what knowledge gaps remain for their use in COPD. Keywords: small airways, COPD, early disease, physiology, emphysema, airflow obstructio

Assessing uncertainties in scattering correction algorithms for reflective tube absorption measurements made with a WET Labs ac-9

In situ absorption measurements collected with a WET Labs ac-9 employing a reflective tube approach were scatter corrected using several possible methods and compared to reference measurements made by a PSICAM to assess performance. Overall, two correction methods performed best for the stations sampled: one using an empirical relationship between the ac-9 and PSICAM to derive the scattering error (ε) in the nearinfrared (NIR), and one where ε was independently derived from concurrent measurements of the volume scattering function (VSF). Application of the VSF-based method may be more universally applicable, although difficult to routinely apply because of the lack of commercially available VSF instrumentation. The performance of the empirical approach is encouraging as it relies only on the ac meter measurement and may be readily applied to historical data, although there are inevitably some inherent assumptions about particle composition that hinder universal applicability. For even the best performing methods, residual errors of 20% or more were commonly observed for many water types. For clear ocean waters, a conventional baseline subtraction with the assumption of negligible near-IR absorption performed as well or better than the above methods because propagated uncertainties were lower than observed with the proportional method

Cardiovascular and musculskeletal co-morbidities in patients with alpha 1 antitrypsin deficiency

Background Determining the presence and extent of co-morbidities is fundamental in assessing patients with chronic respiratory disease, where increased cardiovascular risk, presence of osteoporosis and low muscle mass have been recognised in several disease states. We hypothesised that the systemic consequences are evident in a further group of subjects with COPD due to Alpha-1 Antitrypsin Deficiency (A1ATD), yet are currently under-recognised. Methods We studied 19 patients with PiZZ A1ATD COPD and 20 age, sex and smoking matched controls, all subjects free from known cardiovascular disease. They underwent spirometry, haemodynamic measurements including aortic pulse wave velocity (aPWV), an independent predictor or cardiovascular risk, dual energy X-ray absorptiometry to determine body composition and bone mineral density. Results The aPWV was greater in patients: 9.9(2.1) m/s than controls: 8.5(1.6) m/s, p = 0.03, despite similar mean arterial pressure (MAP). The strongest predictors of aPWV were age, FEV1% predicted and MAP (all p < 0.01). Osteoporosis was present in 8/19 patients (2/20 controls) and was previously unsuspected in 7 patients. The fat free mass and bone mineral density were lower in patients than controls (p < 0.001). Conclusions Patients with A1ATD related COPD have increased aortic stiffness suggesting increased risk of cardiovascular disease and evidence of occult musculoskeletal changes, all likely to contribute hugely to overall morbidity and mortality

Relationship of CT densitometry to lung physiological parameters and health status in alpha-1 antitrypsin deficiency: initial report of a centralised database of the NIHR rare diseases translational research collaborative.

Funder: Foundation for the National Institutes of Health; FundRef: http://dx.doi.org/10.13039/100000009OBJECTIVES: To establish a database network for the study of alpha-1 antitrypsin deficiency (AATD) and compare the results to CT lung density as the most direct measure of emphysema. DESIGN: A central electronic database was established to permit the upload of anonymised patient data from remote sites. Prospectively collected CT data were recorded onto disc, anonymised, analysed at the coordinating centre and compared with the clinical features of the disease. SETTING: Tertiary referral centres with expertise in the management of AATD focused on academic Biomedical Research Units and Wellcome Clinical Research Facilities. PARTICIPANTS: Data were collected from 187 patients over 1 year from eight UK academic sites. This included patient demographics, postbronchodilator physiology, health status and CT. Analysis was undertaken at the coordinating centre in Birmingham. RESULTS: Patient recruitment in the 12 months reached 94% of target (set at 200) covering the whole spectrum of the disease from those with normal lung function to very severe chronic obstructive lung disease. CT scan suitable for analysis was available from 147 (79%) of the patients. CT density, analysed as the threshold for the lowest 15% of lung voxels, showed statistically significant relationships with the objective physiological parameters of lung function as determined by spirometric Global Initiative for Chronic Obstructive Lung Disease (GOLD) severity staging (p<0.001) and carbon monoxide gas transfer (p<0.01). Density also correlated with subjective measures of quality of life (p=0.02). CONCLUSIONS: Establishment of the network for data collection and its transfer was highly successful facilitating future collaboration for the study of this rare disease and its management. CT densitometry correlated well with the objective clinical features of the disease supporting its role as the specific marker of the associated emphysema and its severity. Correlations with subjective measures of health, however, were generally weak indicating other factors play a role

Repurposing Treatments to Enhance Innate Immunity. Can Statins Improve Neutrophil Functions and Clinical Outcomes in COPD?

Drug classes used in the treatment of Chronic Obstructive Pulmonary Disease (COPD) have not changed for many years, and none to date have shown disease-modifying activity. Statins are used to help reduce cardiovascular risk, which is high in many patients with COPD. Their use has been associated with improvements in some respiratory manifestations of disease and reduction in all-cause mortality, with greatest reductions seen in patients with the highest inflammatory burden. The mechanism for these effects is poorly understood. Neutrophils are key effector cells in COPD, and correlate with disease severity and inflammation. Recent in vitro studies have shown neutrophil functions are dysregulated in COPD and this is thought to contribute both to the destruction of lung parenchyma and to the poor responses seen in infective exacerbations. In this article, we will discuss the potential utility of statins in COPD, with a particular emphasis on their immune-modulatory effects as well as presenting new data regarding the effects of statins on neutrophil function in vitro

Direct Evidence for Packaging Signal-Mediated Assembly of Bacteriophage MS2

Using cross-linking coupled to matrix-assisted laser desorption/ionization mass spectrometry and CLIP-Seq sequencing, we determined the peptide and oligonucleotide sequences at the interfaces between the capsid proteins and the genomic RNA of bacteriophage MS2. The results suggest that the same coat protein (CP)-RNA and maturation protein (MP)-RNA interfaces are used in every viral particle. The portions of the viral RNA in contact with CP subunits span the genome, consistent with a large number of discrete and similar contacts within each particle. Many of these sites match previous predictions of the locations of multiple, dispersed and degenerate RNA sites with cognate CP affinity termed packaging signals (PSs). Chemical RNA footprinting was used to compare the secondary structures of protein-free genomic fragments and the RNA in the virion. Some PSs are partially present in protein-free RNA but others would need to refold from their dominant solution conformations to form the contacts identified in the virion. The RNA-binding peptides within the MP map to two sections of the N-terminal half of the protein. Comparison of MP sequences from related phages suggests a similar arrangement of RNA-binding sites, although these N-terminal regions have only limited sequence conservation. In contrast, the sequences of the C-termini are highly conserved, consistent with them encompassing pilin-binding domains required for initial contact with host cells. These results provide independent and unambiguous support for the assembly of MS2 virions via a PS-mediated mechanism involving a series of induced-fit viral protein interactions with RNA