James Stockley

Behavioral and structural differences in migrating peripheral neutrophils from patients with chronic obstructive pulmonary disease.

RATIONALE There are increased neutrophils in the lungs of patients with chronic obstructive pulmonary disease (COPD), but it is unclear if this is due to increased inflammatory signal or related to the inherent behavior of the neutrophils. This is critical, because inaccurate or excessive neutrophil chemotaxis could drive pathological accumulation and tissue damage. OBJECTIVES To assess migratory dynamics of neutrophils isolated from patients with COPD compared with healthy smoking and nonsmoking control subjects and patients with α(1)-antitryspin deficiency. METHODS Migratory dynamics and structure were assessed in circulating neutrophils, using phase and differential interference contrast microscopy and time-lapse photography. The effect of COPD severity was studied. Surface expression of receptors was measured using flow cytometry. The in vitro effects of a phosphoinositide 3-kinase inhibitor (LY294002) were studied. MEASUREMENTS AND MAIN RESULTS COPD neutrophils moved with greater speed than cells from either control group but with reduced migratory accuracy, in the presence of IL-8, growth-related oncogene α, formyl-methionyl-leucyl-phenylalanine, and sputum. This was present across all stages of COPD. Structurally, COPD neutrophils formed fewer pseudopods during migration. There were no differences in surface expression of the receptors CXCR1, CXCR2, or FPR1. LY294002 reduced COPD neutrophil migratory speed while increasing chemotactic accuracy, returning values to normal. The inhibitor did not have these effects in healthy control subjects or patients with a similar degree of lung disease. CONCLUSIONS COPD neutrophils are intrinsically different than cells from other studied populations in their chemotactic behavior and migratory structure. Differences are not due to surface expression of chemoattractant receptors but instead appear to be due to differences in cell signaling.

Age related development of respiratory abnormalities in non-index α-1 antitrypsin deficient studies.

BACKGROUND The role of lung function monitoring in subjects identified as having asymptomatic alpha-1 antitrypsin deficiency (AATD) is uncertain. We investigated for the first time the age these tests start to deviate from results expected in a healthy population with particular reference to the group with the best prognosis (non-smokers), and the order in which this occurs. METHODS Spirometry, gas transfer, health status, and CT densitometry for upper and lower zones were examined in relation to age, gender, ascertainment method and smoking in 591 PiZ AATD subjects using two methods. Firstly, determining the earliest age group at which >50% of subjects consistently had actual test results worse than the healthy population mean by data observation, and secondly predicting the age when this occurred using a logistic regression model. RESULTS Both methods produced similar results. For non-index subjects, gas transfer and health status deviated from normal before the age of 16, followed by upper zone densitometry and FEV(1):FVC ratio (age 29), and finally lower zone densitometry and FEV(1) (age 37). This order was similar in non-index never smokers, but occurred later (from the age of 29-63). CONCLUSIONS Gas transfer, health status and CT densitometry deviate from normal from the mid-teens (up to 30 years prior to conventional spirometry) in AATD.

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.

Small airways disease: time for a revisit?

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.

Pulmonary Physiology of Chronic Obstructive Pulmonary Disease, Cystic Fibrosis, and Alpha-1 Antitrypsin Deficiency

Cystic fibrosis is predominantly an airway disease with marked bronchiectatic changes associated with inflammation, chronic colonization, and progressive airflow obstruction. The condition can be identified in childhood and monitored with detectable airway changes early in life while conventional spirometry remains in the normal range. Alpha-1 antitrypsin deficiency can also be detected early in life through blood spot and genetic testing and leads (in some) to the development of airflow obstruction and a predominant emphysema phenotype with bronchiectatic changes in about 30%. Early detection also allows the natural history of the pulmonary physiological changes to be determined. Chronic obstructive pulmonary disease is usually detected late in the disease process when significant damage has occurred. The condition consists of varying combinations of airway disease, bronchiectasis, colonization, and emphysema. Lessons learned from the physiological evolution of airway disease in cystic fibrosis and the emphysema of alpha-1 antitrypsin deficiency provide strategies to enable early detection of chronic obstructive pulmonary disease in general and its phenotypes.

Maximal mid-expiratory flow detects early lung disease in α1-antitrypsin deficiency

Pathological studies suggest that loss of small airways precedes airflow obstruction and emphysema in chronic obstructive pulmonary disease (COPD). Not all α1-antitrypsin deficiency (AATD) patients develop COPD, and measures of small airways function might be able to detect those at risk. Maximal mid-expiratory flow (MMEF), forced expiratory volume in 1 s (FEV1), ratio of FEV1/forced vital capacity (FVC), health status, presence of emphysema (computed tomography (CT) densitometry) and subsequent decline in FEV1 were assessed in 196 AATD patients. FEV1/FVC, FEV1 % predicted and lung densitometry related to MMEF % pred (r2=0.778, p<0.0001; r2=0.787, p<0.0001; r2=0.594, p<0.0001, respectively) in a curvilinear fashion. Patients could be divided into those with normal FEV1/FVC and MMEF (group 1), normal FEV1/FVC and reduced MMEF (group 2) and those with spirometrically defined COPD (group 3). Patients in group 2 had worse health status than group 1 (median total St Georges Respiratory Questionnaire (SGRQ) 23.15 (interquartile range (IQR) 7.09–39.63) versus 9.67 (IQR 1.83–22.35); p=0.006) and had a greater subsequent decline in FEV1 (median change in FEV1 −1.09% pred per year (IQR −1.91–0.04% pred per year) versus −0.04% pred per year (IQR −0.67–0.03% pred per year); p=0.007). A reduction in MMEF is an early feature of lung disease in AATD and is associated with impaired health status and a faster decline in FEV1. Mid-expiratory flow indicates early disease, worse health status and predicts decline in AATD patients without COPD http://ow.ly/F6K6308355E

Breathing Out: Forced Exhalation, Airflow Limitation

The concept of measuring expired lung volumes to assess lung function has existed since the late seventeenth century. Spirometry in its current form is a versatile and informative assessment of pulmonary ventilation that does not require highly specialised equipment, making it the most common and accessible lung function test.