An example of ventilatory limitation during cardiopulmonary exercise testing in a patient with COPD.

A 64-year-old obese gentleman attended for further evaluation of ongoing dyspnoea in the context of a previous diagnosis of moderate COPD treated with dual long-acting bronchodilators. A cardiopulmonary exercise test (CPET) was performed, which demonstrated reduced peak work and oxygen consumption with evidence of dynamic hyperinflation, abnormal gas exchange and ventilatory limitation despite cardiac reserve. The CPET clarified the physiological process underpinning the patient's dyspnoea and limiting the patient's activities. This, in turn, helped the clinician tailor the patient's management plan.

In vitro and in vivo functional residual capacity comparisons between multiple-breath nitrogen washout devices.

Functional residual capacity (FRC) accuracy is essential for deriving multiple-breath nitrogen washout (MBNW) indices, and is the basis for device validation. Few studies have compared existing MBNW devices. We evaluated in vitro and in vivo FRC using two commercial MBNW devices, the Exhalyzer D (EM) and the EasyOne Pro LAB (ndd), and an in-house device (Woolcock in-house device, WIMR). FRC measurements were performed using a novel syringe-based lung model and in adults (20 healthy and nine with asthma), followed by plethysmography (FRCpleth). The data were analysed using device-specific software. Following the results seen with ndd, we also compared its standard clinical software (ndd v.2.00) with a recent upgrade (ndd v.2.01). WIMR and EM fulfilled formal in vitro FRC validation recommendations (>95% of FRC within 5% of known volume). Ndd v.2.00 underestimated in vitro FRC by >20%. Reanalysis using ndd v.2.01 reduced this to 11%, with 36% of measurements ≤5%. In vivo differences from FRCpleth (mean±sd) were 4.4±13.1%, 3.3±11.8%, -20.6±11% (p<0.0001) and -10.5±10.9% (p=0.005) using WIMR, EM, ndd v.2.00 and ndd v.2.01, respectively. Direct device comparison highlighted important differences in measurement accuracy. FRC discrepancies between devices were larger in vivo, compared to in vitro results; however, the pattern of difference was similar. These results represent progress in ongoing standardisation efforts.

Deep inspiration volume and the impaired reversal of bronchoconstriction in asthma.

It is unclear whether the failure to reverse bronchoconstriction with deep inspiration (DI) in asthma is due to reduced maximal dilatation of the DI. We compared the effect of different DI volumes on maximal dilatation and reversal of bronchoconstriction in nine asthmatics and ten non-asthmatics. During bronchoconstriction, subjects took DI to 40%, 70% and 100% inspiratory capacity, on separate days. Maximal dilatation was measured as respiratory system resistance (Rrs) at end-inspiration and residual dilatation as Rrs at end-expiration, both expressed as percent of Rrs at end-tidal expiration prior to DI. DI volume was positively associated with maximal dilatation in non-asthmatics (ANOVA p=0.055) and asthmatics (p=0.023). DI volume was positively associated with residual dilatation in non-asthmatics (p=0.004) but not in asthmatics (p=0.53). The degree of maximal dilatation independently predicted residual dilatation in non-asthmatics but not asthmatics. These findings suggest that the failure to reverse bronchoconstriction with DI in asthma is not due to reduced maximal dilatation, but rather due to increased airway narrowing during expiration.

Procedures to improve the repeatability of forced oscillation measurements in school-aged children.

Forced oscillation technique (FOT) parameters are less repeatable than spirometry, and the impact of technical factors, such as data acquisition and data filtering, are unknown. FOT was performed, in triplicate, on 48 children (8-11 years) and repeated two weeks later. We examined the separate effects of monitoring tidal volume (V(T)) prior to measurement and length of data acquisition on measurement repeatability. We compared the effects on repeatability of a filtering technique in which complete breaths containing respiratory artefact were rejected and statistical filters in which outlying data points were rejected. Within- and between-session repeatability of respiratory system resistance (Rrs) and reactance (Xrs) were assessed using coefficient of variation (CV) and intra-class correlation coefficient (ICC). Longer data acquisition reduced CV of Rrs and Xrs (60s vs. shorter durations, p ≤ 0.001). Monitoring V(T) reduced CV of Rrs (p = 0.05). Complete breath filtering improved CV and ICC for both Rrs and Xrs. The repeatability of FOT measurements can be improved by optimising data acquisition and filtering.

Stress and strain in the contractile and cytoskeletal filaments of airway smooth muscle.

Stress and strain are omnipresent in the lung due to constant lung volume fluctuation associated with respiration, and they modulate the phenotype and function of all cells residing in the airways including the airway smooth muscle (ASM) cell. There is ample evidence that the ASM cell is very sensitive to its physical environment, and can alter its structure and/or function accordingly, resulting in either desired or undesired consequences. The forces that are either conferred to the ASM cell due to external stretching or generated inside the cell must be borne and transmitted inside the cytoskeleton (CSK). Thus, maintaining appropriate levels of stress and strain within the CSK is essential for maintaining normal function. Despite the importance, the mechanisms regulating/dysregulating ASM cytoskeletal filaments in response to stress and strain remained poorly understood until only recently. For example, it is now understood that ASM length and force are dynamically regulated, and both can adapt over a wide range of length, rendering ASM one of the most malleable living tissues. The malleability reflects the CSK's dynamic mechanical properties and plasticity, both of which strongly interact with the loading on the CSK, and all together ultimately determines airway narrowing in pathology. Here we review the latest advances in our understanding of stress and strain in ASM cells, including the organization of contractile and cytoskeletal filaments, range and adaptation of functional length, structural and functional changes of the cell in response to mechanical perturbation, ASM tone as a mediator of strain-induced responses, and the novel glassy dynamic behaviors of the CSK in relation to asthma pathophysiology.

Mechanisms of airway hyperresponsiveness in asthma.

Airway hyperresponsiveness (AHR) is a fundamental abnormality in asthma. There are many potential factors contributing to the excessive airway response demonstrable on airway challenge. These range from abnormalities of airway smooth muscle, airway remodelling and airway inflammation to abnormalities in the neural control of airway calibre. None of these by themselves fully explains the abnormalities seen on the dose response curves of the asthmatic. In this review, the main mechanisms are described, together with recent evidence providing a pathway by which a number of these mechanisms may interact to cause AHR through abnormality in ventilation distribution and airway closure. There is now evidence for a close relationship between ventilation heterogeneity and AHR which could be exploited clinically.

Disease-specific expression and regulation of CCAAT/enhancer-binding proteins in asthma and chronic obstructive pulmonary disease.

BACKGROUND: CCAAT/enhancer-binding proteins (C/EBPs) control cell proliferation; lack of C/EBPalpha correlates with increased proliferation of bronchial smooth muscle cells (BSMCs) of asthmatic patients. OBJECTIVE: We sought to assess disease-specific expression of C/EBPalpha, beta, delta, and epsilon and the effects of budesonide (10(-8) mol/L) and formoterol (10(-8) mol/L). METHODS: Expression and function of C/EBPalpha, beta, delta, and epsilon BSMCs of control subjects (n = 9), asthmatic patients (n = 12), and patients with chronic obstructive pulmonary disease (COPD; n = 10) were determined. RESULTS: The control group expressed C/EBPalpha, beta, delta, and epsilon, which were upregulated by serum (5%). Budesonide completely inhibited C/EBPalpha and beta expression; formoterol increased C/EBPalpha expression (2-fold). C/EBPdelta and epsilon expression were not affected by the drugs. The asthmatic group did not appropriately express C/EBPalpha. Basal levels of C/EBPbeta, delta, and epsilon were upregulated by serum (5%). Budesonide and formoterol increased C/EBPbeta levels (3.4-fold and 2.5-fold, respectively), leaving C/EBPalpha, delta, and epsilon levels unaffected. The COPD group normally expressed C/EBPalpha, beta, and epsilon, which were upregulated by serum treatment (5%). Basal levels of C/EBPdelta were downregulated by serum in 7 of 10 BSMC lines. Budesonide inhibited C/EBPalpha and beta expression, upregulated C/EBPdelta (3.2-fold), and had no effect on C/EBPepsilon. Formoterol upregulated C/EBPalpha expression (3-fold) but not the other C/EBPs. Protein analysis and electrophoretic mobility shift assay confirmed the disease-specific expression pattern of C/EBPalpha in asthmatic patients and C/EBPdelta in patients with COPD. CONCLUSIONS: The expression and regulation of C/EBPs in BSMCs of asthmatic patients and patients with COPD seems disease specific. Budesonide and formoterol modulate C/EBP expression in a drug- and disease-specific pattern. CLINICAL IMPLICATIONS: The data could provide a method to discriminate between asthma and COPD at an early disease stage.

On the terminology for describing the length-force relationship and its changes in airway smooth muscle.

The observation that the length-force relationship in airway smooth muscle can be shifted along the length axis by accommodating the muscle at different lengths has stimulated great interest. In light of the recent understanding of the dynamic nature of length-force relationship, many of our concepts regarding smooth muscle mechanical properties, including the notion that the muscle possesses a unique optimal length that correlates to maximal force generation, are likely to be incorrect. To facilitate accurate and efficient communication among scientists interested in the function of airway smooth muscle, a revised and collectively accepted nomenclature describing the adaptive and dynamic nature of the length-force relationship will be invaluable. Setting aside the issue of underlying mechanism, the purpose of this article is to define terminology that will aid investigators in describing observed phenomena. In particular, we recommend that the term "optimal length" (or any other term implying a unique length that correlates with maximal force generation) for airway smooth muscle be avoided. Instead, the in situ length or an arbitrary but clearly defined reference length should be used. We propose the usage of "length adaptation" to describe the phenomenon whereby the length-force curve of a muscle shifts along the length axis due to accommodation of the muscle at different lengths. We also discuss frequently used terms that do not have commonly accepted definitions that should be used cautiously.