Chest medicine

This article discusses recent guidelines and management of common respiratory conditions and reviews key papers published over the past five years.peer-reviewe

Identifying matrix metalloproteinase-12 substrates as therapeutic targets in chronic obstructive pulmonary disease

Chronic Obstructive Pulmonary Disease (COPD) is the third commonest cause of death worldwide. Its natural course is a decline in lung function, punctuated by exacerbations, leading to premature death. COPD pathogenesis remains incompletely understood. The disease is widely accepted to result from an excess protease over protective anti-protease activity, leading to extracellular matrix (ECM) damage in the lungs. However, this belief is oversimplified since both harmful pro-inflammatory and protective anti-inflammatory roles are now described for proteases in animal and cell culture models. Matrix Metalloproteinase (MMP)-12 was originally implicated in COPD by its degradation of elastin in the lung ECM. However, newer in vitro evidence reveals MMP-12 to target substrates outside the ECM. Given these newer findings it was hypothesized that MMP-12 cleaves non-ECM proteins in COPD which may contribute to the disease process. This hypothesis was addressed initially using a candidate-based approach, by testing osteopontin and tissue factor pathway inhibitor as potential MMP-12 substrates. However, these proved to be neutrophil elastase targets. Next, a novel proteomic technique called TAILS (Terminal Amine Isotopic Labelling of Substrates) was employed to identify potential MMP-12 substrates using a Mmpl2-/-smoking mouse model. This led to the discovery of new non-ECM MMP-12 substrates in the mouse model. Next, these findings were translated to human COPD sputum to identify potential MMP-12 targets in COPD, both at exacerbation and during stable disease. Similarly, within human COPD sputum non-ECM MMP-12 substrates were discovered, of particular interest, complement factor C3 and the anticoagulant anti-thrombin III, revealing ever new potential roles for MMP-12 in COPD

Identifying matrix metalloproteinase-12 substrates as therapeutic targets in chronic obstructive pulmonary disease

Chronic Obstructive Pulmonary Disease (COPD) is the third commonest cause of death worldwide. Its natural course is a decline in lung function, punctuated by exacerbations, leading to premature death. COPD pathogenesis remains incompletely understood. The disease is widely accepted to result from an excess protease over protective anti-protease activity, leading to extracellular matrix (ECM) damage in the lungs. However, this belief is oversimplified since both harmful pro-inflammatory and protective anti-inflammatory roles are now described for proteases in animal and cell culture models. Matrix Metalloproteinase (MMP)-12 was originally implicated in COPD by its degradation of elastin in the lung ECM. However, newer in vitro evidence reveals MMP-12 to target substrates outside the ECM. Given these newer findings it was hypothesized that MMP-12 cleaves non-ECM proteins in COPD which may contribute to the disease process. This hypothesis was addressed initially using a candidate-based approach, by testing osteopontin and tissue factor pathway inhibitor as potential MMP-12 substrates. However, these proved to be neutrophil elastase targets. Next, a novel proteomic technique called TAILS (Terminal Amine Isotopic Labelling of Substrates) was employed to identify potential MMP-12 substrates using a Mmpl2-/-smoking mouse model. This led to the discovery of new non-ECM MMP-12 substrates in the mouse model. Next, these findings were translated to human COPD sputum to identify potential MMP-12 targets in COPD, both at exacerbation and during stable disease. Similarly, within human COPD sputum non-ECM MMP-12 substrates were discovered, of particular interest, complement factor C3 and the anticoagulant anti-thrombin III, revealing ever new potential roles for MMP-12 in COPD

Depression and its relationship with poor exercise capacity, BODE index and muscle wasting in COPD

SummaryBackgroundThe prevalence of depression in stable COPD patients varies markedly, possibly because of use of different scales. We aimed to assess depression using 2 different depression scales and to examine the association between depression and poor exercise performance, BODE index and muscle wasting in clinically stable COPD patients.Methods122 stable COPD patients were assessed with the Centre for Epidemiologic Studies Depression Scale (CES-D) and the Brief Assessment Schedule Depression Cards (BASDEC). We also assessed patients with spirometry, bioelectrical impedance analysis, 6-minute walk distance (6MWD), St George's Respiratory Questionnaire (SGRQ) and MRC dyspnoea and Borg scales.ResultsThe CES-D and BASDEC scales detected almost similar prevalence rates of depression (21% vs 17%) with a Kappa coefficient of 0.68, p<0.0001. The BASDEC scale detected more depression in women and was more closely associated with dyspnoea than the CES-D. COPD severity was associated with depression when using BODE scores but not when GOLD categories were used. Each of the CES-D and BASDEC depression scores were associated with 6MWD after adjusting for FEV1% predicted, gender, age and pack-years (p=<0.0001 and 0.001, respectively). Also, patients with a 6MWD<350 scored significantly higher on both depression scales. Wasted patients appeared to have higher depression scores, but the difference was statistically insignificant.ConclusionThe administration of different depression scales may affect some of the characteristics of depressed patients rather than the prevalence rate of depression. Depression was associated with poor exercise performance and BODE index in COPD

TAILS proteomics reveals dynamic changes in airway proteolysis controlling protease activity and innate immunity during COPD exacerbations

© 2018 the American Physiological Society. Dys-regulated protease activity is thought to cause parenchymal and airway damage in chronic obstructive pulmonary disease (COPD). Multiple proteases have been implicated in COPD, and identifying their substrates may reveal new disease mechanisms and treatments. However, as proteases interact with many substrates that may be protease inhibitors or proteases themselves, these webs of protease interactions make the wider consequences of therapeutically targeting proteases difficult to predict. We therefore used a systems approach to determine protease substrates and protease activity in COPD airways. Protease substrates were determined by proteomics using the terminal amine isotopic labeling of substrates (TAILS) methodology in paired sputum samples during stable COPD and exacerbations. Protease activity and specific protein degradation in airway samples were assessed using Western blotting, substrate assays, and ex vivo cleavage assays. Two hundred ninety-nine proteins were identified in human COPD sputum, 125 of which were proteolytically processed, including proteases, protease inhibitors, mucins, defensins, and complement and other innate immune proteins. During exacerbations, airway neutrophils and neutrophil proteases increased and more proteins were cleaved, particularly at multiple sites, consistent with degradation and inactivation. During exacerbations, different substrates were processed, including protease inhibitors, mucins, and complement proteins. Exacerbations were associated with increasing airway elastase activity and increased processing of specific elastase substrates, including secretory leukocyte protease inhibitor. Proteolysis regulates multiple processes including elastase activity and innate immune proteins in COPD airways and differs during stable disease and exacerbations. The complexity of protease, inhibitor, and substrate networks makes the effect of protease inhibitors hard to predict which should be used cautiously