Relationship between pulmonary matrix metalloproteinases and quantitative CT markers of small airways disease and emphysema in COPD

Ostridge, Kristoffer; Williams, Nicholas; Kim, Viktoriya; Bennett, Michael J.; Harden, S.; Welch, Lindsay; Bourne, Simon; Coombs, Ngaire; Elkington, Paul; Staples, Karl J.; Wilkinson, Tom

doi:10.1136/thoraxjnl-2015-207428

Cited by 86 publications

(81 citation statements)

References 36 publications

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“…Studies have confirmed that CT densitometry demonstrates higher levels of emphysema in individuals with COPD as opposed to healthy smokers [31][32][33][34] There is also convincing evidence that CT densitometry has strong associations with airflow obstruction [10,[32][33][34][35][36][37][38][39][40][41] and analysis of over 4000 CT scans from the COPDgene study showed a strong negative correlation between %LAA <-950 and forced expiratory volume in 1 second (FEV1) and demonstrated increased emphysema with worsening GOLD severity [33]. CT densitometry also has strong associations with gas transfer (TLCO) [10,[35][36][37][38][39][40], six minute walk distance (6MWD) [32,36,40,42], BODE score [36,39,[43][44][45] and body composition [37,39,46,47].…”

Section: Emphysemamentioning

confidence: 85%

“…Few studies have investigated the link between gas trapping on CT and underlying mechanisms of disease. Our work has shown that CT markers of small airways disease are associated with a number of MMPs (-3, -7, -8, -9, -10 and 12), suggesting these play a key role in small airways remodelling in COPD [31]. The longitudinal changes and the distribution of gas trapping throughout the lungs are unknown.…”

mentioning

confidence: 83%

“…There is still no definite consensus about which of these methods is best and even 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 now different studies use different thresholds. Given the fact that emphysema is an all or nothing phenomenon it seems more intuitive to use CT densitometry, which uses an absolute cut-off to quantify it.Studies have confirmed that CT densitometry demonstrates higher levels of emphysema in individuals with COPD as opposed to healthy smokers [31][32][33][34] There is also convincing evidence that CT densitometry has strong associations with airflow obstruction [10,[32][33][34][35][36][37][38][39][40][41] and analysis of over 4000 CT scans from the COPDgene study showed a strong negative correlation between %LAA <-950 and forced expiratory volume in 1 second (FEV1) and demonstrated increased emphysema with worsening GOLD severity [33]. CT densitometry also has strong associations with gas transfer (TLCO) [10,[35][36][37][38][39]…”

mentioning

confidence: 85%

“…There have also been relatively few studies assessing quantifiable CT markers of disease and markers of underlying biological disease activity, which includes inflammatory markers, microbiology, proteases and other biomarkers. The approach taken in our study highlights how this can be achieved by combining bronchoscopic sampling and CT imaging to demonstrate a potentially important association between proteases and small airways disease in COPD [31]. Similar approaches can be used to further our understanding of the active disease processes and endotypes occurring in different compartments and regions of the lung, hopefully allowing the development of novel targeted therapies.…”

mentioning

confidence: 90%

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Present and future utility of computed tomography scanning in the assessment and management of COPD

Ostridge

Wilkinson

2016

Eur Respir J

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likely to have important implications for understanding disease progression and the future management of this condition [2]. There are currently no significant diseasemodifying medications for COPD and there have not been the improvements in outcome seen in other chronic diseases. Other tools are required in addition to spirometry to help explain the heterogeneity and provide further insights into approaches to study and treat COPD. CT has current practical applications in the routine management and investigation of the disease and with the development of novel analysis techniques has the potential to provide further details about the pulmonary and extra-pulmonary manifestations of COPD. Computed Tomography in Current Clinical PractisePrior to the 1970s histological and post mortem studies were required to study structural changes of the lung. The introduction of CT made it possible to visualise the thorax and assess lung structure non-invasively. In COPD CT can identify key morphological features, including emphysema, bronchial wall thickening and gas trapping. These pathologies contribute directly to airflow obstruction and therefore CT has the potential to provide vital insights into the underlying pathophysiological changes of COPD. Despite this, routine CT imaging has not necessarily been widely adopted in clinical practise and its place in the management and investigation of COPD has not been firmly established. The GOLD guidelines do not routinely recommend CT scanning in COPD and only advise that it may be helpful in differential diagnosis or when surgical options are being considered [3]. This general ambivalence is highlighted by a study of attitudes in respiratory physicians and surgeons in the UK where only 32% thought it necessary for patients with severe COPD to have a CT scan [4].There are a number of reasons why the use of CT has not become routine in COPD. One of the most important is the perceived notion that using CT does not alter management, although this is not strictly true. The National Emphysema Treatment Trial (NETT) demonstrated that patients with advanced upper lobe emphysema and limited exercise ability improved after lung volume reduction surgery [5]. There has also been considerable progress and experience in using endobronchial treatments for severe emphysema including coils, valves, sealant and airway bypass. In the correct patients with severe heterogeneous emphysema these treatments can lead to significant improvement in pulmonary physiology and functional capacity [6, 7]. CT imaging can also identify bullous disease, which may be amenable to surgery and bullectomy can lead to improved health status [8]. It therefore seems clear that patients with severe COPD require CT imaging to determine which patients are appropriate for these techniques.CT imaging can also detect concomitant pulmonary pathology in COPD. Bronchiectasis is particularly prevalent, with studies demonstrating 50% of COPD patients having CT evidence of the disease [9][10][11]. When present bronchiectasis is asso...

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Section: Emphysemamentioning

confidence: 85%

mentioning

confidence: 83%

mentioning

confidence: 85%

mentioning

confidence: 90%

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Present and future utility of computed tomography scanning in the assessment and management of COPD

Ostridge

Wilkinson

2016

Eur Respir J

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“…Furthermore, the finding in the Indian cohort of patients that MMP-10 is increased in the BALF of patients with TB compared with patients with other respiratory diseases indicates that there is some specificity in the increased MMP-10 concentrations in TB. MMP-10 activity has been implicated in other destructive pulmonary pathology, such as chronic obstructive pulmonary disease (41), and was associated with disease severity and prognosis in patients with idiopathic pulmonary fibrosis (42). Although our study implicated MMP-10 in the protease network up-regulated in TB, as MMP-10 was increased in respiratory secretions of patients with TB and at the gene expression level, we did not precisely define the cellular source.…”

Section: Discussionmentioning

confidence: 99%

Early Secretory Antigenic Target-6 Drives Matrix Metalloproteinase-10 Gene Expression and Secretion in Tuberculosis

Brilha

Sathyamoorthy

Stuttaford

et al. 2017

Am J Respir Cell Mol Biol

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Tuberculosis (TB) causes disease worldwide, and multidrug resistance is an increasing problem. Matrix metalloproteinases (MMPs), particularly the collagenase MMP-1, cause lung extracellular matrix destruction, which drives disease transmission and morbidity. The role in such tissue damage of the stromelysin MMP-10, a key activator of the collagenase MMP-1, was investigated in direct Mycobacterium tuberculosis (Mtb)-infected macrophages and in conditioned medium from Mtb-infected monocyte-stimulated cells. Mtb infection increased MMP-10 secretion from primary human macrophages 29-fold, whereas Mtb-infected monocytes increased secretion by 4.5-fold from pulmonary epithelial cells and 10.5-fold from fibroblasts. Inhibition of MMP-10 activity decreased collagen breakdown. In two independent cohorts of patients with TB from different continents, MMP-10 was increased in both induced sputum and bronchoalveolar lavage fluid compared with control subjects and patients with other respiratory diseases (both P , 0.05). Mtb drove 3.5-fold greater MMP-10 secretion from human macrophages than the vaccine strain bacillus Calmette-Guerin (P , 0.001), whereas both mycobacteria up-regulated TNF-a secretion equally. Using overlapping, short, linear peptides covering the sequence of early secretory antigenic target-6, a virulence factor secreted by Mtb, but not bacillus Calmette-Guerin, we found that stimulation of human macrophages with a single specific 15-amino acid peptide sequence drove threefold greater MMP-10 secretion than any other peptide (P , 0.001). Mtb-driven MMP-10 secretion was inhibited in a dose-dependent manner by p38 and extracellular signal-related kinase mitogen-activated protein kinase blockade (P , 0.001 and P , 0.01 respectively), but it was not affected by inhibition of NF-kB. In summary, Mtb activates inflammatory and stromal cells to secrete MMP-10, and this is partly driven by the virulence factor early secretory antigenic target-6, implicating it in TB-associated tissue destruction.

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Use of a 3D inkjet‐printed model to access dust particle toxicology in the human alveolar barrier

Kang

Lee

Jung

2022

Biotech & Bioengineering

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Background: Fine dust particles in the air travel into our body via the airway tract and cause severe respiratory diseases. Thus, the analysis of the effects of dust particles on the respiratory system has been receiving signi cant research interest. However, most studies on the toxicity of dust particles involve two-dimensional (2D) cell cultures, animal models, and epidemiology. Here, we inkjet-printed an threedimensional (3D) alveolar barrier model to study how dust particles cause respiratory diseases. The threelayered in vitro model was exposed to A2 ne test dust with varying concentrations and exposure durations.Results: The results highlighted the destruction of the tissue architecture along with apoptosis in the bioprinted alveolar barrier. The damage at the cellular level induced an increase in the amount of proin ammatory cytokines secreted, followed by triggering of the signal transduction pathway and activation of transcription factors. As a consequence of the release of cytokines, the extracellular matrix was degraded, which led to the collapse of the cell structure, loss of cell polarity, and a decrease in the barrier tightness. Further, the pulmonary surfactant protein-related genes in the dust-treated alveolar tissue were investigated to evaluate the possible role of dust particles in pulmonary surfactant dysfunction.Conclusions: This study demonstrated the use of 3D-printed tissue model to evaluate the physiological impact of ne dust particles on cytotoxicity, alveolar barrier rigidity, and surfactant secretion of an alveolar barrier.

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Relationship between pulmonary matrix metalloproteinases and quantitative CT markers of small airways disease and emphysema in COPD

Cited by 86 publications

References 36 publications

Present and future utility of computed tomography scanning in the assessment and management of COPD

Present and future utility of computed tomography scanning in the assessment and management of COPD

Early Secretory Antigenic Target-6 Drives Matrix Metalloproteinase-10 Gene Expression and Secretion in Tuberculosis

Use of a 3D inkjet‐printed model to access dust particle toxicology in the human alveolar barrier

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