Tissue turnover of collagen type I, III and elastin is elevated in the PCLS model of IPF and can be restored back to vehicle levels using a phosphodiesterase inhibitor

Hansen, N.U.B.; Karsdal, Morten A.; Brockbank, Sarah; Cruwys, Simon; Rønnow, Sarah; Leeming, Diana Julie

doi:10.1186/s12931-016-0394-8

Cited by 44 publications

(28 citation statements)

References 46 publications

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“…The biomarkers analysed in this report have, in addition to in COPD, been found to be significantly elevated in other respiratory diseases, such as idiopathic pulmonary fibrosis [50, 76, 77] and lung cancer [50], indicating that these fragments are likely to originate from pathological turnover of lung tissue, yet no definitive proof currently exists.…”

Section: Discussionmentioning

confidence: 93%

Biomarkers of extracellular matrix turnover are associated with emphysema and eosinophilic-bronchitis in COPD

et al. 2017

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BackgroundChronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction and loss of lung tissue mainly consisting of extracellular matrix (ECM). Three of the main ECM components are type I collagen, the main constituent in the interstitial matrix, type VI collagen, and elastin, the signature protein of the lungs. During pathological remodeling driven by inflammatory cells and proteases, fragments of these proteins are released into the bloodstream, where they may serve as biomarkers for disease phenotypes. The aim of this study was to investigate the lung ECM remodeling in healthy controls and COPD patients in the COPDGene study.MethodsThe COPDGene study recruited 10,300 COPD patients in 21 centers. A subset of 89 patients from one site (National Jewish Health), including 52 COPD patients, 12 never-smoker controls and 25 smokers without COPD controls, were studied for serum ECM biomarkers reflecting inflammation-driven type I and VI collagen breakdown (C1M and C6M, respectively), type VI collagen formation (Pro-C6), as well as elastin breakdown mediated by neutrophil elastase (EL-NE). Correlation of biomarkers with lung function, the SF-36 quality of life questionnaire, and other clinical characteristics was also performed.ResultsThe circulating concentrations of biomarkers C6M, Pro-C6, and EL-NE were significantly elevated in COPD patients compared to never-smoking control patients (all p < 0.05). EL-NE was significantly elevated in emphysema patients compared to smoking controls (p < 0.05) and never-smoking controls (p < 0.005), by more than 250%. C1M was inversely associated with forced expiratory volume in 1 s (FEV1) (r = −0.344, p = 0.001), as was EL-NE (r = −0.302, p = 0.004) and Pro-C6 (r = −0.259, p = 0.015). In the patients with COPD, Pro-C6 was correlated with percent predicted Forced Vital Capacity (FVC) (r = 0.281, p = 0.046) and quality of life using SF-36. C6M and Pro-C6, were positively correlated with blood eosinophil numbers in COPD patients (r = 0.382, p = 0.006 and r = 0.351, p = 0.012, respectively).ConclusionsThese data suggest that type VI collagen turnover and elastin degradation by neutrophil elastase are associated with COPD-induced inflammation (eosinophil-bronchitis) and emphysema. Serological assessment of type VI collagen and elastin turnover may assist in identification of phenotypes likely to be associated with progression and amenable to precision medicine for clinical trials.

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Section: Discussionmentioning

confidence: 93%

Biomarkers of extracellular matrix turnover are associated with emphysema and eosinophilic-bronchitis in COPD

et al. 2017

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“…Collagen type I, a component of ECM, is abundantly secreted by IPF fibroblasts at the site of lung tissue remodeling (50). Increased ECM deposition and tissue stiffening in IPF act as a potent profibrotic stimulus that further enhances expression of collagen type I (51).…”

Section: Discussionmentioning

confidence: 99%

Vimentin intermediate filament assembly regulates fibroblast invasion in fibrogenic lung injury

Surolia

Zheng

et al. 2019

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“…A common characteristic of fibrotic diseases is the formation of fibrous connective tissue such as collagen and elastin. It is also known that turnover in the extracellular matrix is elevated in IPF and associated with disease progression . Recent work has found increased levels of proline, a key constituent of collagen, in lung tissue of IPF patients compared to healthy controls, which was attributed to increased proline production via the ornithine aminotransferase (OAT) pathway .…”

Section: Discussionmentioning

confidence: 99%

Molecular breath analysis supports altered amino acid metabolism in idiopathic pulmonary fibrosis

et al. 2019

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Background and objective: Diagnosis of idiopathic pulmonary fibrosis (IPF) is complex and its pathogenesis is poorly understood. Recent findings indicate elevated levels of proline and other amino acids in lung tissue of IPF patients which may also be of diagnostic value. Following these findings, we hypothesized that such altered metabolic profiles would be mirrored in exhaled breath and could therefore be captured non-invasively in real time. Methods: We aimed to validate these results using realtime exhaled breath analysis by secondary electrospray ionization-mass spectrometry, which can provide a non-invasive, painless and fast insight into the metabolism. Breath analysis was performed in a matched 1:1 case-control study involving 21 patients with IPF and 21 control subjects. Results: We found significantly (P < 0.05) elevated levels of proline, 4-hydroxyproline, alanine, valine, leucine/isoleucine and allysine in breath of IPF patients, whereas pyroglutamic acid and phenylalanine did not show significant differences. This coincides with the amino acid's abundance in pulmonary tissue indicating that our observations reflect progressing fibrosis. In addition, amino acid levels correlated across subjects, further supporting a common underlying pathway. We were able to obtain a cross-validated area under the curve of 0.86, suggesting that these increased amino acid levels in exhaled breath have the potential to be used as biomarkers for IPF. Conclusion: We could validate previous findings of elevated lung tissue amino acid levels in IPF and show that online breath analysis might be a practical tool for a rapid screening for IPF.Clinical trial registration: NCT02437448 at ClinicalTrials.gov SUMMARY AT A GLANCECollagen-related amino acids are significantly increased in exhaled breath of idiopathic pulmonary fibrosis (IPF) patients compared with healthy controls. The detection of these amino acids using realtime breath analysis results in a good discrimination between the groups, indicating the possibility for a rapid, non-invasive screening for IPF.

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Tissue turnover of collagen type I, III and elastin is elevated in the PCLS model of IPF and can be restored back to vehicle levels using a phosphodiesterase inhibitor

Cited by 44 publications

References 46 publications

Biomarkers of extracellular matrix turnover are associated with emphysema and eosinophilic-bronchitis in COPD

Biomarkers of extracellular matrix turnover are associated with emphysema and eosinophilic-bronchitis in COPD

Vimentin intermediate filament assembly regulates fibroblast invasion in fibrogenic lung injury

Molecular breath analysis supports altered amino acid metabolism in idiopathic pulmonary fibrosis

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