Biomarkers Of Elastin Degradation Research Articles

Plasma desmosine, a biomarker of elastin degradation, predicts outcomes in coronary artery disease

Abstract Background Recent evidence from animal studies suggests that elastin degradation accelerates atherosclerosis and increases risk of plaque rupture and subsequent myocardial infarction and stroke. Desmosine is an elastin-specific degradation product. We analysed the prognostic value of plasma desmosine (pDES) in a cohort of patients with coronary artery disease (CAD). Methods Patients with CAD (n=400) undergoing elective coronary angiography were prospectively recruited over 3 years and had bloods drawn for analysis of pDES using a validated stable isotope dilution liquid chromatography-tandem mass spectrometry method. Patients were followed up for 12 months for major adverse cardiovascular events (MACE: composite of death, myocardial infarction, target vessel repeat revascularisation, target lesion revascularisation, and heart failure hospital admission). The upper limit of normal for pDES is 0.35 ng/mL. The predictive value of pDES for MACE was analysed with Cox-proportional hazards ratio (HR) model and Kaplan-Meier survival analysis. Results During follow-up, there were 36 MACE events. Median pDES level across the entire cohort was 0.3 ng/mL (IQR 0.23–0.41 ng/mL). Patients with a pDES level >0.35 ng/mL were more likely to be male and older with a mean age of 69.7±10.3 years, have a history of prior stroke or transient ischaemic attack (TIA) and COPD. In univariable analysis, a pDES level of >0.35 ng/mL was associated with an increased risk of MACE (HR 4.76, 95% CI: 2.34–9.68, p<0.001). In multivariable analysis, pDES >0.35 ng/mL was associated with risk of MACE after adjustment for age, sex, COPD status and previous stroke and TIA (HR 3.97; 95% CI: 1.82–8.67, p=0.001) (Figure). Conclusion Increased elastin degradation as measured by elevated pDES levels, predicts outcomes in patients with CAD independent of traditional cardiovascular risk factors and may play a role as a future biomarker in these patients. Kaplan-Meier survival analysis Funding Acknowledgement Type of funding source: None

P101 Biomarkers of elastin degradation are associated with clinical and biochemically active disease in Crohn’s disease

Abstract Background In Crohn’s disease (CD), the extensive and potentially transmural inflammation results in increased activity of both matrix metalloproteases (MMPs) and serine proteases, causing a higher degree of intestinal tissue remodelling. This increased proteolytic activity could potentially cause degradation and loss of function of mechanical and functional matrix proteins, such as elastin. Therefore, we sought to investigate the association between biomarkers of elastin degradation and the disease activity in CD patients. Methods Seventy-two CD patients and 29 healthy donors (HD) were included in the study. Disease activity was determined according to the Crohn’s disease activity index score (CDAI >150) and/or a faecal calprotectin (fCALP >250). Additionally, CD patients were endoscopically assessed according to the simple endoscopic score (SES) for CD. Different protease derived biomarkers of elastin degradation: protease-3 (ELP-3), MMP-7 (ELM-7) and cathepsin-G (EL-CG) was measured in serum by ELISA. One-way ANOVA (Kruskal–Wallis) was applied for the statistical analysis. Results The levels of ELP-3 was significantly elevated in active CD when compared with the HD (p < 0.001), and inactive CD (p < 0.01). Levels of EL-G were significantly elevated when comparing active CD and HD (p < 0.05), with the same result observed for the levels of EL-CG when comparing active CD and the HD (p < 0.05). Endoscopically, ELP-3 was shown significantly elevated in moderate–to-severe CD patients when compared with the HD (p < 0.01). Conclusion In this study, measurements of the elastin degradation markers were capable of differentiating between CD patients with either a clinically active or biochemically active disease, with the biomarker levels being significantly highest in the patients with an active disease. This was also the case when assessing endoscopic disease activity, where the protease-3-derived biomarker levels were highest in patients of moderate-to-severe disease activity. As such, the data provide indications of the beneficial use of these serum biomarkers as additional disease activity assessment tools for CD patients.

Cystic fibrosis disease severity correlates with plasma levels of desmosine and isodesmosine, biomarkers of elastin degradation.

Novel methodological approaches now demonstrate that the unique elastin degradation products desmosine and isodesmosine are detectable in plasma of cystic fibrosis patients and correlate to lung function, exacerbation frequency and disease progression http://bit.ly/2VwZOcx

Chronic Obstructive Pulmonary Disease. A Biomarker and a Potential Therapy.

This article assesses developments in cardiorespiratory medicine since the Nobel Prize in Physiology or Medicine was awarded in 1956 for advancements in the study of cardiorespiratory disease. In chronic obstructive pulmonary disease, advances were accelerated by the discovery of a genetically determined cause for pulmonary emphysema in the genetic abnormality alpha-1 antitrypsin deficiency. This causes a deficiency of the inhibitor of neutrophil elastase, which results in increased degradation of lung elastin and the development of pulmonary emphysema. This discovery gave focus to two amino acids that reside only in body elastin, desmosine and isodesmosine, which can be measured as biomarkers of elastin degradation in body fluids with increased accuracy and sensitivity. Studies of this biomarker have shown that augmentation therapy in alpha-1 antitrypsin deficiency does decrease lung and body elastic tissue degradation and in the RAPID (Randomized, Placebo-controlled Trial of Augmentation Therapy in Alpha-1 Proteinase Inhibitor Deficiency) Study, over 4 years, showed a preservation of lung density by computer tomography correlating with decreases in plasma levels of desmosine and isodesmosine. This insight indicates the potential of agents that prevent lung elastin degradation. Such an agent is hyaluronan aerosol, which is deficient in post mortem lungs with chronic obstructive pulmonary disease and has been shown to block elastin degradation, possibly by a barrier function. Thus it would appear that hyaluronan could have therapeutic potential in chronic obstructive pulmonary disease.

Biomarkers in Alpha-1 Antitrypsin Deficiency Chronic Obstructive Pulmonary Disease.

Biomarkers of pathogenesis in chronic obstructive pulmonary disease (COPD) can significantly accelerate drug development. In COPD related to alpha-1 antitrypsin deficiency, the role of neutrophil elastase and its inhibition by alpha-1 antitrypsin protein focused interest on elastin degradation and the development of pulmonary emphysema. Amino acids desmosine and isodesmosine are unique cross-links in mature elastin fibers and can serve as biomarkers of elastin degradation when measured in body fluids. This review gives a perspective on what has been learned by the earliest measurements of desmosine and isodesmosine followed by later studies using methods of increased sensitivity and specificity and the meaning for developing new therapies. Also included are brief statements on the biomarkers fibrinogen, CC-16, and Aa-Val-360 in COPD.

Inhalation of LPS induces inflammatory airway responses mimicking characteristics of chronic obstructive pulmonary disease

Inhalation of lipopolysaccharide (LPS) produces both systemic and pulmonary inflammatory responses. The aim of this study was to further characterize the response to LPS in order to develop a human model suitable for early testing of drug candidates developed for the treatment for chronic obstructive pulmonary disease (COPD). Blood and induced sputum were obtained 4, 24 and 48 h following inhalation of saline and LPS (5 and 50 μg). Blood was analysed for C-reactive protein (CRP), α(1)-antitrypsin and neutrophils/leucocytes, and sputum was analysed for biomarkers of neutrophil inflammation and remodelling activities, i.e. neutrophil elastase (NE) protein/activity and α(1)-antitrypsin. Levels of tumour necrosis factor-α (TNFα) were measured in both blood and sputum. Urine was collected 0-24 and 24-48 h postchallenge, and desmosine, a biomarker of elastin degradation, was measured. Lipopolysaccharide inhalation induced dose-dependent flu-like symptoms and increases in plasma CRP and α(1)-antitrypsin as well as increases in blood neutrophil/leucocyte numbers. Furthermore, LPS produced increases in sputum TNFα and sputum NE activity. Urine levels of desmosine were unaffected by the LPS challenge. All subjects recovered 48 h postchallenge, and indices of inflammatory activity were significantly lower at this observation point cf 24 h postchallenge. Inhalation of LPS in healthy volunteers can be used as a safe and stable model of neutrophil inflammation. Blood/plasma and sputum indices can be employed to monitor the response to LPS. We suggest that this model may be used for initial human studies of novel COPD-active drugs.

Liberation of desmosine and isodesmosine as amino acids from insoluble elastin by elastolytic proteases

The development of atherosclerotic lesions and abdominal aortic aneurysms involves degradation and loss of extracellular matrix components, such as collagen and elastin. Releases of the elastin cross-links desmosine (DES) and isodesmosine (IDE) may reflect elastin degradation in cardiovascular diseases. This study investigated the production of soluble elastin cross-linking structures by proteinases implicated in arterial diseases. Recombinant MMP-12 and neutrophil elastase liberated DES and IDE as amino acids from insoluble elastin. DES and IDE were also released from insoluble elastin exposed to monocyte/macrophage cell lines or human primary macrophages derived from peripheral blood monocytes. Elastin oxidized by reactive oxygen species (ROS) liberated more unconjugated DES and IDE than did non-oxidized elastin when incubated with MMP-12 or neutrophil elastase. These results support the exploration of free DES and IDE as biomarkers of elastin degradation.

Desmosine as a biomarker of elastin degradation in COPD: current status and future directions

Desmosine (DES) and isodesmosine (IDES) are two unusual, tetrafunctional, pyridinium ring-containing amino acids involved in elastin cross-linking. Being amino acids unique to mature, cross-linked elastin, they are useful for discriminating peptides derived from elastin breakdown from precursor elastin peptides. According to these features, DES and IDES have been extensively discussed as potentially attractive indicators of elevated lung elastic fibre turnover and markers of the effectiveness of agents with the potential to reduce elastin breakdown. In the present manuscript, immunology-based and separation methods for the evaluation of DES and IDES are discussed, along with studies reporting increased levels of urine excretion in chronic obstructive pulmonary disease (COPD) patients with and without alpha(1)-antitrypsin deficiency. The results of the application of DES and IDES as surrogate end-points in early clinical trials in COPD are also reported. Finally, recent advances in detection techniques, including liquid chromatography tandem mass spectrometry and high-performance capillary electrophoresis with laser-induced fluorescence, are discussed. These techniques allow detection of DES and IDES at very low concentration in body fluids other than urine, such as plasma or sputum, and will help the understanding of whether DES and IDES are potentially useful in monitoring therapeutic intervention in COPD.