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Respiratory Medicine Feb 2017Pleuroparenchymal fibroelastosis (PPFE) is a rare interstitial pneumonia with upper lobe predominance and fibroelastosis. Although definite diagnosis requires surgical...
BACKGROUND
Pleuroparenchymal fibroelastosis (PPFE) is a rare interstitial pneumonia with upper lobe predominance and fibroelastosis. Although definite diagnosis requires surgical lung biopsy (SLB), SLB is often difficult because of its complications such as refractory pneumothorax.
OBJECTIVE
To evaluate urinary desmosines (degradation product of mature elastin) as a novel biomarker in patients with PPFE.
METHODS
Biopsy-proven patients with PPFE (n = 14) were prospectively enrolled. Levels of urinary desmosines in patients with PPFE were measured with liquid chromatography-tandem mass spectrometry (LC-MS/MS) and compared with those in patients with idiopathic pulmonary fibrosis (IPF), patients with chronic obstructive pulmonary disease (COPD), and controls.
RESULTS
Levels of urinary desmosines were significantly higher in patients with PPFE than those in patients with IPF (48.4 vs. 28.6 ng/mg creatinine, p = 0.034), patients with COPD (8.0 ng/mg creatinine, p < 0.001), or controls (17.4 ng/mg creatinine, p < 0.001). Desmosines discriminated between PPFE and IPF (area under the curve [AUC] = 0.708), and between PPFE and controls (AUC = 0.956). However, levels of desmosines were not correlated with physiological parameters in patients with PPFE.
CONCLUSIONS
Urinary desmosines may be a useful diagnostic biomarker in patients with PPFE. Measurement of desmosines combined with specific clinical and radiological features of PPFE may lead to an accurate diagnosis without SLB in patients with PPFE.
Topics: Aged; Biomarkers; Biopsy; Desmosine; Diagnosis, Differential; Elastic Tissue; Female; Fibrosis; Humans; Idiopathic Pulmonary Fibrosis; Lung; Lung Diseases, Interstitial; Male; Middle Aged; Prospective Studies; Pulmonary Disease, Chronic Obstructive; ROC Curve; Tandem Mass Spectrometry; Tomography, X-Ray Computed
PubMed: 28137498
DOI: 10.1016/j.rmed.2016.12.013 -
American Journal of Respiratory and... May 2017Sputum neutrophil elastase and serum desmosine, which is a linked marker of endogenous elastin degradation, are possible biomarkers of disease severity and progression...
RATIONALE
Sputum neutrophil elastase and serum desmosine, which is a linked marker of endogenous elastin degradation, are possible biomarkers of disease severity and progression in bronchiectasis. This study aimed to determine the association of elastase activity and desmosine with exacerbations and lung function decline in bronchiectasis.
METHODS
This was a single-center prospective cohort study using the TAYBRIDGE (Tayside Bronchiectasis Registry Integrating Datasets, Genomics, and Enrolment into Clinical Trials) registry in Dundee, UK. A total of 433 patients with high-resolution computed tomography-confirmed bronchiectasis provided blood samples for desmosine measurement, and 381 provided sputum for baseline elastase activity measurements using an activity-based immunosassay and fluorometric substrate assay. Candidate biomarkers were tested for their relationship with cross-sectional markers of disease severity, and with future exacerbations, mortality and lung function decline over 3 years.
MEASUREMENT AND MAIN RESULTS
Elastase activity in sputum was associated with the bronchiectasis severity index (r = 0.49; P < 0.0001) and was also correlated with the Medical Research Council dyspnea score (r = 0.34; P < 0.0001), FEV% predicted (r = -0.33; P < 0.0001), and the radiological extent of bronchiectasis (r = 0.29; P < 0.0001). During a 3-year follow-up, elevated sputum elastase activity was associated with a higher frequency of exacerbations (P < 0.0001) but was not independently associated with mortality. Sputum elastase activity was independently associated with FEV decline (β coefficient, -0.139; P = 0.001). Elastase showed good discrimination for severe exacerbations with an area under the curve of 0.75 (95% confidence interval [CI], 0.72-0.79) and all-cause mortality (area under the curve, 0.70; 95% CI, 0.67-0.73). Sputum elastase activity increased at exacerbations (P = 0.001) and was responsive to treatment with antibiotics. Desmosine was correlated with sputum elastase (r = 0.42; P < 0.0001) and was associated with risk of severe exacerbations (hazard ratio 2.7; 95% CI, 1.42-5.29; P = 0.003) but not lung function decline.
CONCLUSIONS
Sputum neutrophil elastase activity is a biomarker of disease severity and future risk in adults with bronchiectasis.
Topics: Aged; Biomarkers; Bronchiectasis; Cohort Studies; Desmosine; Disease Progression; Female; Humans; Leukocyte Elastase; Lung; Male; Middle Aged; Neutrophils; Prospective Studies; Registries; Severity of Illness Index; Sputum; United Kingdom
PubMed: 27911604
DOI: 10.1164/rccm.201605-1027OC -
Pathophysiology : the Official Journal... Dec 2016This study aimed to evaluate fibrosis and elastin destruction in childhood interstitial lung disease (chILD) patients.
OBJECTIVE
This study aimed to evaluate fibrosis and elastin destruction in childhood interstitial lung disease (chILD) patients.
METHODS
Sixty patients and twenty healthy children were recruited. On admission, evaluation of chILD severity was made using Fan chILD score. Participants provided urine and blood samples. Plasma levels of transforming growth factor (TGF)-β, connective tissue growth factor (CCN2), soluble factor related apoptosis (sFas) and long non-coding RNAs and urinary levels of desmosine/urinary creatinine (UDes/UCr) were measured.
RESULTS
In patients, clinical findings were crackles (100.00%), tachypnea (65.00%), cardiomegaly (45.00%), digital clubbing (43.30%), cough (33.00%), cyanosis (26.70%), hepatomegaly (28.30%) and wheezes (23.30%). Categorizing of the patients with Fan chILD clinical score revealed that most patients 33.30% scored (3, symptomatic with abnormal saturation/cyanosis during exercise) then 28.30% scored (5, symptomatic with clinical and echocardiographic features of pulmonary hypertension), 18.30% scored (2, symptomatic with normal room air saturations), 15.00% scored (1, asymptomatic) and 5.00% scored (4, symptomatic with abnormal room air saturation/cyanosis at rest). TGF-β, CCN2, sFas, lncrRNA-2700086A05Rik relative gene expression and UDes/UCr levels were higher in patients than controls (P=0.002, P=0.001, P=0.001, P=0.001, P=0.001, respectively). In patients, significant positive correlations were found between TGF-β and CCN2, sFas, UDes/UCr; between CCN2 and both sFas and UDes/UCr; between UDes/UCr and sFas. Morbidity and mortality rates were 46.70% and 10.00%, respectively.
CONCLUSION
Markers of fibrosis (TGF-β, sFas, CCN2) and elastin destruction (UDes/UCr) were increased in chILD especially in patients with long disease duration. So blockage of their pathways signals may offer novel therapeutic targets.
PubMed: 27686729
DOI: 10.1016/j.pathophys.2016.09.001 -
The European Respiratory Journal Oct 2016
Topics: Adult; Age Factors; Aged; Aged, 80 and over; Desmosine; Elastin; Female; Forced Expiratory Volume; Humans; Isodesmosine; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Smoking; Time Factors
PubMed: 27587547
DOI: 10.1183/13993003.01125-2016 -
Pharmacology Research & Perspectives Jun 2016Vascular tissue contains abundant elastic fibers that contribute to vessel elasticity. Vonapanitase (formerly PRT-201) is a recombinant human chymotrypsin-like elastase...
Vascular tissue contains abundant elastic fibers that contribute to vessel elasticity. Vonapanitase (formerly PRT-201) is a recombinant human chymotrypsin-like elastase family member 1 (CELA1) shown to cleave the elastin component of elastic fibers, resulting in increased vessel diameter. The purpose of these current studies was to determine vein diameter, wall thickness, elastin content, and vonapanitase potency in veins used in a model of arteriovenous fistula (AVF) and in patients undergoing AVF creation for hemodialysis access to guide dose selection for human trials. Rabbit linguofacial, maxillary, and external jugular veins, and human basilic and upper and lower arm cephalic veins were dissected postmortem and sectioned into 2 mm length rings. Rings were incubated in vonapanitase at 37°C at varying concentrations and times. Elastin content was estimated histologically and by quantifying desmosine, a protein cross-link unique to elastin. Rabbit veins were substantially thinner and contained less elastin than human veins. In human veins, elastin content was greatest in basilic and least in lower arm cephalic. Vonapanitase removed elastin in a time- and concentration-dependent manner in all vein types. A lower concentration of vonapanitase was required to remove elastin from rabbit relative to human veins. In summary, vonapanitase reduced the elastin content of rabbit and human veins but did so at a lower concentration in the rabbit veins. Rabbit models may overestimate the potency of vonapanitase in humans. These results indicate that human dose selection should be guided by human vein ring experiments.
PubMed: 27433340
DOI: 10.1002/prp2.229 -
Acta Medica Portuguesa Mar 2016Elastosis perfurans serpiginosa is a rare perforating dermatosis found primarily in adolescents and young adults, characterized by transepidermal elimination of abnormal...
Elastosis perfurans serpiginosa is a rare perforating dermatosis found primarily in adolescents and young adults, characterized by transepidermal elimination of abnormal elastic fibers. The only drug known capable of inducing elastosis perfurans serpiginosa is D-penicillamine. We report the case of a 52 year-old woman with keratotic papules arranged in an annular pattern with central clearing and centrifugal growth, located in the anterior cervical region. The patient was chronically treated with D-penicillamine for Wilson disease. Lesion biopsy showed transepidermal elimination of thickened, eosinophilic, branched, sawtooth-like elastic fibers. The clinical and pathological findings were consistent with elastosis perfurans serpiginosa secondary to D-penicillamine. It is estimated that elastosis perfurans serpiginosa occurs in 1% of patients treated with D-penicillamine. By blocking directly or indirectly the desmosine cross-links between elastin molecules, D-penicillamine leads to the synthesis of abnormal dermal and extracutaneous elastic fibers. Elastosis perfurans serpiginosa may be the first manifestation of a multisystemic degenerative process of elastic connective tissue.
PubMed: 27285100
DOI: 10.20344/amp.6749 -
Cardiovascular Pharmacology: Open Access Apr 2016Vessel injury at the time of Arteriovenous Fistula (AVF) creation may lead to neointimal hyperplasia that impairs AVF maturation. Vonapanitase, a recombinant human...
BACKGROUND
Vessel injury at the time of Arteriovenous Fistula (AVF) creation may lead to neointimal hyperplasia that impairs AVF maturation. Vonapanitase, a recombinant human chymotrypsin-like elastase family member 1, is an investigational drug under development to improve AVF maturation and patency. The current studies were designed to document vonapanitase effects in human cephalic veins that are used in AVF creation.
METHODS
Human cephalic veins were mounted on a perfusion myograph. Vonapanitase 1.2, 4, 13.2, and 40 μg/ml or saline was applied drop wise on the vein followed by saline rinse. Vein segments were cut into rings for elastin content determination by desmosine radioimmunoassay and histology. Fluorescently-labelled vonapanitase was applied to veins and adventitial imaging was performed using laser scanning confocal microscopy. time course experiments were performed by treating rabbit jugular veins and harvesting 1 h and 4 h after vonapanitase treatment.
RESULTS / CONCLUSION
Vonapanitase reduced desmosine content in a dose-related manner. Histology also confirmed a dose-related reduction in elastic fiber staining. Fluorescently-labelled vonapanitase persistently localized to elastic fibers in the vein adventitia. experiments showed a reduction in desmosine content in jugular veins from 1 h to 4 h following treatment. These data suggest that vonapanitase targets elastin in elastic fibers in a dose related manner and that elastase remains in the vessel wall and has catalytic activity for at least 1 h.
PubMed: 27275001
DOI: 10.4172/2329-6607.1000178 -
The European Respiratory Journal May 2016Elastin degradation is a key feature of emphysema and may have a role in the pathogenesis of atherosclerosis associated with chronic obstructive pulmonary disease...
Elastin degradation is a key feature of emphysema and may have a role in the pathogenesis of atherosclerosis associated with chronic obstructive pulmonary disease (COPD). Circulating desmosine is a specific biomarker of elastin degradation. We investigated the association between plasma desmosine (pDES) and emphysema severity/progression, coronary artery calcium score (CACS) and mortality.pDES was measured in 1177 COPD patients and 110 healthy control subjects from two independent cohorts. Emphysema was assessed on chest computed tomography scans. Aortic arterial stiffness was measured as the aortic-femoral pulse wave velocity.pDES was elevated in patients with cardiovascular disease (p<0.005) and correlated with age (rho=0.39, p<0.0005), CACS (rho=0.19, p<0.0005) modified Medical Research Council dyspnoea score (rho=0.15, p<0.0005), 6-min walking distance (rho=-0.17, p<0.0005) and body mass index, airflow obstruction, dyspnoea, exercise capacity index (rho=0.10, p<0.01), but not with emphysema, emphysema progression or forced expiratory volume in 1 s decline. pDES predicted all-cause mortality independently of several confounding factors (p<0.005). In an independent cohort of 186 patients with COPD and 110 control subjects, pDES levels were higher in COPD patients with cardiovascular disease and correlated with arterial stiffness (p<0.05).In COPD, excess elastin degradation relates to cardiovascular comorbidities, atherosclerosis, arterial stiffness, systemic inflammation and mortality, but not to emphysema or emphysema progression. pDES is a good biomarker of cardiovascular risk and mortality in COPD.
Topics: Adult; Aged; Biomarkers; Body Composition; Bronchodilator Agents; Calcinosis; Cardiovascular Diseases; Case-Control Studies; Coronary Vessels; Desmosine; Disease Progression; Elastin; Emphysema; Female; Forced Expiratory Volume; Humans; Inflammation; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Pulse Wave Analysis; Respiratory Function Tests; Risk Factors; Smoking; Vascular Stiffness
PubMed: 27009168
DOI: 10.1183/13993003.01824-2015 -
Chronic Obstructive Pulmonary Diseases... Mar 2016Desmosine (DES) and isodesmosine (IDES) have been widely discussed as potential biomarkers of COPD. However, their clinical utility and validity remains unproven. This...
Desmosine (DES) and isodesmosine (IDES) have been widely discussed as potential biomarkers of COPD. However, their clinical utility and validity remains unproven. This study aims to progress DES/IDES evaluation as a chronic obstructive pulmonary disease (COPD) biomarker by investigating its urinary excretion in a large sample cohort with respect to a) which factors influence DES/IDES levels in a population of healthy control individuals and COPD individuals; b) whether DES/IDES levels enable the differentiation between COPD individuals and healthy control individuals; c) whether DES/IDES can be used to differentiate between fast and slow decliners in lung function. Urinary DES and IDES were quantified in 365 individuals (147 healthy control individuals and 218 COPD individuals) from the Evaluation of COPD Longitudinally to Indentify Predictive Surrogate Endpoints (ECLIPSE) study (NCT00292552) by employing a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Age, gender, body mass index (BMI) and smoking have a significant (<0.05) influence on DES/IDES urinary excretion and need to be corrected for when investigating DES/IDES as a disease biomarker. Urinary DES/IDES allowed a statistically relevant differentiation (<0.05) between stable COPD individuals and healthy control individuals, however, assay sensitivity and specificity were low (62% and 73%, respectively). Furthermore, urinary DES/IDES does not allow the differentiation of fast and slow decliners in lung function. The present results suggest that while urinary DES/IDES excretion is related to COPD, it is not a sensitive or specific biomarker for COPD diagnosis or prognosis.
PubMed: 28848880
DOI: 10.15326/jcopdf.3.2.2015.0159 -
Investigative Ophthalmology & Visual... Jan 2016Current literature contains scant information regarding the extent of enzymatic collagen cross-linking in the keratoconus (KC) cornea. The aim of the present study was...
PURPOSE
Current literature contains scant information regarding the extent of enzymatic collagen cross-linking in the keratoconus (KC) cornea. The aim of the present study was to examine levels of enzymatic lysyl oxidase-derived cross-links in stromal collagen in KC tissue, and to correlate the cross-link levels with collagen fibril stability as determined by thermal denaturation temperature (Tm).
METHODS
Surgical KC samples (n = 17) and Eye-Bank control (n = 11) corneas of age 18 to 68 years were analyzed. The samples were defatted, reduced (NaBH4), hydrolyzed (6N HCl at 110°C for 18 hours), and cellulose enriched before analysis by C8 high-performance liquid chromatography equipped with parallel fluorescent and mass detectors in selective ion monitoring mode (20 mM heptafluorobutyric acid/methanol 70:30 isocratic at 1 mL/min). Nine different cross-links were measured, and the cross-link density was determined relative to collagen content (determined colorimetrically). The Tm was determined by differential scanning calorimetry.
RESULTS
Cross-links detected were dihydroxylysinonorleucine (DHLNL), hydroxylysinonorleucine, lysinonorleucine (LNL), and histidinohydroxylysinonorleucine in both control and KC samples. Higher DHLNL levels were detected in KC, whereas the dominant cross-link, LNL, was decreased in KC samples. Decreased LNL levels were observed among KC ≤ 40 corneas. There was no difference in total cross-link density between KC samples and the controls. Pyridinolines, desmosines, and pentosidine were not detected. There was no notable correlation between cross-link levels with fibril instability as determined by Tm.
CONCLUSIONS
Lower levels of LNL in the KC cornea suggest that there might be a cross-linking defect either in fibrillar collagen or the microfibrillar elastic network composed of fibrillin.
Topics: Adolescent; Adult; Aged; Chromatography, High Pressure Liquid; Cornea; Humans; Keratoconus; Mass Spectrometry; Middle Aged; Protein-Lysine 6-Oxidase; Young Adult
PubMed: 26780316
DOI: 10.1167/iovs.15-18105