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Respiratory Research Dec 2017The role of neutrophil elastase (NE) is poorly understood in bronchiectasis because of the lack of preclinical data and so most of the assumptions made about NE... (Review)
Review
The role of neutrophil elastase (NE) is poorly understood in bronchiectasis because of the lack of preclinical data and so most of the assumptions made about NE inhibitor potential benefit is based on data from CF. In this context, NE seems to be a predictor of long-term clinical outcomes and a possible target of treatment. In order to better evaluate the role of NE in bronchiectasis, a systematic search of scientific evidence was performed.Two investigators independently performed the search on PubMed and included studies published up to May 15, 2017 according to predefined criteria. A final pool of 31 studies was included in the systematic review, with a total of 2679 patients. For each paper data of interest were extracted and reported in table.In this review sputum NE has proved useful as an inflammatory marker both in stable state bronchiectasis and during exacerbations and local or systemic antibiotic treatment. NE has also been associated with risk of exacerbation, time to next exacerbation and all-cause mortality. This study reviews also the role of NE as a specific target of treatment in bronchiectasis. Inhibition of NE is at a very early stage and future interventional studies should evaluate safety and efficacy for new molecules and formulations.
Topics: Biomarkers; Bronchiectasis; Cross-Sectional Studies; Humans; Leukocyte Elastase; Sputum
PubMed: 29258516
DOI: 10.1186/s12931-017-0691-x -
The Journal of Biological Chemistry Sep 2018Elastin is an essential vertebrate protein responsible for the elasticity of force-bearing tissues such as those of the lungs, blood vessels, and skin. One of the key...
Elastin is an essential vertebrate protein responsible for the elasticity of force-bearing tissues such as those of the lungs, blood vessels, and skin. One of the key features required for the exceptional properties of this durable biopolymer is the extensive covalent cross-linking between domains of its monomer molecule tropoelastin. To date, elastin's exact molecular assembly and mechanical properties are poorly understood. Here, using bovine elastin, we investigated the different types of cross-links in mature elastin to gain insight into its structure. We purified and proteolytically cleaved elastin from a single tissue sample into soluble cross-linked and noncross-linked peptides that we studied by high-resolution MS. This analysis enabled the elucidation of cross-links and other elastin modifications. We found that the lysine residues within the tropoelastin sequence were simultaneously unmodified and involved in various types of cross-links with different other domains. The Lys-Pro domains were almost exclusively linked via lysinonorleucine, whereas Lys-Ala domains were found to be cross-linked via lysinonorleucine, allysine aldol, and desmosine. Unexpectedly, we identified a high number of intramolecular cross-links between lysine residues in close proximity. In summary, we show on the molecular level that elastin formation involves random cross-linking of tropoelastin monomers resulting in an unordered network, an unexpected finding compared with previous assumptions of an overall beaded structure.
Topics: 2-Aminoadipic Acid; Animals; Biopolymers; Cattle; Desmosine; Dipeptides; Elastin; Humans; Lysine; Protein Domains; Tropoelastin
PubMed: 30108173
DOI: 10.1074/jbc.RA118.004322 -
Annals of the American Thoracic Society Aug 2016Biomarkers of pathogenesis in chronic obstructive pulmonary disease (COPD) can significantly accelerate drug development. In COPD related to alpha-1 antitrypsin... (Review)
Review
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.
Topics: Biomarkers; Desmosine; Elastin; Fibrinogen; Humans; Isodesmosine; Leukocyte Elastase; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Uteroglobin; alpha 1-Antitrypsin Deficiency
PubMed: 27564670
DOI: 10.1513/AnnalsATS.201509-574KV -
Bioorganic & Medicinal Chemistry Dec 2021Desmosine and isodesmosine are crosslinking amino acids of elastin, which is an essential component of the dermal extracellular matrix protein. Quantitative analysis of...
Desmosine and isodesmosine are crosslinking amino acids of elastin, which is an essential component of the dermal extracellular matrix protein. Quantitative analysis of crosslinker desmosines in human skin dermis has not been fully achieved due to the insoluble nature of elastin protein. In the present study, chemical synthesis of isotopically labeled desmosine, desmosine-C,N, was carried out via isoChichibabin pyridinium synthesis starting from corresponding isotopically labeled amino acids. Isotope-dilution LC-MS/MS analysis of desmosine and isodesmosine utilizing synthetic desmosine-C,N enabled the quantitative analysis of desmosines in human skin for the first time. Thus, ca. 1.43 μg of desmosines was detected from analysis of 1 mg of dry human skin.
Topics: Carbon Isotopes; Chromatography, Liquid; Desmosine; Humans; Isodesmosine; Molecular Structure; Nitrogen Isotopes; Skin; Tandem Mass Spectrometry
PubMed: 34839160
DOI: 10.1016/j.bmc.2021.116519 -
Macromolecular Bioscience Nov 2023Elastin is an essential extracellular matrix protein that enables tissues and organs such as arteries, lungs, and skin, which undergo continuous deformation, to stretch...
Elastin is an essential extracellular matrix protein that enables tissues and organs such as arteries, lungs, and skin, which undergo continuous deformation, to stretch and recoil. Here, an approach to fabricating artificial elastin with close-to-native molecular and mechanical characteristics is described. Recombinantly produced tropoelastin are polymerized through coacervation and allysine-mediated cross-linking induced by pyrroloquinoline quinone (PQQ). A technique that allows the recovery and repeated use of PQQ for protein cross-linking by covalent attachment to magnetic Sepharose beads is developed. The produced material closely resembles natural elastin in its molecular, biochemical, and mechanical properties, enabled by the occurrence of the cross-linking amino acids desmosine, isodesmosine, and merodesmosine. It possesses elevated resistance against tryptic proteolysis, and its Young's modulus ranging between 1 and 2 MPa is similar to that of natural elastin. The approach described herein enables the engineering of mechanically resilient, elastin-like materials for biomedical applications.
Topics: Elastin; Tropoelastin; Amino Acids; Proteolysis
PubMed: 37441796
DOI: 10.1002/mabi.202300203 -
Journal of the American Society For... May 2015Elastin is a vital protein of the extracellular matrix of jawed vertebrates and provides elasticity to numerous tissues. It is secreted in the form of its soluble...
Elastin is a vital protein of the extracellular matrix of jawed vertebrates and provides elasticity to numerous tissues. It is secreted in the form of its soluble precursor tropoelastin, which is subsequently cross-linked in the course of the elastic fiber assembly. The process involves the formation of the two tetrafunctional amino acids desmosine (DES) and isodesmosine (IDES), which are unique to elastin. The resulting high degree of cross-linking confers remarkable properties, including mechanical integrity, insolubility, and long-term stability to the protein. These characteristics hinder the structural elucidation of mature elastin. However, MS(2) data of linear and cross-linked peptides released by proteolysis can provide indirect insights into the structure of elastin. In this study, we performed energy-resolved collision-induced dissociation experiments of DES, IDES, their derivatives, and DES-/IDES-containing peptides to determine characteristic product ions. It was found that all investigated compounds yielded the same product ion clusters at elevated collision energies. Elemental composition determination using the exact masses of these ions revealed molecular formulas of the type CxHyN, suggesting that the pyridinium core of DES/IDES remains intact even at relatively high collision energies. The finding of these specific product ions enabled the development of a similarity-based scoring algorithm that was successfully applied on LC-MS/MS data of bovine elastin digests for the identification of DES-/IDES-cross-linked peptides. This approach facilitates the straightforward investigation of native cross-links in elastin.
Topics: Animals; Cattle; Chromatography, High Pressure Liquid; Cross-Linking Reagents; Desmosine; Elastin; Humans; Isodesmosine; Models, Molecular; Molecular Structure; Molecular Weight; Oligopeptides; Peptide Fragments; Peptide Mapping; Protein Stability; Proteolysis; Spectrometry, Mass, Electrospray Ionization; Stereoisomerism; Tandem Mass Spectrometry; Tropoelastin
PubMed: 25604393
DOI: 10.1007/s13361-014-1075-9 -
IUBMB Life May 2020Elastic fibers are essential assemblies of vertebrates and confer elasticity and resilience to various organs including blood vessels, lungs, skin, and ligaments. Mature... (Review)
Review
Elastic fibers are essential assemblies of vertebrates and confer elasticity and resilience to various organs including blood vessels, lungs, skin, and ligaments. Mature fibers, which comprise a dense and insoluble elastin core and a microfibrillar mantle, are extremely resistant toward intrinsic and extrinsic influences and maintain elastic function over the human lifespan in healthy conditions. The oxidative deamination of peptidyl lysine to peptidyl allysine in elastin's precursor tropoelastin is a crucial posttranslational step in their formation. The modification is catalyzed by members of the family of lysyl oxidases and the starting point for subsequent manifold condensation reactions that eventually lead to the highly cross-linked elastomer. This review summarizes the current understanding of the formation of cross-links within and between the monomer molecules, the molecular sites, and cross-link types involved and the pathological consequences of abnormalities in the cross-linking process.
Topics: 2-Aminoadipic Acid; Aging; Animals; Blood Vessels; Connective Tissue Diseases; Elastic Tissue; Elastin; Humans; Ligaments; Lung; Lysine; Microfibrils; Oxidation-Reduction; Protein Processing, Post-Translational; Protein-Lysine 6-Oxidase; Skin
PubMed: 31834666
DOI: 10.1002/iub.2213 -
Frontiers in Medicine 2023Developing an effective treatment for pulmonary emphysema will require a better understanding of the molecular changes responsible for distention and rupture of alveolar...
Developing an effective treatment for pulmonary emphysema will require a better understanding of the molecular changes responsible for distention and rupture of alveolar walls. A potentially useful approach to studying this process involves the concept of emergence in which interactions at different levels of scale induce a phase transition comprising a spontaneous reorganization of chemical and physical systems. Recent studies in our laboratory provide evidence of this phenomenon in pulmonary emphysema by relating the emergence of airspace enlargement to the release of elastin-specific desmosine and isodesmosine (DID) crosslinks from damaged elastic fibers. When the mean alveolar diameter exceeded 400 μm, the level of peptide-free DID in human lungs was greatly increased, reflecting rapid acceleration of elastin breakdown, alveolar wall rupture, and a phase transition to an active disease state that is less responsive to treatment. Based on this finding, it is hypothesized that free DID in urine and other body fluids may serve as a biomarker for early detection of airspace enlargement, thereby facilitating timely therapeutic intervention and reducing the risk of respiratory failure.
PubMed: 38164218
DOI: 10.3389/fmed.2023.1322283 -
Journal of the American Heart... Oct 2019Background It is recognized that factors beyond aortic size are important in predicting outcome in abdominal aortic aneurysm (AAA) disease. AAA is characterized by the... (Observational Study)
Observational Study
Background It is recognized that factors beyond aortic size are important in predicting outcome in abdominal aortic aneurysm (AAA) disease. AAA is characterized by the breakdown of elastin within the aortic tunica media, leading to aortic dilatation and rupture. The aim of this study was to investigate the association of plasma desmosine (pDES), an elastin-specific degradation product, with disease severity and clinical outcome in patients with AAA. Methods and Results We measured pDES and serum biomarker concentrations in 507 patients with AAAs (94% men; mean age, 72.4±6.1 years; mean AAA diameter, 48±8 mm) and 162 control subjects (100% men; mean age, 71.5±4.4 years) from 2 observational cohort studies. In the longitudinal cohort study (n=239), we explored the incremental prognostic value of pDES on AAA events. pDES was higher in patients with AAA compared with control subjects (mean±SD: 0.46±0.22 versus 0.33±0.16 ng/mL; <0.001) and had the strongest correlation with AAA diameter (=0.39; <0.0001) of any serum biomarker. After adjustment for baseline AAA diameter, pDES was associated with an AAA event (hazard ratio, 2.03 per SD increase [95% CI, 1.02-4.02]; =0.044). In addition to AAA diameter, pDES provided incremental improvement in risk stratification (continuous net reclassification improvement, 34.4% [95% CI, -10.8% to 57.5%; =0.09]; integrated discrimination improvement, 0.04 [95% CI, 0.00-0.15; =0.050]). Conclusions pDES concentrations predict disease severity and clinical outcomes in patients with AAA. Clinical Trial Registration http://www.isrctn.com. Unique identifier: ISRCTN76413758.
Topics: Aged; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Biomarkers; Cardiac Catheterization; Desmosine; Female; Follow-Up Studies; Humans; Incidence; Male; Prognosis; Prospective Studies; Survival Rate; Ultrasonography; United Kingdom
PubMed: 31595818
DOI: 10.1161/JAHA.119.013743 -
Methods in Cell Biology 2018The functional form of elastin is a highly cross-linked polymer that organizes as sheets or fibers in the extracellular matrix. Purification of the mature protein is...
The functional form of elastin is a highly cross-linked polymer that organizes as sheets or fibers in the extracellular matrix. Purification of the mature protein is problematic because its insolubility precludes its isolation using standard wet-chemistry techniques. Instead, relatively harsh experimental approaches designed to remove nonelastin "contaminates" are employed to generate an insoluble product that has the amino acid composition expected of elastin. Although soluble, tropoelastin also presents problems for isolation and purification. The protein's extreme stickiness and susceptibility to proteolysis require careful attention during purification and in tropoelastin-based assays. This chapter describes the most common approaches for purification of elastin and for preparing solubilized forms of the protein.
Topics: Alkalies; Animals; Elastin; Extracellular Matrix; Hot Temperature; Microscopy, Electron; Molecular Imaging; Proteolysis; Solubility; Staining and Labeling
PubMed: 29310779
DOI: 10.1016/bs.mcb.2017.08.012