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Lung Elastin and Matrix* FREE TO VIEW

Barry C. Starcher, MD
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*From the Department of Biochemistry, University of Texas Health Center at Tyler, Tyler, TX.

Correspondence to: Barry C. Starcher, MD, Department of Biochemistry, University of Texas Health Center at Tyler, PO Box 2003, Tyler, TX 75710



Chest. 2000;117(5_suppl_1):229S-234S. doi:10.1378/chest.117.5_suppl_1.229S-a
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The extracellular matrix has been defined as the structural network of collagens, elastin, glycoproteins and proteoglycans, surrounding stromal cells, and underlying endothelial and epithelial cells.1In addition to structural properties, the extracellular matrix also functions as a dynamic modulator of various biological processes. This is accomplished through the selective binding and subsequent release of growth factors and cytokines, and through its interaction with cell surface receptors.24 Although collagen and elastic fibers are the major constituents of the extracellular matrix, the overall function is defined by the interrelationships between all the various components.

The development of an organ as complex as the lung commands cellular multiplication and differentiation, and requires an integrated system of signals to modulate these processes. The extracellular matrix provides the environment and architecture necessary for the expansion of each lung compartment. In this review, all components of the extracellular matrix will not be covered, nor will there be an attempt to cover all the major connective tissue-rich organs. This is somewhat restricting, since so much of the valuable information on the extracellular matrix that is available has been derived from studies on the vascular system and the skin. We will be confined primarily to the development and role of elastin in the lung and its relationship to other elastin-associated matrix glycoproteins.

The vasculature, conducting airways, and terminal airspace compartments of the lung require an elastic symmetry that can undergo repeated extension and recoil throughout the life of the lung. These properties are met beautifully by the elastic fibers which, by their structure and orientation, determine the patterns of distension and recoil in most organs. The elastic fiber organization in the lung is amazingly uniform for all vertebrates, with the possible exception of birds, where the architecture and movement of air through the lung is atypical.

Elastin is synthesized and secreted from several cell types in the lung depending on the anatomic location. These include chondroblasts, myofibroblasts, and mesothelial and smooth muscle cells. Messenger RNA translation occurs on the surface of the rough endoplasmic reticulum, and with the release of a signal peptide, the protein travels through the lumen of the rough endoplasmic reticulum, where it is secreted via secretory vesicles to the plasma membrane as a 72-kd soluble form known as tropoelastin.5A specific elastin-binding protein apparently chaperones tropoelastin intracellularly, protecting it from proteolysis.6The elastin-binding protein also forms a three-protein receptor complex that is important in directing tropoelastin to sites of fiber formation.7Tropoelastin occurs as multiple, distinct isoforms due to extensive alternative splicing of a single-gene transcript.89 In most instances, the splicing occurs in a cassette-like manner, where an exon is either included or deleted. A functional role for the alternatively spliced exons and different isoforms of tropoelastin has not been determined, although there is some indication that one of these exons may encode a protein required for tropoelastin interaction with microfibrillar proteins.10 Alternative splicing appears to be developmentally regulated, with age-related changes in isoform ratios being observed in all species that have been investigated.89,11 Complementary DNA analysis has shown that tropoelastin is comprised of a modular structure containing alternating hydrophobic domains rich in glycine, proline, valine, and highly conserved cross-linking domains rich in alanine and lysine (Fig 1 ). Posttranslational modifications of tropoelastin are minimal yet very important. There is no evidence for glycosylation, and hydroxylation of proline is variable and apparently not required for synthesis or fiber formation.,89 The formation of lysine-derived cross-links, however, is essential for the unique properties of the mature elastin protein.

As tropoelastin is secreted from the cell, it interacts with specific glycoprotein microfibrils, which are necessary for tropoelastin alignment and the subsequent formation of elastic fibers.12During this process, the copper-dependent enzyme, lysyl oxidase, oxidatively deaminates specific epsilon aminos of lysine to form allysine. Typically, three allysines and one ε amino from a lysine spontaneously condense to form desmosine or isodesmosine (Fig 2 ).14 These hydrophilic cross-linking domains are helical and typically contain stretches of lysine separated by either two or three alanines. This arrangement positions the lysines near each other on the same side of the helix, resulting in a favorable conformation for desmosine and isodesmosine formation.8 Most desmosine cross-linking occurs between two elastin molecules; however, there is evidence that a third chain can be bridged through a lysinonorleucine cross-link. 15

Although tropoelastin is rapidly metabolized by a variety of proteolytic enzymes, the mature elastin molecule is an exceedingly stable and insoluble protein, with a turnover approaching the life span of the animal under normal circumstances.1617 However, heritable disorders that lead to uncontrolled proteolysis, incomplete cross-linking, or abnormal assembly of the elastic fiber can result in pathologic conditions such as dissecting aneurysms and reduced pulmonary function.1821 Environmentally induced injuries can also lead to the same pathologic events, most notably pulmonary emphysema and fibrosis.2223 Repair of damaged elastic fibers can occur, although the physiologic function of the tissue may never return to normal.24 This is particularly true for the lung, where the unique alveolar architecture is very difficult if not impossible to reconstruct.

The organization of elastin in the lung extracellular matrix begins at the pseudoglandular stage of lung development in association with sites of airway branching.25Elastin synthesis is increased during the canalicular and saccular stage of fetal development and reaches a peak during alveolarization in the neonatal stage. The development of alveoli by septation is intimately related to the elastic fiber network. In the developing lung, the elastic fibers concentrate in areas of stress, forming a ring around the opening of the alveoli and concentrating at alveolar junctions. From this ring, small elastic fibers stretch out in several directions to form a delicate latticework that establishes the boundaries of the intervening space through which new alveoli emerge. Each new septum begins as a crest that is demarcated by these elastic fibers, which separate adjoining alveoli of the same alveolar duct (lateral wall septa), as well as alveoli of adjacent alveolar ducts (roof septa). All of the septa thus formed are continuous with each other, and each chamber is open to an alveolar duct. The fibers extend out to form a latticework within each wall and also extend out to join the network of the next septa. This provides a continuity of fibers over the whole complex of septa within one acinus, and by interconnecting to the axial and peripheral fiber systems, there is a fiber continuum established throughout the lung.26 The fact that elastin synthesis coincides with alveolarization has led to the consensus that proper elastic fiber formation is required for normal alveolarization. This apparently is the circumstance in fibrillin defects, where microfibrillular assembly can be severely impaired, resulting in abnormal lung development.

Another major component of the extracellular matrix that is closely tied to elastin metabolism is the 10- to 12-nm glycoprotein microfibrils.89 Microfibrils are thought to facilitate elastin fibrillogenesis, where they act as a scaffold for elastin assembly.27These fibers are comprised of the large, 350-kd glycoprotein fibrillin-1 and its homolog fibrillin-2,2829 and a much smaller 31-kd glycoprotein, termed microfibril-associated glycoprotein.30Other glycoproteins including lysyl oxidase have also been localized to the microfibrils, yet their roll in elastin fibrogenesis, other than the cross-linking requirement for lysyl oxidase, is not known. Most interest has been focused on fibrillin, since it is present in the largest amounts and since mutations in the fibrillin gene are responsible for Marfan’s syndrome.31 Pulmonary complications of this disease include honeycombing, bullous emphysema, bronchiectasis, and spontaneous pneumothoraces.19

Fibrillin is a gene family consisting of two large modular proteins composed of 54 domains. The primary structure of fibrillin-1 shows many cysteine-rich sequences homologous to epidermal growth factor or transforming growth factor-α1 binding protein. Mutations occur along the whole fibrillin gene and include deletions, nonsense, and missense mutations.3233 These mutations can affect the cysteines in epidermal growth factor-like domains, resulting in loss of calcium binding.34 This, in turn, can cause domain misfolding that results in destabilization of the entire superstructure of the microfibril.

Close to 100 distinct disease-associated single mutations have been attributed to the fibrillin gene.32 Most mutations are nonrecurring and are dispersed throughout the gene and have no overt phenotypic association. In severe neonatal incidents of Marfan’s syndrome, the mutations cluster between exons 24 to 26 and exon 32.35Despite the multitude of different mutations and the absence of correlation between phenotype and genotype at a molecular level, biochemical analysis has enabled the division of Marfan’s fibroblasts into five groups.36 It is important to note that in severe Marfan-like disorders, fibrillin synthesis can apparently be normal, yet the product is unable to fold properly, yielding a matrix that is unsatisfactory for normal elastin fiber growth and assembly. This is apparently the cause of the emphysematous-like lesions that are observed in the lungs of tight-skin mouse.

The tight-skin mouse is an autosomal-dominant mutation characterized by multiple defects in connective tissue metabolism.37One of the notable defects in these animals is the development of severely emphysematous-appearing lungs characterized by airspace enlargement and almost a complete lack of normal alveolar development.38A series of studies suggested that the emphysematous lungs resulted from elastic fiber damage caused by excessive neutrophil elastase activity.3941 These findings were challenged by a study where tight-skin mice were crossed with beige mice, yielding a mutant strain of tight-skin mice deficient in neutrophil elastase. These mutant mice developed pulmonary lesions with the same degree of severity as the tight-skin mouse.42It was suggested that these lesions were developmental and resulted from impaired alveolar maturation, probably caused by matrix protein defects other than elastin. Within a few years, the question was settled with the discovery of a genomic duplication of 30 to 40 kilobase within the tight-skin mouse fibrillin-1 gene.43The mutation produces a mutant transcript that is 3 kilobase larger than the wild-type transcript that is synthesized and incorporated into microfibrils along with normal fibrillin.44 The consequence is an abnormal microfibril with altered molecular organization. As has been shown for certain Marfan’s syndrome patients, the copolymerization of normal and abnormal fibrillin is universally disruptive for microfibril structure and function. Without the correct scaffolding, elastin is not properly deposited and elastic fiber formation is defective or prevented. In addition, altered growth factor binding to the mutant microfibrils may contribute to the increased synthesis of extracellular matrix molecules observed in the tight-skin mouse. We have observed that messenger RNA levels during different stages of development in the lungs and skin of tight-skin mouse were normal for several matrix proteins including collagen, tropoelastin, and fibrillin. However, ultraviolet light irradiation of hairless tight-skin mice showed a remarkable resistance to tumor development and prevented epithelial thickening, hair follicle hypertrophy, and solar elastosis, compared to normal mice. These are all changes in the skin that are signaled by growth factors or cytokines, and illustrates the importance of normal matrix development for modulation of signal transduction. It is quite possible that in neonatal tight-skin mouse lungs, the inability of normal growth factor signaling, in addition to defective elastic fiber deposition, contributes to the cessation of the alveolarization process. This leads to the immature or emphysematous appearance of the lung in mature mice.

Perhaps some of the more exciting new reports on lung development and matrix involvement have come from studies demonstrating the dramatic effect of retinoic acid on the induction of septation. Retinoids have been shown to directly affect pulmonary gene expression and have long been implicated as important signal molecules for lung development. Retinoic acid is specifically bound by cellular retinoic acid-binding protein,45which increases soon after birth in the rat and peaks on day 10 postnatally, which coincides with rat lung differentiation and tropoelastin up-regulation.46 Administering retinoic acid to fetal rats was shown to induce airway branching.47Recently, it was demonstrated that daily intraperitoneal injections of all-trans-retinoic acid in postnatal rats leads to a substantial increase in the number of alveoli.48 Even more dramatic results were obtained when retinoic acid was administered daily to young adult rats 25 days after they had been instilled in the lungs with elastase. Twelve days after treatment with all-trans-retinoic acid, evidence of lung damage and symptoms of experimental emphysema were reversed.49 It was not clear from this study whether damaged elastic fibers were repaired or whether the apparent return to normalcy only reflected the formation of new alveoli. This raises many questions about the removal of damaged elastic fibers and remodeling of impaired alveolar walls following lung injury. Is tissue reconstruction a major part of this repair, or do we see primarily debridement coupled with new alveolar growth?

Retinoic acid modulation of septation and lung development is a very active area of interest at present, yet little is known about the role of the extracellular matrix in this signaling process. It is obvious that all the components required to assemble the microfibrils and elastic fibers for new alveoli must also be up-regulated. In addition to retinoic acid, elastin synthesis during normal lung development is regulated by a variety of growth factors, including insulin-like growth factor-1, transforming growth factor-α1, basic fibroblast growth factor, and glucocorticoids.46

Proteolytic degradation of lung elastin and the role of protease inhibitors have been covered in previous reviews.5051 Elastin has played a pivotal role in efforts to quantitate the catabolic events that may be occurring in the lung, or to measure the efficacy of therapeutic interventions. Desmosine cannot be absorbed from the diet; it is recovered without further metabolism in the urine, and is found only in elastin.52There are several micromethods for measuring desmosine, such a high-performance liquid chromatography,53isotope dilution,54 enzyme-linked immunosorbent assay,55and radioimmunoassay.56The radioimmunoassay for desmosine is very specific and will measure picomole quantities in tissue hydrolysates, urine, or any solution where the desmosines are not in large peptides or proteins. Lung injury that involves matrix catabolism has been assumed to be represented by some degree of elastin destruction. The fragmented elastin is then further metabolized, and free desmosine or small peptides can be recovered in the urine and used as an index of lung injury. This has been true for experimental animal models of emphysema, where large doses of elastase remove up to 50% of the lung elastin. This becomes much more difficult when attempting to quantitate chronic injury or losses due to only minor lung injury. In a recent study, we measured the kinetics of desmosine (elastin) turnover resulting from elastase-induced injury or severe fibrosis (Fig 3 ).57 Removal of fragmented elastin from the lung and transport through the blood to the urine was very rapid, and most of the pools had returned to normal desmosine levels within 24 h, even though as much as 25% of the total lung elastin was removed. An unexpected finding in this study was that over half of the desmosine-containing elastin fragments were sequestered by the kidneys, reaching peak levels after 3 days, and then were slowly released over a period of several days. Severely fibrotic lungs showed minimal elastin damage, representing < 0.1% of the total lung elastin as estimated by desmosine analysis. We saw no evidence of increased desmosine in any of the kinetic compartments for the fibrotic animals. It appears that the kinetics of elastin removal from the lung dictate minimal levels of urine desmosine and minimize the power of urine desmosine assays for chronic, low-level tissue destruction.

In summary, the components of the extracellular matrix form an integrated system of interconnecting molecules that are required for the normal development and functioning of the lung. This matrix provides both a structural element and a medium for growth factor storage and signal transduction. Elastic fibers are a major constituent of the extracellular matrix and an essential element of the lung, providing the architectural foundation as well as the stretch and recoil required for normal function. These fibers are remarkably resilient and long lived. However, even a single gene mutation in another component of the matrix can result in defective elastic fiber formation and impaired pulmonary function. Exciting new directions may lead to mechanisms that allow reinitiation of septation and alveolarization, or provoke elastic fiber repair in injured lungs.

Figure Jump LinkFigure 1. Diagrammatic structure of human elastin complementary DNA. The Figure illustrates the alternating hydrophobic and hydrophilic cross-linking exons. Exon 26 is hydrophilic, yet it does not encode for cross-linking sequences in elastin. Arrows designate exons known to participate in alternate splicing.Grahic Jump Location
Figure Jump LinkFigure 2. Structure of the primary cross-linking amino acids of elastin, desmosine, and isodesmosine. Both are derived from the posttranslational enzymatic oxidation of the ε aminos of lysine by the lysyl oxidase.Grahic Jump Location
Figure Jump LinkFigure 3. Kinetics of desmosine clearance from the lung following proteolytic injury to elastin.Grahic Jump Location
Hay, ED (1981) Cell biology of extracellular matrix.J Cell Biol91,205S-223S
 
Hass, TA, Plow, EF Integrin-ligand interactions: a year in review.Curr Opin Cell Biol1994;6,656-662
 
Humphries, MJ Integrin activation: the link between ligand binding and signal transduction.Curr Opin Cell Biol1996;8,632-640
 
Amenta, PS, Harrison, D Expression and potential role of the extracellular matrix in hepatic ontogensis: a review.Microsc Res Tech1997;39,372-386
 
Sandberg, LB, Weissman, N, Smith, DW The purification and partial characterization of a soluble elastin-like protein from copper-deficient porcine aorta.Biochemistry1969;8,2940-2945
 
Hinek, A, Rabinovitch, M 67-kD elastin binding protein is a protective “companion ” of extracellular insoluble elastin and intracellular tropoelastin.J Cell Biol1994;126,563-574
 
Mecham, RP, Hinek, A, Entwistle, R, et al Elastin binds to a multifunctional 67-kilodalton peripheral membrane protein.Biochemistry1989;28,3716-3722
 
Vrhovski, B, Weiss, AS Biochemistry of tropoelastin.Eur J Biochem1998;259,1-18
 
Rosenbloom, J, Abrams, WB, Mecham, R Extracellular matrix 4: the elastic fiber.FASEB J1993;7,1208-1218
 
Pollack, J, Baule, V, Rich, CB, et al Tropoelastin isoforms: from the gene to the matrix.J Biol Chem1990;265,3697-3702
 
Heim, RA, Pierce, RA, Deak, SB, et al Alternative splicing of rat tropoelastin mRNA is tissue-specific and developmentally regulated.Matrix1991;11,359-366
 
Mecham, RP Elastin synthesis and fiber assembly.Ann N Y Acad Sci1991;624,137-146
 
Eyre, DR, Paz, MA, Gallop, PM Crosslinking in collagen and elastin.Annu Rev Biochem1984;53,717-748
 
Reiser, K, McCormick, RL, Rucker, RB Enzymatic and nonenzymatic cross-linking of collagen and elastin.FASEB J1992;6,2439-2449
 
Brown-Augsburger, P, Tisdale, C, Broekelmann, T, et al Identification of an elastin cross-linking domain that joins three peptides chains: possible role in nucleated assembly.J Biol Chem1995;270,17778-17783
 
Dubic, MA, Rucker, RB, Cross, CE, et al Elastin metabolism in rodent lung.Biochem Biophys Acta1981;672,303-306
 
Shapiro, SD, Endicott, SK, Province, MA, et al Marked longevity of human lung parenchymal elastic fibers deduced from prevalence of D-aspartate and nuclear weapons-related radiocarbon.J Clin Med1991;87,1828-1834
 
Milewicz, DM Molecular genetics of Marfan syndrome and Ehlers-Danlos type IV.Curr Opin Cardiol1998;13,198-204
 
Wood, JR, Bellamy, D, Child, AH, et al Pulmonary disease in patients with Marfan syndrome.Thorax1984;39,780-784
 
Crystal, RG Alpha 1-antitrypsin. deficiency, emphysema, and liver disease: genetic basis and strategies for therapy.J Clin Invest1990;85,1343-1352
 
Ewart, Ak, Jin, WS, Atkinson, D Supravalvular aortic stenosis associated with a deletion disrupting the elastin gene.J Clin Invest1994;93,1071-1077
 
Crouch, E Pathobiology of pulmonary fibrosis.Am J Physiol1990;159,L159-L184
 
Kumar, RK, Lykke, AW Messages and handshakes: cellular interactions in pulmonary fibrosis.Pathology1995;27,18-26
 
Kuhn, C Repairing the cables of the lung.Am J Respir Cell Mol Biol1997;17,287-288
 
Pierce, RA, Mariani, TJ, Senior, RM Elastin in lung development and disease. In Chadwick DJ, Goode JA, eds. The molecular biology and pathology of elastic tissues.1995,199-214 Wiley. UK:
 
Weibel ER, Bachofen H. The fiber scaffold of lung parenchyma. In: Crystal RG, West JB, eds. The lung. Lippincott-Raven, 1997:1139–1146.
 
Cleary, EG, Gibson, MA Elastic tissue, elastin and elastin associated microfibrils. Comper, WD eds.The structure and function of extracellular matrix1983,95-140 Gordon and Breach. New York, NY:
 
Saki, LY, Keene, DR, Engvall, E Fibrillin, a new 350-kD glycoprotein, is a component of extracellular microfibrils.J Cell Biol1986;103,2499-2509
 
Kielty, CM, Shuttleworth, CA Microfibrillar elements of the dermal matrix.Microscopy Res Tech1997;38,413-427
 
Gibson, MA, Cleary, EG The immunohistochemical localization of microfibril-associated glycoprotein (MAGP) in elastic and non-elastic tissues.Immunol Cell Biol1987;65,345-356
 
Dietz, HC, Cutting, GR, Pyeritz, RE, et al Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene.Nature1991;352,337-339
 
Hayard, C, Brock, DJH Fibrillin-1 mutations in Marfan syndrome and other type-1 fibrillinopathys.Hum Mutat1997;10,415-423
 
Kattunen, L, Kattunen, L, Puhakka, L, et al Mutations in the fibrillin gene responsible for dominant ectopia lentis and neonatal Marfan syndrome.Nat Genet1994;6,64-69
 
Maurer, P, Hohenester, E Structural and functional aspects of calcium binding in extracellular matrix proteins.Matrix Biol1997;15,569-580
 
Putnam, EA, Cho, M, Zinn, AB, et al Delineation of the Marfan phenotype associated with mutations in exons 23–32 of the FBN1 gene.Am J Med Genet1996;62,233-242
 
Aoyama, T, Francke, U, Furthmayr, H Quantitative differences in biosynthesis and extracellular deposition of fibrillin in cultured fibroblasts distinguish five groups of Marfan syndrome patients and suggest distinct pathogenetic mechanisms.J Clin Invest1994;94,130-137
 
Green, MC, Sweet, HO, Bunker, LE Tight-skin, a new mutation of the mouse causing excessive growth of connective tissue and skeleton.Am J Pathol1976;82,493-511
 
Szapiel, SV, Fulmer, JD, Hunninghake, GW, et al Hereditary emphysema in the tight-skin (Tsk/+) mouse.Am Rev Respir Dis1981;123,680-685
 
Giovanni, A, Rossi, GW, Hunninghake, JE Hereditary emphysema in the tight-skin mouse.Am Rev Respir Dis1984;129,850-855
 
Martorana, PA, vanEven, PE, Gardi, C, et al A 16-month study of the development of genetic emphysema in tight-skin mice.Am Rev Respir Dis1989;139,226-232
 
DeSanti, MM, Gardi, C, Martorana, PA, et al Immunoelectron-microscope demonstration of elastase in emphysematous lungs of tight-skin mice.Exp Mol Pathol1989;51,18-32
 
Starcher, B, James, J Evidence that genetic emphysema in tight-skin mice is not caused by neutrophil elastase.Am Rev Respir Dis1991;143,1365-1368
 
Siracusa, LD, McGrath, R, Ma, Q, et al A tandem duplication within the fibrillin 1 gene is associated with the mouse tight skin mutation.Genome Res1996;6,300-313
 
Kielty, CM, Raghunath, M, Siracusa, LD, et al The tight skin mouse: demonstration of mutant fibrillin-1 production and assembly into abnormal microfibrils.J Cell Biol1998;140,1159-1166
 
Dolle, P, Ruberte, E, Leroy, P, et al Retinoic acid-binding proteins: I. A system study of their differential patterns of transcription during mouse organogenesis.Development1990;110,1133-1151
 
Mariani, TJ, Sandefur, S, Pierce, RA Elastin in lung development.Exp Lung Res1997;23,131-145
 
Cardoso, WV, Williams, MC, Mitsialis, SA, et al Retinoic acid induces changes in the pattern of airway branching and alters epithelial cell differentiation in the developing lungin vitro.Am J Respir Cell Mol Biol1995;12,464-476
 
Massaro, GD, Massaro, D Postnatal treatment with retinoic acid increases the number of pulmonary alveoli in rats.Am J Physiol1996;270,L305-L310
 
Massaro, GD, Massaro, D Retinoic acid treatment abrogates elastase-induced pulmonary emphysema in rats.Nat Med1997;3,675-677
 
Janoff, A Elastase and emphysema: current assessment of the protease-antiprotease hypothesis.Am Rev Respir Dis1985;132,417-433
 
Snider, GL, Lucey, EC, Stone, PJ Animal models of emphysema.Am Rev Respir Dis1986;133,149-169
 
Starcher, BC, Goldstein, RA Studies on the absorption of desmosine and isodesmosine.J Lab Clin Med1979;94,848-852
 
Covault, HP, Lubrano, T, Dietz, AA, et al Liquid-chromatographic measurement of elastin.Clin Chem1982;28,1465-1468
 
Stone, PJ, Bryan-Rhadfi, J, Lucey, EC, et al Measurement of urinary desmosine by isotope dilution and high performance liquid chromatography.Am Rev Respir Dis1991;144,284-290
 
Osakabe, T, Seyama, Y, Yamashita, S Comparison of ELISA and HPLC for the determination of desmosine and isodesmosine in aortic tissue elastin.J Clin Lab Anal1995;9,293-296
 
Starcher, B, Conrad, M A role for neutrophil elastase in the progression of solar elastosis.Connect Tissue Res1995;31,133-140
 
Starcher, B, Peterson, B The kinetics of elastolysis: elastin catabolism during experimentally induced fibrosis.Exp Lung Res1999;25,407-424
 

Figures

Figure Jump LinkFigure 1. Diagrammatic structure of human elastin complementary DNA. The Figure illustrates the alternating hydrophobic and hydrophilic cross-linking exons. Exon 26 is hydrophilic, yet it does not encode for cross-linking sequences in elastin. Arrows designate exons known to participate in alternate splicing.Grahic Jump Location
Figure Jump LinkFigure 2. Structure of the primary cross-linking amino acids of elastin, desmosine, and isodesmosine. Both are derived from the posttranslational enzymatic oxidation of the ε aminos of lysine by the lysyl oxidase.Grahic Jump Location
Figure Jump LinkFigure 3. Kinetics of desmosine clearance from the lung following proteolytic injury to elastin.Grahic Jump Location

Tables

References

Hay, ED (1981) Cell biology of extracellular matrix.J Cell Biol91,205S-223S
 
Hass, TA, Plow, EF Integrin-ligand interactions: a year in review.Curr Opin Cell Biol1994;6,656-662
 
Humphries, MJ Integrin activation: the link between ligand binding and signal transduction.Curr Opin Cell Biol1996;8,632-640
 
Amenta, PS, Harrison, D Expression and potential role of the extracellular matrix in hepatic ontogensis: a review.Microsc Res Tech1997;39,372-386
 
Sandberg, LB, Weissman, N, Smith, DW The purification and partial characterization of a soluble elastin-like protein from copper-deficient porcine aorta.Biochemistry1969;8,2940-2945
 
Hinek, A, Rabinovitch, M 67-kD elastin binding protein is a protective “companion ” of extracellular insoluble elastin and intracellular tropoelastin.J Cell Biol1994;126,563-574
 
Mecham, RP, Hinek, A, Entwistle, R, et al Elastin binds to a multifunctional 67-kilodalton peripheral membrane protein.Biochemistry1989;28,3716-3722
 
Vrhovski, B, Weiss, AS Biochemistry of tropoelastin.Eur J Biochem1998;259,1-18
 
Rosenbloom, J, Abrams, WB, Mecham, R Extracellular matrix 4: the elastic fiber.FASEB J1993;7,1208-1218
 
Pollack, J, Baule, V, Rich, CB, et al Tropoelastin isoforms: from the gene to the matrix.J Biol Chem1990;265,3697-3702
 
Heim, RA, Pierce, RA, Deak, SB, et al Alternative splicing of rat tropoelastin mRNA is tissue-specific and developmentally regulated.Matrix1991;11,359-366
 
Mecham, RP Elastin synthesis and fiber assembly.Ann N Y Acad Sci1991;624,137-146
 
Eyre, DR, Paz, MA, Gallop, PM Crosslinking in collagen and elastin.Annu Rev Biochem1984;53,717-748
 
Reiser, K, McCormick, RL, Rucker, RB Enzymatic and nonenzymatic cross-linking of collagen and elastin.FASEB J1992;6,2439-2449
 
Brown-Augsburger, P, Tisdale, C, Broekelmann, T, et al Identification of an elastin cross-linking domain that joins three peptides chains: possible role in nucleated assembly.J Biol Chem1995;270,17778-17783
 
Dubic, MA, Rucker, RB, Cross, CE, et al Elastin metabolism in rodent lung.Biochem Biophys Acta1981;672,303-306
 
Shapiro, SD, Endicott, SK, Province, MA, et al Marked longevity of human lung parenchymal elastic fibers deduced from prevalence of D-aspartate and nuclear weapons-related radiocarbon.J Clin Med1991;87,1828-1834
 
Milewicz, DM Molecular genetics of Marfan syndrome and Ehlers-Danlos type IV.Curr Opin Cardiol1998;13,198-204
 
Wood, JR, Bellamy, D, Child, AH, et al Pulmonary disease in patients with Marfan syndrome.Thorax1984;39,780-784
 
Crystal, RG Alpha 1-antitrypsin. deficiency, emphysema, and liver disease: genetic basis and strategies for therapy.J Clin Invest1990;85,1343-1352
 
Ewart, Ak, Jin, WS, Atkinson, D Supravalvular aortic stenosis associated with a deletion disrupting the elastin gene.J Clin Invest1994;93,1071-1077
 
Crouch, E Pathobiology of pulmonary fibrosis.Am J Physiol1990;159,L159-L184
 
Kumar, RK, Lykke, AW Messages and handshakes: cellular interactions in pulmonary fibrosis.Pathology1995;27,18-26
 
Kuhn, C Repairing the cables of the lung.Am J Respir Cell Mol Biol1997;17,287-288
 
Pierce, RA, Mariani, TJ, Senior, RM Elastin in lung development and disease. In Chadwick DJ, Goode JA, eds. The molecular biology and pathology of elastic tissues.1995,199-214 Wiley. UK:
 
Weibel ER, Bachofen H. The fiber scaffold of lung parenchyma. In: Crystal RG, West JB, eds. The lung. Lippincott-Raven, 1997:1139–1146.
 
Cleary, EG, Gibson, MA Elastic tissue, elastin and elastin associated microfibrils. Comper, WD eds.The structure and function of extracellular matrix1983,95-140 Gordon and Breach. New York, NY:
 
Saki, LY, Keene, DR, Engvall, E Fibrillin, a new 350-kD glycoprotein, is a component of extracellular microfibrils.J Cell Biol1986;103,2499-2509
 
Kielty, CM, Shuttleworth, CA Microfibrillar elements of the dermal matrix.Microscopy Res Tech1997;38,413-427
 
Gibson, MA, Cleary, EG The immunohistochemical localization of microfibril-associated glycoprotein (MAGP) in elastic and non-elastic tissues.Immunol Cell Biol1987;65,345-356
 
Dietz, HC, Cutting, GR, Pyeritz, RE, et al Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene.Nature1991;352,337-339
 
Hayard, C, Brock, DJH Fibrillin-1 mutations in Marfan syndrome and other type-1 fibrillinopathys.Hum Mutat1997;10,415-423
 
Kattunen, L, Kattunen, L, Puhakka, L, et al Mutations in the fibrillin gene responsible for dominant ectopia lentis and neonatal Marfan syndrome.Nat Genet1994;6,64-69
 
Maurer, P, Hohenester, E Structural and functional aspects of calcium binding in extracellular matrix proteins.Matrix Biol1997;15,569-580
 
Putnam, EA, Cho, M, Zinn, AB, et al Delineation of the Marfan phenotype associated with mutations in exons 23–32 of the FBN1 gene.Am J Med Genet1996;62,233-242
 
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