(Chest. 2000;117:229S-234S.)
© 2000
American College of Chest Physicians
Lung Elastin and Matrix*
Barry C. Starcher, MD
*
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
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Introduction
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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.1
In 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.2
3
4
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.
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Elastin: Biochemistry and Unique Properties
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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.5
A specific elastin-binding protein
apparently chaperones tropoelastin intracellularly, protecting it from
proteolysis.6
The elastin-binding protein also forms a
three-protein receptor complex that is important in directing
tropoelastin to sites of fiber formation.7
Tropoelastin
occurs as multiple, distinct isoforms due to extensive alternative
splicing of a single-gene transcript.8
9
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.8
9
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.8
9
The formation of lysine-derived cross-links,
however, is essential for the unique properties of the mature elastin
protein.
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Figure 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.
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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.12
During this process, the copper-dependent
enzyme, lysyl oxidase, oxidatively deaminates specific epsilon aminos
of lysine to form allysine. Typically, three allysines and one 
amino from a lysine spontaneously condense to form desmosine or
isodesmosine (Fig 2
).13
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
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Figure 2. Structure of the primary cross-linking amino acids
of elastin, desmosine, and isodesmosine. Both are derived from the
posttranslational enzymatic oxidation of the aminos of lysine by
the lysyl oxidase.
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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.16
17
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.18
19
20
21
Environmentally induced
injuries can also lead to the same pathologic events, most notably
pulmonary emphysema and fibrosis.22
23
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.
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Lung Elastic Fiber Development
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The organization of elastin in the lung extracellular matrix
begins at the pseudoglandular stage of lung development in association
with sites of airway branching.25
Elastin 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.
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Elastin-Associated Microfibrils
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Another major component of the extracellular matrix that is
closely tied to elastin metabolism is the 10- to 12-nm glycoprotein
microfibrils.8
9
Microfibrils are thought to
facilitate elastin fibrillogenesis, where they act as a scaffold
for elastin assembly.27
These fibers are comprised of the
large, 350-kd glycoprotein fibrillin-1 and its homolog
fibrillin-2,28
29
and a much smaller 31-kd glycoprotein,
termed microfibril-associated glycoprotein.30
Other
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
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Fibrillin
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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-
1 binding protein. Mutations
occur along the whole fibrillin gene and include deletions, nonsense,
and missense mutations.32
33
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
32.35
Despite 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.
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Tight-Skin Mouse Model of Scleroderma and Marfan’s Syndrome
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The tight-skin mouse is an autosomal-dominant mutation
characterized by multiple defects in connective tissue
metabolism.37
One 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.38
A series of studies
suggested that the emphysematous lungs resulted from elastic fiber
damage caused by excessive neutrophil elastase
activity.39
40
41
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.42
It 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.43
The 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.
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Alveolarization and Repair
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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,45
which 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.47
Recently, 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-1,
basic fibroblast growth factor, and
glucocorticoids.46
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Evaluation of Lung Distribution
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Proteolytic degradation of lung elastin and the role of protease
inhibitors have been covered in previous reviews.50
51
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.52
There are several
micromethods for measuring desmosine, such a high-performance liquid
chromatography,53
isotope dilution,54
enzyme-linked immunosorbent assay,55
and
radioimmunoassay.56
The 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.
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Introduction
Elastin: Biochemistry and Unique...
