Circulation. 1995;91:2488-2496
(Circulation. 1995;91:2488-2496.)
© 1995 American Heart Association, Inc.
Atherosclerosis: Basic Mechanisms
Oxidation, Inflammation, and Genetics
Judith A. Berliner, PhD;
Mohamad Navab, PhD;
Alan M. Fogelman, MD;
Joy S. Frank, PhD;
Linda L. Demer, MD, PhD;
Peter A. Edwards, PhD;
Andrew D. Watson, BS;
Aldons J. Lusis, PhD
From the Atherosclerosis Research Unit and the Departments of Medicine
(J.A.B., M.N., A.M.F., J.S.F., L.L.D., P.A.E., A.J.L.), Pathology (J.A.B.,
A.D.W.), Physiology (J.S.F., L.L.D.), Biological Chemistry (P.A.E.), and
Microbiology and Molecular Genetics (A.J.L.), University of California School
of Medicine, Los Angeles, and the College of Letters and Sciences (A.J.L.),
Los Angeles, Calif.
Correspondence to Alan M. Fogelman, MD, Department of Medicine, UCLA
School of Medicine, Los Angeles, CA 90024-1736.
 |
Abstract
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Abstract The clinical events resulting from atherosclerosis
are
directly related to the oxidation of lipids in LDLs that become
trapped
in the extracellular matrix of the subendothelial space. These
oxidized
lipids activate an NF
B-like transcription factor and induce
the
expression of genes containing NF
B binding sites. The protein
products
of these genes initiate an inflammatory response that
initially
leads to the development of the fatty streak. The progression
of
the lesion is associated with the activation of genes that induce
arterial
calcification, which changes the mechanical characteristics
of
the artery wall and predisposes to plaque rupture at sites
of monocytic
infiltration. Plaque rupture exposes the flowing
blood to tissue factor
in the lesion, and this induces thrombosis,
which is the proximate
cause of the clinical event. There appear
to be potent genetically
determined systems for preventing lipid
oxidation, inactivating
biologically important oxidized lipids,
and/or modulating the
inflammatory response to oxidized lipids
that may explain the differing
susceptibility of individuals
and populations to the development of
atherosclerosis. Enzymes
associated with HDL may play an important role
in protecting
against lipid oxidation in the artery wall and may
account in
part for the inverse relation between HDL and risk
for atherosclerotic
clinical events.
Key Words: atherosclerosis • lipids • genes • antioxidants • lipoproteins
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Introduction
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At one time, atherosclerosis was
thought to be a degenerative
disease that was an inevitable consequence
of aging. Research
in the last two decades has shown that
atherosclerosis is neither
a degenerative disease nor inevitable. On
the contrary, atherosclerosis
seems to be a chronic inflammatory
condition that is converted
to an acute clinical event by the induction
of plaque rupture,
which in turn leads to thrombosis.
1
What are the basic mechanisms
that induce this sequence of events? Fig
1
depicts a model of
the sequence of changes in the
artery wall that lead to a clinical
event. The underlying hypothesis
presented here is that components
of the earliest lesion, the fatty
streak, which itself is not
clinically significant, are also
responsible for the latter
events that lead to clinically significant
disease
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Lipids and Atherogenesis
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Table 1
depicts some of the steps in fatty
streak development.
The first is lipoprotein transport into the artery
wall. This
concentration-dependent process does not require
receptor-mediated
endocytosis.
2 3 The seminal
findings by
Brown and Goldstein
4 that atherosclerosis is induced in
multiple species by mutations
that involve a single gene, the LDL
receptor, provide strong
evidence that elevations in LDL levels are
sufficient to induce
all the components of the atherosclerotic
reaction.
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Lipoprotein Retention in the Artery Wall
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Schwenke and her late colleague Carew
5 6 provided
convincing
evidence that for any given lipoprotein concentration in the
plasma,
lipoprotein retention in the artery wall was more important
than
the rate of transport into the artery wall. Kruth
7
and Simionescu
et al
8 first reported early changes in the
lipoproteins retained
in the artery wall. Frank and
Fogelman
9 extended these findings
with state-of-the-art
ultrastructural techniques and demonstrated
that LDL was rapidly
transported across an intact endothelium
and became trapped in the
three-dimensional cage work of fibers
and fibrils secreted by the
artery wall cells.
10 The intimate
association of
LDL
11 with the extracellular matrix of the subendothelial
space
explains how the concentration of apolipoprotein B (apoB), the
major
protein of LDL, is found in higher concentrations in the artery
wall
than in the plasma.
12 13 14 Early
lesions appear to
develop
at sites of
predilection
15 16 17 18 19 20 21 22
that are related
to
hemodynamic and mechanical
factors.
23 24 25
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Lipoprotein Oxidation
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The cells of the artery wall secrete oxidative products from
multiple
pathways that can seed the LDL trapped in the subendothelial
space
and initiate lipid
oxidation.
26 27 28 29 Studies
by Navab
and
colleagues
30 with serum containing cocultures of human
artery
wall cells in which an endothelial monolayer was maintained
on
multilayers of smooth muscle cells indicated that the matrix
provided
by these artery wall cells could produce microenvironments
that could
exclude the water-soluble antioxidants of plasma.
It is not surprising
then that oxidative modification of the
trapped lipoproteins does, in
fact, occur, as was suggested
more than a decade
ago
31 32 33 34 35
and subsequently proved
in the late
1980s.
36 37 38 39
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Mildly and Highly Oxidized LDL
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The oxidative modification of the trapped LDL is thought to
occur
in two stages. The first stage occurs before monocytes
are recruited
and results in the oxidization of lipids in LDL
with little change in
apoB. The second stage begins when monocytes
are recruited to the
lesion, convert into macrophages, and contribute
their enormous
oxidative capacity. In this second stage, the
LDL lipids are further
oxidized, but the protein portion of
LDL is also modified, leading to a
loss of recognition by the
LDL receptor and a shift to recognition by
the scavenger receptors
and/or the oxidized LDL
receptor.
40 41 42 This shift in receptor
recognition
leads to
cellular uptake of the LDL by receptors that are not
regulated by the
cholesterol content of the cell. The result
is a massive accumulation
of cholesterol. Such cholesterol-loaded
cells have a foamy cytoplasm
and have been called foam cells;
they are the hallmark of the arterial
fatty streak.
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Oxidized LDL Is a Potent Inducer of Inflammatory Molecules
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What are the mechanisms by which the oxidation of LDL leads
to
this inflammatory reaction? Berliner and colleagues
43
reported
that the mild oxidation of LDL yielded oxidized lipids that
induced
monocytes but not neutrophils to bind to endothelial cells.
Treatment
of endothelial cells with this oxidized lipid induced changes
in
molecules that affect all three stages
44 of monocyte
binding:
tethering, activation, and attachment (Table 2
).
Levels of the
tethering molecule P-selectin are
increased intracellularly
by mildly oxidized LDL and can be released by
a variety of substances,
including highly oxidized LDL.
45
In vivo studies have also
suggested that P-selectin can be released by
oxidized LDL,
46 and P-selectin expression has been shown
to be increased in
human lesions.
45 47 Moreover,
mildly
oxidized LDL induced endothelial
cells to produce the potent monocyte
activators monocyte chemoattractant
protein 1 (MCP-1),
48
monocyte colony stimulating factor (M-CSF),
49 and
GRO.
50 While M-CSF and MCP-1 appear to be soluble
molecules,
GRO was found bound to heparin-like molecules on the
endothelial
cell surface.
50 Another adhesion molecule,
VCAM-1, has been
implicated in the development of fatty streaks in
rabbits.
51 Mildly oxidized LDL does not induce VCAM-1 or
ICAM-1 expression,
52 and the adhesion molecule induced by
mildly oxidized LDL has
yet to be completely identified. Navab and
colleagues
30 demonstrated
that LDL added to cocultures of
human aortic endothelial and
smooth muscle cells also led to the
production of MCP-1 and
monocyte migration into the subendothelial
space. Rajavashisth
and colleagues
49 demonstrated the
presence of M-CSF in atherosclerotic
lesions in rabbits. Subsequent to
these findings, others reported
that MCP-1 and M-CSF were present
in lesions from animals and
humans.
53 54 Studies by
Cushing and Fogelman
55 suggested that
differentiating
monocytes also produced MCP-1 that could amplify
their own recruitment
into lesions. Consistent with this hypothesis
was the finding by Neiken
and colleagues
56 that MCP-1 was expressed
most in lesion
areas where monocyte density was greatest. Charo
and
colleagues
57 recently cloned the receptor for MCP-1,
providing
a potential new target for interrupting this reaction.
How does mildly oxidized LDL induce a set of genes with protein
products that lead to monocyte adherence, migration, and conversion
into macrophages without inducing a neutrophilic or lymphocytic
reaction? Parhami and colleagues58 reported that mildly
oxidized LDL induces elevated levels of cAMP by a G protein–mediated
mechanism. These high levels of cAMP decrease the expression of ELAM-1
(a receptor to which neutrophils bind) while increasing the molecules
noted above. Mildly oxidized LDL induces these inflammatory molecules
both by inducing increased rates of gene transcription and by
stabilizing the mRNA for these genes.59
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HDL May Protect by Inhibiting LDL Oxidation
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HDL was found to protect against LDL oxidation by metal ions
in
vitro
60 61 and to prevent the production of mildly
oxidized
LDL by the artery wall cells in a coculture
model.
30 However,
HDL obtained either from patients
undergoing surgery or after
myocardial infarction in which
apolipoprotein A-I was displaced
from the HDL by the acute phase
reactant serum amyloid A not
only was not protective against LDL
modification but actually
enhanced LDL modification by the
cocultures.
62 Two enzyme systems
associated with normal
HDL have been reported to inhibit LDL
oxidation in vitro. Stafforini
and colleagues
63 reported that
the platelet activating
factor acetylhydrolase was effective
in preventing metal ion–dependent
oxidation of LDL. Mackness
and colleagues
64 reported that
a second enzyme associated with
HDL, paraoxonase, also inhibited LDL
oxidation in vitro. Both
enzymes have been found to protect against LDL
modification
in the coculture system.
65 66 Thus, the
inverse relation between
risk for atherosclerotic events and HDL levels
may be due to
enzymes associated with HDL that protect against LDL
oxidation
and the putative role of HDL in reverse cholesterol
transport.
67 Moreover, because these enzymes are
associated with only a
small fraction of HDL particles, this may, in
part, explain
why some patients with low levels of total HDL
cholesterol may
not have clinically significant atherosclerosis and
others with
relatively normal levels of HDL cholesterol may have
premature
atherosclerosis. However, this hypothesis has yet to be
tested.
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Oxidation and Lesion Progression
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Fig 2
depicts in cartoon form some
of the molecular and cellular
mechanisms responsible for the sequence
of events described
in Fig 1
. This scheme would predict that
conditions
that increased
the oxidative waste of artery wall cells would increase
the
seeding of LDL trapped in the subendothelial space, as suggested
by
Witztum and Steinberg
26 29 and
Parthasarathy.
27 28 Increased
levels of HDL
containing
enzymes that prevented the formation
of or destroyed the biologically
active lipids generated in
the mildly oxidized LDL would prevent the
ensuing inflammatory
reaction. Once started, however, the reaction
would tend to
amplify itself. Navab et al
68 reported that
artery wall cells
interacted with monocytes by inducing mRNA for the
gap junction
protein connexin43, which was accompanied by increased
production
of matrix molecules and involved interleukin-1 (IL-1) and
interleukin-6.
Ross
69 demonstrated that monocyte
macrophages are a potent
source of a powerful smooth muscle cell growth
factor and chemoattractant
platelet-derived growth factor (PDGF). This
would explain, in
part, the migration of smooth muscle cells into the
lesion.
Products of lipoprotein oxidation have also been shown to
affect
other events associated with atherogenesis. The secretion of
IL-1,
a growth factor for smooth muscle cells, has been shown to be
stimulated
by oxidized lipids.
70 Lysophosphatidylcholine,
a product of
LDL oxidation, has been shown to be a chemoattractant for
monocytes
71 and T-lymphocytes,
72 to induce
the adhesion molecules VCAM-1
and ICAM-1,
73 and to
increase levels of PDGF and heparin-binding
epidermal growth factor
mRNA in endothelial cells
74 and smooth
muscle
cells.
75 Highly oxidized LDL also can inhibit endothelial
cell
migration and may impair the repair of ulcerated plaques in
advanced
lesions.
76 Highly oxidized LDL has also been
shown to be toxic
to macrophages
77 and as a result may
contribute to amplification
of the inflammatory process and the
formation of the necrotic
core found in advanced lesions. With the
death of some of the
macrophage foam cells, lipid droplets could be
released and
phagocytized by the smooth muscle cells, producing smooth
muscle
cell foam cells, as suggested by Wolfbauer and
colleagues.
78 The involvement of the immune system in the
development of
lesions
79 80 81 may
increase
82 or
decrease
83 84 the inflammatory
reaction.
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Figure 2. This page and facing page, Schematics showing
molecular and cellular mechanisms for some events described in Fig
1.
A, Development of the fatty streak. B, Progression to advanced lesion.
Small grey cells with round black nuclei represent lymphocytes;
red droplets in cells, lipid inclusions. C, Advanced lesion with plaque
rupture and thrombus. D, Cross section of artery corresponding to panel
A. E, Cross section of artery corresponding to panel B. F, Cross
section of artery corresponding to panel C. EC indicates endothelial
cells; IEL, internal elastic lamina; SMC, smooth muscle cells; MM-LDL,
mildly oxidized LDL; Ox-LDL, highly oxidized LDL; +, positive
induction; X-LAM, adhesion molecule induced by MM-LDL; MCP-1, monocyte
chemoattractant protein-1; M-CSF, monocyte colony stimulating factor;
ROS, reactive oxygen species; and Ca, calcification resulting from the
action of the pericyte-like cells. Adapted with permission in part from
Fig 1, page 374, Berliner JA, Haberland ME. The role of
oxidized low
density lipoprotein in atherogenesis. Curr Opin Lipidol.
1993;4:373-381.
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Glagov et al85 demonstrated that in all species the lesion
grows out toward the adventitia until a critical point is reached, at
which time the lesion can no longer expand outward at the expense of
the normal media and then begins to encroach on the lumen. The lesion
grows by the migration of new mononuclear cells that enter at the
shoulder regions of the lesion,86 the proliferation of
both monocyte macrophages87 and smooth muscle
cells,88 the production of an exuberant extracellular
matrix,89 and the accumulation of extracellular lipid in a
necrotic core.7 90
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Genetic Factors Affecting Lipid Oxidation and Inflammation
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Liao and colleagues
91 reasoned that if oxidized
lipids were
responsible for the induction of a set of genes that
induced
the chronic inflammatory response characteristic of the fatty
streak,
these genes might be induced in any tissue that accumulated
the
oxidized lipids. They used mouse livers as a convenient
tissue for
detailed genetic studies. Mice that readily develop
fatty streaks in
their aortas on an atherogenic diet (C57BL/6)
were compared with mice
that never developed fatty streaks on
the same atherogenic diet
(C3H/HeJ), despite the fact that the
two strains develop similar levels
of the atherogenic apoB-containing
lipoproteins in their blood on this
diet. On the atherogenic
diet, both strains accumulated substantial
amounts of total
lipid, cholesterol, and triglycerides in their livers
that did
not significantly differ between the two strains. However, the
fatty
streak–susceptible strain (C57BL/6) accumulated significantly
more
oxidized lipid than did the fatty streak–resistant strain
(C3H/HeJ).
Associated with these higher levels of oxidized lipids was
the
activation of an NF
B-like transcription factor and the
expression
of genes that contain NF
B binding sites:
JE,
the mouse homologue
of MCP-1, colony stimulating factors, serum amyloid
A, and heme
oxygenase in the fatty streak–susceptible C57BL/6 mice
but
not in the fatty streak–resistant C3H/HeJ
mice.
91 92
Injection of mildly oxidized LDL into the mice induced the
same set of
genes in the liver.
91 93 These results were
consistent
with
the hypothesis that the atherogenic diet resulted in the
accumulation
of oxidized lipids in certain tissues (eg, liver and
arteries),
with the resulting inflammatory response to this oxidative
stress
genetically determined.
94 While these data were
suggestive
of a genetically determined rate of formation or destruction
of
oxidized lipids or that the intensity of the inflammatory response
to
these lipids was genetically determined, the association or
lack of
association of these phenomena with two genetically
distinct strains
did not directly prove a genetic link. Fortunately,
recombinant inbred
strains derived from the parental strains
were available to directly
test the hypothesis. Crossbreeding
of the parental strains allowed the
genomes of the two strains
to be extensively intermingled because of
chromosomal crossover.
If the level of oxidized lipids, the activation
of the NF
B-like
transcription factor, the expression of the
inflammatory genes,
and the development of aortic fatty streaks all
cosegregated
together as the two genomes were randomly distributed by
extensive
crossbreeding, it would be strong evidence that these
phenomena
were genetically linked. Results of the analysis revealed
that
indeed there was cosegregation and suggested that a major gene
contributing
to aortic lesion development in this mouse model,
previously
termed
Ath-1, may control either the accumulation
of lipid peroxides
in tissues or the cellular responses to such lipid
peroxides.
95
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Calcification and Plaque Rupture
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Recent evidence suggests that the site of intimal rupture or
erosion
of thrombosed coronary atherosclerotic plaques is characterized
by
an inflammatory process regardless of the dominant plaque
morphology.
96 97 It is thought that mechanical
factors are
involved in the
actual rupture of the plaque at such sites of
structural weakness.
Demer
98 reported that the mechanical
characteristics of atherosclerotic
plaque are due to calcification of
the lesions. Fig 3
demonstrates
that the mechanical
characteristics observed in human coronary
arteries were not reproduced
in the aorta of rabbits with LDL
receptor deficiency even when they
were placed on a cholesterol-rich
diet and had extensive aortic
atherosclerosis. However, as Fig
3
shows, when the aortas of
these
animals were induced to calcify,
they had mechanical characteristics
identical to those seen
in atherosclerotic human coronary arteries.
Demer et al
99 argued
that the presence of a soft plaque
with a point of weakness
induced by inflammation sitting on an area of
calcification
predisposes to plaque rupture because of the presence of
a tissue
interface of differing physical properties that is subjected
to
the pulsatile changes of the arterial blood pressure. "Hardening
of
the arteries" has long been thought to be an inevitable
consequence
of aging. However, Demer and her colleagues
99
reported that
this is no more an inevitable degenerative change than is
the
development of other components of the inflammatory reaction.
Bostrom
et al
100 and Watson et al
101
demonstrated that a heretofore
unrecognized cell in large and medium
arteries is responsible
for calcification. This cell has many of the
characteristics
of pericytes found in the microcirculation. These
cells, called
calcifying vascular cells, were induced to calcify by
expression
of the same set of genes as those expressed during bone
formation.
The expression of these genes was induced by tissue growth
factor-ß
and oxysterol, two agents known to be present in the
fatty streak
and the developing atherosclerotic lesion. It is possible
that
other chronic inflammatory reactions such as tuberculosis may
induce
calcification by similar mechanisms. In the artery wall,
however,
the calcification-induced changes in the mechanical
characteristics
of the tissue predispose to plaque
rupture.
102 103 104 105 106
Recent studies in mice indicate that
arterial calcification
may be under genetic control.
107
The changes in the mechanical
characteristics of the arterial tissue
induced by calcification
are superimposed on changes in the matrix that
result from increased
expression of matrix metalloproteinases and
matrix degrading
activity in the shoulder region of the
lesion.
108 109 Thus,
mechanical forces are applied to
an
area of structural weakness
and predispose to plaque rupture.
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Figure 3. Line graphs showing pressure-volume recordings
during inflation of angioplasty balloon. Pressure-volume recordings
were made as described by Demer.98 Top, Upper curve is
from a human during the first balloon inflation in an atherosclerotic
coronary artery. Note the break in the curve, indicating plaque
fracture. The lower curve was recorded from the same patient at the
same site at the end of the procedure. Note that the curve is smooth
and shifted to the right, indicating a return toward normal
distensibility. Middle, A pressure-volume recording during balloon
inflation in the aorta of a cholesterol-fed Watanabe heritable
hyperlipidemic (WHHL) rabbit.98 Note that the curves are
smooth and superimposed and do not have a break. This trend is
identical to that of the curve obtained during balloon inflation in a
normal rabbit aorta.98 Bottom, Upper curve
represents balloon inflation in the aorta of a cholesterol-fed
WHHL rabbit after the aorta was induced to calcify.98 The
lower curve was recorded from the same rabbit at the same site at the
end of the procedure. Note the similarity in the fracture patterns
obtained in the calcified rabbit aorta (bottom) and the atherosclerotic
human coronary artery (top).
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Thrombosis
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The endothelium usually has anticoagulant properties. The potent
coagulant,
tissue factor, usually is expressed only in the adventitia.
(This
makes teleological sense because one would want to induce
clotting
if the artery were opened to the adventitial side.) Oxidized
LDL
has been shown to induce endothelial cells
110 111
and
monocytes
112 to express high levels of tissue factor. In
addition, Drake
and colleagues
113 demonstrated that there
is abundant tissue
factor in the intima of atherosclerotic lesions.
Plasminogen
activator inhibitor levels are also increased when
endothelial
cells are exposed to oxidized LDL.
114
Consequently, plaque
rupture would expose the flowing blood to these
high levels
of tissue factor and result in clotting with the induction
of
a clinical event. The normal response to thrombin formation
is
vasodilation,
115 which would favor the mechanical removal
of
a clot. Oxidized LDL has been shown to induce the expression
of
endothelin,
116 to inhibit the expression of nitric oxide
synthase,
and to inhibit the resulting
vasodilation.
117 118 119 Thus,
LDL
further contributes to
arterial occlusion by thrombus. In
addition to the local reduction in
nitric oxide, it is also
quite clear that platelet accumulation and
local increases in
thromboxane A
2, serotonin, ADP,
platelet activating factor,
and activated thrombin, together with a
local reduction in prostacyclin,
contribute to
thrombosis.
120 121
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Oxidation of LDL Produces Oxidized Lipids With Differing Biological
Activities
|
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Atherosclerotic lesions contain multiple oxidized lipids derived
from
the lipids in LDL.
122 The biological properties of
the lipids
in mildly oxidized LDL have been seen to be different from
those
induced by the lipids in highly oxidized LDL (eg, the expression
of
tissue factor by endothelial cells was induced by mildly oxidized
LDL
but not by highly oxidized LDL
110 ; the lipids in
highly oxidized
LDL were cytotoxic,
123 whereas the lipids
in mildly oxidized
LDL were not
43 ). Fig 4
depicts a scheme in which LDL undergoes
various degrees of oxidation.
The activation of the NF
B-like
transcription factor and the increase
in the genes induced by
mildly oxidized LDL are due to the appearance
of specific oxidized
lipids that appear to be oxidized phospholipids
but are as yet
unidentified.
65 66 With continued
oxidation, these bioactive
lipids are presumed to be destroyed and new
ones formed that
account for the different biological activity of
highly oxidized
LDL. These latter lipids include
lysophosphatidylcholine and
oxidized
sterols.
71 73 74 75 123
The final identification of
the specific biologically active lipids in
mildly oxidized LDL
will likely yield new targets of opportunity for
intervention.
One possibility is that these lipids are by chance
similar to
lipids in bacteria that evoke similar chronic inflammatory
responses
such as
Mycobacterium
tuberculosis.
124
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Figure 4. Diagram of the change in the biological activities
of LDL with increasing degrees of oxidation. The solid line
represents the level of induction of mediators of chronic
inflammation; dashed line, the level of cytotoxicity. MM-LDL indicates
mildly oxidized LDL; Ox-LDL, oxidized LDL.
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Pharmacological Intervention at the Level of the Artery Wall
|
|---|
The prevention and treatment of atherosclerosis currently are
appropriately
directed to lowering LDL levels and raising HDL levels.
As we
understand the basic mechanisms more fully, new strategies may
emerge.
125 We may learn how to specifically raise the
levels of HDL subfractions
that carry the enzymes that prevent the
formation of or destroy
the biologically active lipids in oxidized LDL.
If we can identify
the major genes that control the formation of
biologically active
oxidized lipids or control the intensity of the
response to
these lipids, we may be able to devise strategies that will
favorably
modify the functions controlled by these genes. As we
understand
the basic mechanisms of arterial calcification, we may be
able
to devise strategies that will allow us to maintain normal artery
wall
mechanics and prevent plaque rupture. So far, at least one
anti-inflammatory
compound has been identified that inhibits in vitro
the formation
of biologically active mildly oxidized LDL and smooth
muscle
proliferation without inhibiting endothelial cell
proliferation.
126 127 The future will undoubtedly
reveal a
number of new strategies
for preventing and treating
atherosclerosis.
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Acknowledgments
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This work was supported in part by NIH grant HL-30568 and the
M.K.
Grey and Laubisch Funds at the University of California, Los
Angeles.
Received January 9, 1995;
revision received February 27, 1995;
accepted February 28, 1995.
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Abstract
Introduction