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8ß1 during Pulmonary and Hepatic Fibrosis
From the Division of Pulmonary and Critical Care
Medicine,*
Department of Medicine, Mount Sinai School
of Medicine, New York, New York; the Division of
Gastroenterology,
Duke University Medical
Center, Durham, North Carolina; the Department of Neurology and
Neuroscience,
Weill Medical College of
Cornell, New York, New York; the Institute for Vascular Biology and
Thrombosis Research,§
University of Vienna,
Vienna, Austria; and the Cardiovascular
Institute,¶
Departments of Medicine and Pathology,
Mount Sinai School of Medicine, New York, New York
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Abstract |
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8, documented its high expression in
lung tissue, and established it as a receptor for the matrix
proteins fibronectin, vitronectin, and tenascin. We now
demonstrate that alveolar interstitial cells are the primary cell type
expressing 8ß1 in the lung parenchyma. Expression of 8ß1 is
concentrated primarily along the thinned extensions of cells and at the
tips of filopodia. Because of its unique distribution in alveolar
interstitial cells, we hypothesized that it may play a role in
the fibrotic response after injury. In bleomycin-induced pulmonary
fibrosis, there is increased expression of 8ß1 by
interstitial fibroblasts, the majority of which coexpress
smooth muscle actin, a marker of tissue myofibroblasts. To
establish a more general role for 8ß1 during organ
fibrosis, we further examined its expression in two rat models
of liver fibrosis. During hepatic injury due to either carbon
tetrachloride injury or bile duct ligation, we demonstrate
de novo expression of 8ß1 in activated hepatic
stellate cells, the myofibroblast equivalent in liver. Taken
together, the data localize 8ß1 to myofibroblast-like
cells during wound healing and suggest that signal transduction through
the 8ß1 integrin may contribute to the fibrotic response of
organs to injury.
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Introduction |
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In normal lung, the interstitium contains a population of mesenchymal
cells called alveolar myofibroblasts or contractile interstitial cells
(CICs).1
CIC-mediated functions are particularly important
during the establishment of pulmonary fibrosis. These cells express
myogenic intermediate filaments, including desmin and vimentin. CICs
are postulated to control the ventilation-perfusion ratio by alveolar
wall contraction during breathing.1-3
In contrast to
pericytes (myofibroblasts associated with capillaries) and alveolar
ring cells (smooth muscle-like cells found at the corners of alveolar
ducts),4
CICs/myofibroblasts do not express -smooth
muscle actin under normal conditions.5
However, during
pulmonary fibrosis, CICs undergo a phenotypic modulation to a smooth
muscle-like phenotype characterized by expression of -smooth muscle
actin5
and proliferation and increased synthesis of ECM
proteins, including collagen and fibronectin. As pulmonary fibrosis
progresses, the percentage of CICs in the lung increases from 30% to
80%, accompanied by a 10-fold increase in cell number.6
In the liver, the cell type analogous to the alveolar contractile
interstitial cell is the hepatic stellate cell (formerly known as the
lipocyte or Ito cell).7
In the normal liver, stellate
cells manifest a quiescent phenotype and do not express smooth
muscle-specific proteins. After liver injury, stellate cells
"activate," whereby they express -smooth muscle
actin,8
proliferate, and produce abundant extracellular
matrix proteins.9
Activated stellate cells also acquire
the ability to contract, a key feature of the cirrhotic
liver.10
Altered extracellular matrix composition in fibrosis leads to cellular
responses that are mediated through integrins. Integrins are a family
of cell adhesion receptors composed of and ß subunits that
influence many cellular activities, including adhesion, migration,
proliferation, apoptosis, and cell survival, all of which can modulate
the development of pulmonary fibrosis. For example, treatment of mice
with antibodies to the leukocyte integrin ß2 subunit dramatically
decreases collagen deposition after lung injury.11
Mice
lacking the ß6 integrin subunit, which is expressed in airway
epithelium after injury,12
are protected from the
development of bleomycin-induced pulmonary fibrosis.13
The
prevention of pulmonary fibrosis in ß6-deficient mice is due to a
defect in the activation of TGF-ß1 in the lung.13
Previous work from our laboratory has identified a potential role for
the integrin 8ß1 in lung fibrosis. We have cloned the human
integrin subunit 8, which is found it to be highly expressed in the
normal lung,14
and showed that 8ß1 is a receptor for
the matrix proteins fibronectin, tenascin, and
vitronectin.15-17
We now demonstrate that alveolar
contractile interstitial cells are the predominant 8-expressing
cells in the lung parenchyma. Because interaction of CICs with the ECM
may be important for the development of pulmonary fibrosis, we examined
the expression pattern of 8 during bleomycin-induced pulmonary
fibrosis. We also examined two models of hepatic fibrosis to determine
whether this integrin has a generalized role in the response to organ
injury. We find the integrin 8ß1 is a marker of activated
CICs/myofibroblasts and that proliferation of 8-expressing cells
appears to be a common feature of fibrosis.
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Materials and Methods |
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Rabbit polyclonal antibodies to the human 8 cytoplasmic domain
were previously characterized.14,15
The immortalized rat
hepatic stellate cell line HSC-T6 was a generous gift from Dr. Scott
Friedman (Mount Sinai School of Medicine, New York). The HSC-T6 cell
line was generated by transfection of primary hepatic stellate cells
with an expression plasmid encoding the SV40 large T antigen as
previously described.18
HSC-T6 cells retain all features
of activated stellate cells, including expression of desmin, smooth
muscle actin, and glial acidic fibrillary protein, and it can esterify
retinol into retinyl esters.18
Immunoelectron Microscopy
Lungs from adult Sprague-Dawley rats were sequentially perfused
through the thoracic aorta with 1) normal saline (0.9%) containing
1000 U/ml of heparin, 2) 50 ml of 3.75% acrolein and 2%
paraformaldehyde in phosphate buffer (pH 7.4) (PB), and 3) 200 ml of
2% paraformaldehyde in PB. The lungs were removed and stored in the
last fixative for an additional 30 minutes. Sections (50 µm thick)
were cut on a vibratome, collected in PB, and treated with 1% sodium
borohydride in PB for 30 minutes before immunocytochemical labeling.
Rabbit polyclonal antibody to human 8 subunit14
(1:1000, with 0.035% Triton in the diluent) was localized
immunocytochemically, using the avidin-biotin complex (ABC) peroxidase
method, and processed for electron microscopy as previously
described.19
Isolation of Rat Lung Fibroblasts
Lungs were initially perfused with phosphate-buffered saline (PBS)/10 mmol/L EDTA via the right ventricle, during simultaneous inflation and deflation through cannulated trachea. The lungs were removed en bloc and lavaged with PBS/10 mmol/L EDTA, followed by instillation of prewarmed collagenase (250 mg/ml)/trypsin (2.5 µg/ml) in PBS with penicillin/streptomycin (P/S)/gentamycin for 30 minutes at 37°C and then instillation with cold trypsin inhibitor (type II-S (Sigma T9128)/DNase (Sigma D-5025) (250 mg TI, 1 mg DNase, 10 ml fetal bovine serum, 90 ml PBS). Trachea, bronchi, major structures, and other extraneous tissues were excised, and the remainder of th tissue was minced into 2–4-mm pieces. Tissue was suspended in PBS/0.5% trypsin, stirred at 37°C for 30 minutes, and then filtered through nylon mesh. Cells were washed with PBS and resuspended in Dulbecco’s modified Eagle’s medium/10% fetal bovine serum/P/S/fungizone. Macrophages were depleted by repeated adherence to IgG-coated plates. The remaining cells were plated and incubated overnight.
Immunofluorescence
Freshly isolated fibroblasts were grown on fibronectin-coated
chamber slides for 1 day and fixed and permeabilized with 2%
paraformaldehyde/0.1% Triton X-100 for 10 minutes. Slides were blocked
with 3% bovine serum albumin and then incubated with anti-8
antibody (10 µg/ml) for 1 hour at room temperature, washed with PBS,
and incubated with biotin-conjugated donkey anti-rabbit IgG (1:50)
(Amersham, Arlington Heights, IL) for 1 hour at room temperature,
followed by PBS wash. Coverslips were then incubated with
fluorescein-conjugated streptavidin (1:100) (Amersham) for 15 minutes
at room temperature, washed with PBS, and mounted with Vectashield
(Vector Laboratories, Burlingame, CA).
Western Blot
Freshly isolated fibroblasts were grown for 3–5 days, and cells
were lysed with 200 mmol/L octyl--D-glucopyranoside/100
mmol/L Tris-HCl/1 mmol/L phenylmethylsulfonyl fluoride for 1 hour at
4°C and centrifuged twice at 2000 rpm for 10 minutes each. The
protein concentrations were determined by the Bradford Assay. Samples
(30 µg/well) were separated by sodium dodecyl sulfate-polyacrylamide
gel electrophoresis (SDS-PAGE) under nonreducing conditions on 7.5%
acrylamide gel, and electrophoretically transferred to a nylon membrane
(Hybond-N; Amersham). Filters were blocked with 1% dry milk/1% bovine
serum albumin/0.02% Tween-20/PBS for 2 hours, probed with the
anti-8 antibody for 1 hour, rinsed in PBS, and then probed with an
alkaline phosphatase-conjugated goat anti-rabbit antibody at a dilution
of 1:3000 for 30 minutes. After rinsing in PBS, color was developed
with the Protoblot alkaline phosphatase detection system (Promega).
Bleomycin-Induced Pulmonary Fibrosis
C57Bl/6 mice were maintained in a pathogen-free environment. Bleomycin (Mead-Johnson) was dissolved in sterile saline, and 0.075 U was administered intratracheally by direct visualization after cutdown. As a control, saline alone was administered intratracheally. Mice were sacrificed at 2 days, 4 days, 6 days, 2 weeks, 4 weeks, and 9 weeks after initial bleomycin installation. Lungs were perfused with PBS/heparin and then immersed in 10% sucrose solution overnight at 4°C. Tissues were embedded in OCT and then frozen in nitrogen-chilled butane. Five-micron sections were processed as previously described.14 Sections were incubated in 5% bovine serum albumin for 1 hour at room temperature and then incubated with the primary antibody overnight at 4°C. After washing in PBS, sections were incubated with peroxidase-conjugated goat anti-rabbit secondary antibody (Vector Laboratories) for 1 hour at room temperature. The reaction product was visualized after incubation of the sections with diamino benzidine (DAB Plus kit; Zymed Laboratories). Sections were counterstained with hematoxylin, sequentially dehydrated in ethanol solutions, transferred to xylene, and mounted with Permount (Fisher).
For colocalization immunofluorescence studies, lung sections were
incubated with 8 antibody (1:1000) and Cy3-conjugated -smooth
muscle actin antibody (Sigma), followed by biotin-conjugated donkey
anti-rabbit IgG (1:100) (Amersham), then fluorescein-conjugated
streptavidin (1:100) (Amersham) for 15 minutes at room temperature,
washed with PBS, and mounted with Vectashield (Vector Laboratories).
Slides were examined on a Zeiss Axioskop (Thornwood, NY) equipped with
filter sets for fluorescein isothiocyanate (FITC) and rhodamine/Cy3
(Chroma Technology, Brattleboro, VT). Images were collected using a
Spot 2 cCCD camera (Diagnostic Instruments, Sterling Heights, MI).
Black-and-white images (8-bit) were collected for each channel (ie,
FITC and Cy3) and then merged into the respective RGB channels in Adobe
Photoshop. Colocalization of 8 expression (green) and -smooth
muscle actin expression (red) was determined by overlap of the two
fluorochromes (yellow).
To determine the proportion of 8-expressing cells that did not
express -smooth muscle actin in fibrotic lesions, we counted the
number of 8-positive/-smooth muscle-negative and
8-positive/-smooth muscle-positive cells in four independent,
x40 fields containing areas of fibrosis from three different mice,
4–6 days after bleomycin administration.
Models of Hepatic Fibrosis
Hepatic fibrosis was induced in adult Sprague-Dawley rats by carbon tetrachloride (CCl4) administration or bile duct ligation as previously described.8 To induce biliary obstruction, the common bile duct was ligated and sectioned. Periductal fibrosis occurred by 5 days, and biliary cirrhosis occurred by 14 days. CCl4 was administered at a dose of 1.0 ml CCl4/kg body weight at weekly intervals via gavage. Early bridging fibrosis was apparent by 3–4 weeks. Tissues were processed for immunohistochemistry as above.
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8ß1 Is Expressed in Alveolar Interstitial Cells
In the normal lung parenchyma, immunoreactivity for 8ß1 was
seen within the alveoli septa by light microscopy.14
To
determine the cell type expressing 8ß1 in the lung parenchyma, we
performed immunoelectron microscopy of normal rat lung.
Immunoreactivity for 8 was localized to the interstitial cells
(Figure 1, A–D)
. In contrast, epithelial
cells and endothelial cells lacked immunoreactivity for 8. Many of
the interstitial cells expressing 8 labeling contained contractile
filaments (Figure 1A
, asterisk), identifying them as
CICs.2
In these cells, 8 immunoreactivity was found at
discrete patches along the cell membrane and was often concentrated at
the tips of the filopodia cells as they protruded into the fused
basement membrane of the endothelial and epithelial cells (Figure 1C
,
arrow). This pattern is reminiscent of the localization of 8ß1 at
synaptic densities in the hippocampus.19
8-labeling was
frequently concentrated at areas along the thin extensions of
interstitial cells. It is of interest that a lipid droplet was
identified within an 8-immunoreactive cell (Figure 1D
, arrowhead),
consistent with the notion that these cells are similar to the hepatic
stellate cells that contain cytoplasmic droplets of retinyl esters.
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8ß1 in lung interstitial fibroblasts, we
analyzed isolated primary rat lung fibroblasts by Western blot and
immunofluorescence. Fibroblasts isolated from normal rat lung express
8ß1 by Western blot (Figure 2A)
.
Immunofluorescence of isolated fibroblasts identified a subpopulation
of 8ß1-expressing cells. When pulmonary fibroblasts were grown on
fibronectin-coated plates, 8ß1 was concentrated at focal contacts,
consistent with its role as a receptor for fibronectin (Figure 2B)
.
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8ß1 during Fibrosis in VivoPulmonary Fibrosis
Because 8ß1 is expressed in CICs in the lung, which are
important in the development of pulmonary fibrosis, we examined the
expression pattern of 8ß1 in an experimental model of pulmonary
fibrosis. Pulmonary fibrosis in C57/black wild-type mice was produced
by intratracheal instillation of bleomycin, a standard technique
resulting in reproducible, nonfatal pulmonary inflammation followed by
fibrosis in mice (see Materials and Methods). In the saline-treated
control mouse lung, there was preservation of normal alveolar
architecture with baseline expression of 8ß1 in the alveolar
interstitial cells (Figure 3A)
. The
expression pattern of 8ß1 in saline-treated mouse lung was
identical to normal mouse lung. Within 2–4 days after bleomycin
instillation, alveolar wall thickening was present, with the collapse
of some alveoli. The vast majority of cells within areas of alveolar
wall thickening were immunoreactive for 8 (Figure 3, B–F)
. Patches
of inflammatory cells that were negative for 8ß1 were observed
within alveolar spaces (Figure 3D)
. Vascular smooth muscle and airway
smooth muscle were positive for 8ß1 (Figure 3C)
, as observed in
normal lung.
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8-positive cellular infiltration were observed, with an
expansion in the number of 8-reactive cells and complete
obliteration of normal alveolar architecture (Figure 3, G–I)
. Although
the majority of cells within the fibrotic lesions were
8ß1-positive, occasional 8ß1-negative cells were also
identified. In areas of more established fibrosis, there was decreased
cellularity.
During pulmonary fibrosis, CICs activate and newly express -smooth
muscle actin. To investigate whether the activated CICs coexpressed
8ß1 and -smooth muscle actin, we double-labeled sections for
8ß1 and -smooth muscle actin (Figure 4)
. Colocalization of 8ß1 and
-smooth muscle actin occurred in vascular and airway smooth muscle.
In the parenchyma, -smooth muscle actin-positive cells were
identified in areas of alveolar wall thickening. The vast majority of
these cells were 8ß1 immunoreactive. However, a subpopulation of
8ß1-positive cells were identified that were -smooth muscle
actin-negative (Figure 4
, white arrows). In areas of fibrosis, the
percentage of 8ß1-positive/-smooth muscle actin-negative cells
(compared to 8-positive/-smooth muscle-positive cells) ranged
from 8% to 55%, with an average of 16%. In contrast,
normal-appearing areas of lung parenchyma contained >90% cells that
were 8-positive/-smooth muscle-negative.
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The expression of 8ß1 in two mechanistically different models
of hepatic fibrosis was examined using carbon tetrachloride-induced
hepatic fibrosis and bile duct ligation-induced hepatic fibrosis. In
normal liver, 8ß1 immunoreactivity was confined to the smooth
muscle cells surrounding vessels and bile ducts (Figure 5,A and D)
, with none detected in the
parenchyma or hepatocytes. After bile duct ligation (2 weeks),
extensive bile duct proliferation occurred, with portal inflammation
and fibrosis. The cells surrounding the proliferating bile ductules
were immunoreactive for 8ß1, and the bile duct epithelium remained
negative for 8ß1 (Figure 5, B and E)
. The increased 8ß1
immunoreactivity was limited to areas of ductal proliferation and
perisinusoidal cells; 8ß1 was not seen within the parenchyma. The
pattern of expression of 8ß1 is identical to that observed with
stellate cells after bile duct ligation.8
After
CCl4 administration (4 weeks), extensive bridging
fibrosis was present between portal areas of the lobule. Cells within
the fibrotic bands of tissue were immunoreactive for 8ß1 (Figure 5, C and F)
, an expression pattern identical to that of stellate cells
after CCl4 administration.8
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8ß1 by activated stellate cells, we
immunoprecipitated lysates from immortalized activated rat stellate
cells (HSC T6 cells) with the anti-8 antibody. HSC T6 maintains the
phenotype of activated stellate cells, including gel contraction, and
-smooth muscle actin expression. Although transfection with SV40 T
antigen may alter some patterns of gene expression compared to primary
cells, its phenotype is faithful to primary activated stellate cells in
all major parameters studied to date. Immunoprecipitation of
biotinylated cell lysates revealed two bands corresponding to the
and ß subunits (Figure 6)
. In contrast,
8ß1 was not detected in endothelial cells, Kupffer cells, or
hepatocytes derived from normal or fibrotic livers (data not shown).
Thus immunohistochemistry and immunoprecipitation suggest that
activated hepatic stellate cells are the primary source of 8ß1.
Given the increasing recognition that stellate cells represent a
heterogeneous population in liver,20,21
these data do not
exclude the possibility that only a subset of this cell type expresses
8ß1 in vivo.
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8ß1 by electron microscopy. The cell surface
localization is consistent with its role as a cell adhesion molecule.
The ultrastructural localization concentration at tips of cell
protrusion is suggestive of a role of 8ß1 in the migration or
adhesion of CICs and/or matrix remodeling. During pulmonary fibrosis,
there is increased immunoreactivity of 8ß1. Although we cannot
determine whether increased 8ß1 expression represents an increased
number of 8-positive cells or increased cellular expression per
cell, the pattern is consistent with expression by the proliferating
population of interstitial cells. It is likely that increased 8ß1
expression facilitates interaction of cells with the provisional matrix
laid down after injury and mediates cell matrix signal transduction
important in the development of fibrosis By providing an essential link between the cell and the extracellular matrix, integrins play a pivotal role in the fibrotic response to injury. Interaction of integrins with ECM ligands results in intracellular signal transduction and modification of cell behavior. Many of these behaviors, such as migration, contractility, ECM production and degradation,22 cell survival, and proliferation,23 contribute to the development of fibrosis. Thus information on the expression of integrins that mediate these behaviors may help us understand the mechanisms involved during the development of fibrosis.
8ß1 is in a unique position to relay specific signals to
myofibroblast-like or smooth muscle cells. Much of the focus in the
lung has been on the expression of the classic fibronectin receptor
5ß1. 5ß1 is expressed in a variety of cell types found in the
lung after injury, such as macrophages, lymphocytes, neutrophils,
endothelial cells, and epithelial cells, in addition to
fibroblasts,24,25
whereas 8ß1 expression is limited
to interstitial fibroblasts and smooth muscle cells.14
Therefore, the binding of 8ß1 to its ligands, such as fibronectin,
vitronectin, or tenascin, may transduce specific signals to activated
myofibroblasts that are important in the generation of fibrosis.
Fibronectin, a ligand for 8ß1, has been extensively characterized
in the context of pulmonary and hepatic fibrosis. Increased fibronectin
synthesis and deposition is an important early event following lung
injury.26
In addition, increased capillary permeability is
seen with lung injury, which results in the exudation of plasma
components such as fibronectin into air spaces. Fibronectin is a
proliferative and haptotactic signal for fibroblasts27,28
and leads to migration of fibroblasts to abnormal locations, such as
air spaces, where they deposit ECM proteins and contribute to
obliteration of normal lung architecture. Fibronectin staining is
concentrated along the slender processes of fibroblasts during
pulmonary fibrosis,29
in a distribution similar to that of
8ß1 staining. In the liver, EDA fibronectin is synthesized within
24 hours after injury by endothelial cells. Interaction of EDA
fibronectin with stellate cells leads to their synthesis of smooth
muscle proteins, extracellular matrix proteins (including fibronectin),
and stellate cell activation.30
Migration of fibroblasts
over a provisional matrix in early wound healing is mediated in part by
integrins.31
We have shown that 8ß1 mediates the
migration of cells on fibronectin and therefore may have a role in the
migration of fibroblasts over a fibronectin gradient after injury
(unpublished data).
Our data also suggest that 8ß1 may contribute to the organ
contraction by fibroblasts, through interaction with increased
fibronectin deposited in the provisional wound matrix. Contractility of
activated myofibroblasts leads to tissue distortion and dysfunction in
both lung and liver. Because CICs in lung and stellate cells in liver
are both important mediators of contraction during fibrosis,
information about the receptors mediating this activity is essential.
For example, the collagen-binding integrins 1ß1 and 2ß1
mediate contraction of collagen gels and play a role in the development
of disease in liver.32
Fibronectin contributes to fibrin
clot retraction through the integrin 5ß1.33
Other
fibronectin receptors, such as 8ß1, may also contribute to the
contractile response by interacting with components of the provisional
wound matrix during injury and facilitate retraction.
Examination of the fibrotic response to pulmonary injury has broad
relevance to other tissues, particularly liver. Much like CICs in lung,
we show that 8ß1 expression by stellate cells is increased during
hepatic fibrosis. Nonetheless, there are several differences between
the two cell types. Although 8ß1 expression increases in both
pulmonary and hepatic fibrosis, 8ß1 is expressed in resting CICs
in the lung but is not expressed in stellate cells in the normal liver.
In the normal adult liver, stellate cells contain intracellular
droplets of retinoids (once thought to be lipids; hence the former
nomenclature "lipocytes"). After injury, retinoid droplets are
lost. In the developing lung, a similar population of lipid-containing
interstitial cells (LICs) exists.34
However, with lung
maturation, LICs lose the lipid droplets and become CICs.
Interestingly, another difference between CICs and stellate cells is
that CICs express contractile microfilaments at rest, whereas stellate
cells only express contractile microfilaments after
injury.35
The data collectively support the notion that
there is significant heterogeneity among connective tissue cells in
normal and fibrotic tissues. Heterogeneity of cells of fibroblast
lineage in the liver is an important, emerging concept.20
In addition to desmin-positive and desmin-negative stellate cells, a
recent report suggests that a subpopulation of liver myofibroblasts,
distinct from retinoid-containing stellate cells, exists in the liver
and may have a role in the development of fibrosis.21
The
expression of 8ß1 may help define a subpopulation of
myofibroblast-like cells in the liver that may be important in the
development of fibrosis.
The transition of myofibroblast-like cells to an activated, smooth
muscle-like phenotype is a characteristic response to injury of many
other organs. After lung injury, activated CICs (ie, -smooth muscle
actin-expressing cells) express 8ß1. Likewise, during experimental
glomerulonephritis, mesangial cells in the kidney proliferate and
express -smooth muscle actin.36
It is of interest that
mesangial cells express 8ß1 in normal kidney.14
Whether 8ß1 is involved in the transition of fibroblasts to an
activated phenotype remains to be tested.
In summary, we have shown that the integrin 8ß1 is expressed in
alveolar CICs by electron microscopy and is predominately expressed
along the filopodia and thinned extensions of the interstitial cells.
We have shown that fibroblasts isolated from lung express 8ß1 by
Western blot and that 8ß1 localizes to focal contacts by
immunofluorescence. Furthermore, expression of 8ß1 is increased
after the development of pulmonary and hepatic fibrosis and colocalized
with -smooth actin expression. Our data support a potential role for
the integrin 8ß1 in pulmonary fibroblast response after injury.
Moreover, parallel expression patterns of 8ß1 after liver injury
point to a broader role for this integrin in organizing ECM during
wound healing. Expression of 8ß1 by interstitial cells may be
important for signals generated through interaction with extracellular
matrix proteins secreted after injury, such as fibronectin. Further
studies examining the mechanisms by which 8ß1 contributes to
tissue injury and repair are under way.
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Acknowledgements |
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Footnotes |
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Supported by AHA-Heritage Affiliate Grant-in-Aid (L. M. S.) and NIH HL18974 (T. A. M.).
Accepted for publication February 16, 2000.
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 G. Thibault, M.-J. Lacombe, L. M. Schnapp, A. Lacasse, F. Bouzeghrane, and G. Lapalme Upregulation of alpha 8beta 1-integrin in cardiac fibroblast by angiotensin II and transforming growth factor-beta 1 Am J Physiol Cell Physiol, November 1, 2001; 281(5): C1457 - C1467. [Abstract] [Full Text] [PDF]
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 G. Thibault, P. Tardif, and G. Lapalme Comparative Specificity of Platelet {alpha}IIb{beta}3 Integrin Antagonists J. Pharmacol. Exp. Ther., March 1, 2001; 296(3): 690 - 696. [Abstract] [Full Text]
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