close

Вход

Забыли?

вход по аккаунту

?

Extravascular fibrin formation and dissolution in synovial tissue of patients with osteoarthritis and rheumatoid arthritis.

код для вставкиСкачать
996
EXTRAVASCULAR FIBRIN FORMATION AND
DISSOLUTION IN SYNOVIAL TISSUE O F
PATIENTS WITH OSTEOARTHRITIS AND
RHEUMATOID ARTHRITIS
J. BRICE WEINBERG, ANNE M. M. PIPPEN, and CHARLES S. GREENBERG
Fibrin deposition is a prominent finding in the
synovium of patients with rheumatoid arthritis (RA).
Macrophages are found in increased numbers in RA
synovium, and these cells are known to produce a
variety of procoagulant and anticoagulant molecules.
Using immunohistologic techniques, the content and
distribution of several important components of the
coagulation system in the synovium of patients with RA,
osteoarthritis (OA), or traumatic joint abnormalities
requiring surgery were investigated. Samples from 3
patients from each category were examined in detail.
RA synovium (compared with that of patients with OA
or joint trauma) had increased numbers of macrophages
and increased expressionlcontent of fibrinogen, tissue
factor, factor XIII, tissue transglutaminase, crosslinked fibrin (fibrin D dimer), urokinase-type plasminogen activator, and cu,-plasmin inhibitor. Macrophage
content in RA synovium was increased in both the lining
cell areas and the interstitial cell areas. Fibrinogen was
distributed throughout the tissue in all samples and was
greater in RA synovium. In trauma and OA synovia,
tissue factor was seen only in association with vessels
(endothelial cells), but in RA synovium, it was markedly
increased throughout the tissues. While fibrin D dimer
From the Veterans Administration and Duke University
Medical Centers, Durham, North Carolina.
Supported in part by the Veterans AfFairs Research Service. the James Swiger Hematology Kesearch Fund, and NIH grants
PO1 AI-23308,1’01 32682. HI,-38245, and P50 AR-39162. Dr. Greenberg is an Established Investigator of the American Heart Association.
J. Brice Weinberg, MD; Anne M. M. Pippen, HS; Charles
S. Greenberg, MD.
Address reprint requests to J. Brice Weinberg, MD, Veterans Affairs and Duke University Medical Centers, 151G, Durham,
NC 27705.
Submitted for publication October 12, 1990: accepted in
revised form February 28, 1991.
Arthritis and Rheumatism, Vol. 34, No. 8 (August 1991)
was seen in small amounts in synovial lining cell areas of
trauma and OA synovia, it was present in increased
amounts in the lining cell and interstitial cell areas of RA
synovium. Factor XI11 and tissue transglutaminase were
present in scant amounts in trauma and OA synovia, but
there were increased amounts of both (especially tissue
transglutaminase) in RA synovium in the vessel, lining
cell, and interstitial cell areas. Urokinase and a2plasmin inhibitor were also markedly increased in RA
synovium. These results suggest that in inflamed synovium, there is ongoing extravascular tissue fibrin formation and dissolution that correlates with the degree of
inflammation and macrophage content. Extravascular
coagulationlfibrinolysis in RA represents a potential
target for therapeutic intervention in this disease.
Mononuclear phagocytes (monocytes and macrophages) are found in normal and inflamed synovial
tissue (1,2). In normal synovium, many of the cells
lining the joint space (the synovial lining cells or the
“type A” cells [I]) are of mononuclear phagocyte
origin. Rheumatoid arthritis (RA) is a systemic inflammatory disease with a synovitis characterized by synovial tissue hyperplasia, with increased numbers of
synovial lymphocytes and mononuclear phagocytes,
accompanied by variable degrees of synovial fibroblast
proliferation (2). Cartilage and bone destruction may
accompany the synovial tissue changes. Synovial macrophages, having migrated there from the blood as
monocytes ( l ) , play important roles in initiating, propagating, and maintaining the inflammation (2). Various
investigators have noted that fibrin is found in the
synovial tissue in RA (3,4). Indeed, in most types of
inflammation (especially immunologically induced inflammation such as delayed-type hypersensitivity re-
997
FIBRIN FORMATION/DISSOLUTION IN RA SYNOVIUM
Table 1. Results of immunofluorescence studies of synovial tissue from trauma patients, osteoarthritis (OA) patients, and rheumatoid arthritis
(RA) Datients*
RA patients
(sample no.)
OA patients
(sample no.)
Trauma patients
(sample no.)
33
36
86
90
I46
8
25
Elbow
Knee
Acet.
ASNIAS
1 yr.
10 yrs.
2+ LC, 2+ LC,
2 + IC
2+ IC
3+LC, 3+LC,
I + IC
I + IC
4 + EC 4 + EC
14
Knee
ASA
3 yrs.
1 + LC
5
Hip
ASA
3 yrs.
1 + LC
I + LC
t LC
t LC
I + LC
1 + LC
0
2+ IC
3+ EC
3+ EC
I + EC
Factor XIII
I+ 1c
I + IC
2+ IC
2+ LC
2+ LC
Tissue plasminogen
activator
Urokinase plasminogen
activator
I + EC
0
0
I + EC
1 + EC
I + LC,
1 + IC
0
14
Hand (PIP)
NSAID/MTX
5 yrs.
3+ LC,
3+ 1 c
4+ LC,
4+ 1 c
4 + EC,
4 + IC,
4+ LC
3+ LC,
3+ IC
4+ EC,
4+ IC,
4+ LC
2+ LC,
2+ IC
I + EC
13
Knee
PredJMTX
>20 yrs.
2+ LC,
2+ IC
4 + LC,
4 + IC
4+ EC,
4 + IC,
4+ LC
4+ LC
0
0
0
0
0
I + EC
1+ IC,
3+ EC
0
0
2+ IC
2
0
1 + LC,
1+ EC
15
Knee
ASA/NSAID
>I0 yrs.
3+ LC,
3+ IC
4 + LC,
3+ IC
4 + EC,
4 + IC,
4+ LC
2+ LC,
2+ IC
4 + EC,
4+ IC,
4+ LC
3 + LC,
3+ IC
I + IC,
f EC
4 + EC,
4 + IC,
4+ LC
3+ LC,
3+ IC
3+
3+
3+
3+
3+
4+
4+
4+
2+
161
178
Tissue factor
1
Hand (PIP)
Acet.
20 yrs.
I + LC,
I + 1c
I + LC,
I + IC
3+ EC
11
Shouldei
None
< 1 mo.
1 + LC,
I + IC
1 + LC,
1 + IC
1 + LC
Fibrin D dimer
t LC
Tissue transglutaminase
Inflammation score
Joint assessed
Treatment
Disease duration
CD14 (Leu-M3)
Fibrinogen
cu,-plasmin inhibitor
212
20
LC:
t IC
I + LC, 4 + LC,
3 + IC
I + 1c
1 + EC 3+ EC,
1 + IC
EC,
IC,
LC
LC,
IC
4 + EC,
4+ IC,
4+ LC
4+ LC,
4 + IC
t EC
EC,
IC,
LC
IC
* The inflammation scores, based on immunohistologic examination, were derived as described elsewhere (27,28). Other scores were based on
immunofluorescence intensity, using a scale of W + ,where 0 = negative and 4+ = greatest intensity. PIP = proximal interphalangeal; Acet.
= acetaminophen; ASA = acetylsalicylic acid; IAS = intraarticular steroid; NSAID = nonsteroidal antiinflammatory drug; MTX =
methotrexate; Pred. = prednisone; LC = lining cells; 1C = interstitial cells; EC = endothelial cells.
actions), extravascular fibrin formation is prominent
( 3 3 ) . Coagulation is apparently initiated by tissue
factor (TF; thromboplastin) that is expressed on macrophages, endothelial cells, and/or fibroblasts (6,7),
resulting in activation of the extrinsic pathway of
coagulation with eventual formation of fibrin from
fibrinogen. Fibrin can be cross-linked by transglutaminases (factor XI11 or tissue transglutaminase [TTG])
to form a relatively stable, insoluble meshwork of
covalently cross-linked fibrin (8), and the fibrin can be
further modified by attachment of various components
of the biomatrix and/or by degradation by plasmin
(9-11). Products of the coagulation reactions act to
amplify the inflammatory reaction by attracting more
inflammatory cells to the site through the chemotactic
activities of thrombin (12) and fibrin(ogen) degradation
products (13). Also, the extravascular fibrin meshwork
serves as a provisional matrix onto which inflammatory and endothelial cells can adhere and migrate (5).
In addition to other numerous different functions, macrophages are known to elaborate/express
several different enzymedfactors involved in the formation and dissolution of fibrin. Included are TF
(7,14), prothrombinase (15), factor XI11 (16), TTG
(16), and plasminogen activators (urokinase [uPA])
(17). The purpose of this study was to determine (using
immunohistologic techniques) the presence and distribution of several different procoagulant and anticoagulant molecules in tissues from patients who had
trauma necessitating joint surgery, and from patients
with severe osteoarthritis (OA) and RA requiring joint
surgery. The results demonstrate that RA synovium
has increased numbers of macrophages and increased
expression/content of fibrinogen, TF, factor XIII,
TTG, cross-linked fibrin (fibrin D dimer), uPA, and
a,-plasmin inhibitor (a2-PI).
MATERIALS AND METHODS
Specimens of sterile human synovial tissue were
obtained from the Duke University Department of Pathology
as “discarded material.” The subjects were those requiring
WEINBERG ET AL
998
joint surgery/resection for recent severe trauma or severe
RA or OA. RA and OA were diagnosed by standard criteria
(18). The patients’ records were reviewed to determine
disease duration, medications, and a clinical estimate of
disease activity at the time of the surgery. All OA and RA
patients had advanced disease. Although the “trauma”
samples approximated normal samples most closely, we did
not consider them actually normal because of tissue damage,
hemarthrosis, etc. Synovial samples (-5 X 5 X 5 mm) were
frozen rapidly in liquid nitrogen. Serial, 4 mm-thick, frozen
sections were made and analyzed after staining with hematoxylin and eosin (H & E) and by indirect immunofluorescence techniques after staining as described previously (19).
After H & E staining, synovial tissue samples were scored
(in a blinded manner) for the degree of inflammation as
described elsewhere (20).
For immunofluorescence studies, the following primary antibodies were used: Leu-M3 (mouse monoclonal
anti-CD14, macrophage) (21), rabbit anti-human fibrinogen
(Dakopatts, Copenhagen, Denmark), mouse monoclonal
Al-3 (anti-human brain TF) (22), rabbit anti-human factor
XI11 a chain (Calbiochem, La Jolla, CA) (16), mouse monoclonal anti-guinea pig TTG (23), DD386/22 (mouse monoclonal anti-human fibrin D-dimer) (24), rabbit anti-human uPA
and rabbit anti-human tissue PA (tPA; from Dr. H . Berger,
Jr., Burroughs Wellcome, Research Triangle Park, NC) (25),
and rabbit anti-human a,-PI (American Diagnostica, New
York, NY) (26). Secondary antibodies were fluorescein
isothiocyanate (F1TC)-conjugated goat anti-mouse immunoglobulin and FITC-conjugated goat anti-rabbit immunoglobulin (Tago, Burlingame, CA). Anti-fibrinogen reacts with
both fibrinogen and fibrin. Otherwise, the primary antibodies
are specific for the designated antigens, as determined by
immunoblots and/or immunoprecipitations detailed elsewhere (21-26).
The tissues were examined with the use of a Zeiss
microscope using epifluorescence and phase-contrast optics.
Controls, in which supernatant from mouse myeloma P3
cells or normal rabbit serum was used as primary “antibody” (instead of the primary antibodies designated above),
showed no reactivity with the appropriate secondary
antibody.
RESULTS
Macrophages, as determined by CD14 expression (21), were present in low numbers scattered in the
interstitium and in the lining cell areas of synovium
from trauma and OA patients (Table 1). As others have
noted from immunohistologic studies (27) and as we
have seen from our studies quantitating macrophages
in enzymatically dissociated synovial tissues (28), RA
synovium had more lining cell and interstitial area
macrophages than did trauma or OA synovium. Fibrinogen was distributed throughout the synovial tissue in all of the samples we examined, being most
prominent in the areas lining the synovial space. There
was more fibrinogen apparent in the tissues from RA
patients, with increased staining in the interstitial
areas.
Tissue factor, or tissue thromboplastin, was
seen primarily in association with vessels (especially
with or near endothelial cells) in trauma and OA
synovium. In synovium from RA patients, there was a
marked increase in TF in all areas of the tissue
(vessels, interstitiurn, and lining cell areas) (Figure
1A). When the tissues were examined with antibody
DD386/22, an antibody that recognizes fibrin D dimer
(a product of fibrin that has been cross-linked by a
transglutaminase [TTG or factor XIII], and then partially degraded by plasmin [24]), tissue from trauma
and OA patients had very little positivity. The only
positive cells were in the synovial lining cell areas
(Figure 1B). However, the RA synovial tissues expressed much more fibrin D dimer in the synovial
lining areas, as well as in the interstitium (Figure 1B).
The enzymes capable of cross-linking fibrin are
TTG and factor XI11 (8,16). Factor XI11 is produced by
megakaryocytes (platelets) and mononuclear phagocytes, while TTG is produced by endothelial cells and
mononuclear phagocytes (8,16). TTG was not seen or
was seen only in very low amounts in synovium from
trauma patients (Figure 2A). In OA patient synovium,
TTG was present in very low amounts, being limited
primarily to vessels (mainly endothelial cells), but in
RA synovium, TTG expression was dramatically increased in the tissues (vessels, lining cell areas, and
interstitial areas) (Figure 2A). Factor XIII was noted
in low amounts scattered in the synovial interstitium of
trauma patients (Figure 2B). In OA synovium, there
was slightly more factor XIII, primarily in the synovial
lining cell areas, but in RA synovium, the amount was
markedly increased and present in vessels, lining cell
areas, and in the interstitium (Figure 2B).
Once fibrin is formed, it can be degraded by
plasmin. Plasmin is formed by the action of plasminogen activator on the proenzyme plasminogen (1 1).
Urokinase-type plasminogen activator is found primarily in mononuclear phagocytes (11,17), while tissuetype plasminogen activator is found primarily in endothelial cells (1 1). By immunofluorescence, tPA was not
seen or was seen only in small amounts in the endothelial cell areas of tissue from patients with trauma,
OA, and RA (Table 1). Urokinase-type PA was not
seen in synovium from trauma patients, but it was
present in synovium from OA patients, primarily in the
synovial lining cell areas (macrophage areas) (Figure
3A). In synovium from RA patients, the amount of
uPA was dramatically increased, being seen in vessels,
FIBRIN FORMATION/DISSOLUTION IN RA SYNOVIUM
999
A
B
Figure 1. Expression of A, tissue factor and B, fibrin D-dimer in synovial tissue from trauma (“normal”) patients, osteoarthritis (OA) patients,
and rheumatoid arthritis (RA) patients, by phase-contrast microscopy (top panels) and fluorescence microscopy (bottom panels). In tissue from
trauma and OA patients, tissue factor is seen primarily in the vessels (endothelial cells), but in the synovium from the RA patient, tissue factor
is increased and is seen in essentially all areas. Fibrin D-dimer is seen in small amounts and is limited to the lining cell areas of synovium from
trauma and OA patients, but in synovium from the RA patient, there is increased content of fibrin D-dimer, and it is present in the interstitial
cell area as well as the lining cell area. (Magnification x 400.)
WEINBERG ET AL
1000
A
B
Figure 2. Expression of A, tissue transglutaminase and B, factor XI11 in synovial tissue from trauma (“normal”) patients, osteoarthritis (OA)
patients, and rheumatoid arthritis (RA) patients, by phase-contrast microscopy (top panels) and fluorescence microscopy (bottom panels).
Tissue transglutaminase is present only in scant amounts in tissue from trauma and OA patients, being limited primarily to the vessel areas,
but in RA synovium, there is an increased amount, which is distributed throughout the tissue. Factor XI11 is present in increased amounts and
spread diffusely throughout the RA synovium. (Magnification x 400.)
FIBRIN FORMATION/DISSOLUTION IN RA SYNOVIUM
1001
Figure 3. Expression of plasminogen activator (urokinase) in synovial tissue from trauma (“normal”) patients, osteoarthritis (OA)
patients, and rheumatoid arthritis (RA) patients, by phase-contrast microscopy (top panel) and fluorescence microscopy (bottom
panel). Urokinase is present in small amounts in synovia from trauma and OA patients, being seen primarily in the lining cell areas.
However, in RA synovium, there is an increased amount, which is distributed throughout the tissue. (Magnification x 400.)
as well as in the lining cell and interstitial areas (Figure
3). The primary inhibitor of plasmin is a2-PI (29).
There was no (or very little) a,-PI in trauma or OA
tissue, but it was increased in RA synovium, being
distributed generally throughout the synovium. Table
1 displays the immunofluorescence, histologic, and
inflammation scores, and clinical data.
Thus, in summary, synovial tissues from RA
patients have increased numbers of macrophages,
increased amounts of fibrinogen, TF, fibrin D dimer,
TTG, factor XIII, uPA, and az-PI. This suggests that
in inflamed synovium, there is ongoing extravascular
tissue fibrin formation and dissolution that correlates
with the degree of inflammation and the macrophage
content.
DISCUSSION
By interacting with B and T lymphocytes and
through their secretion of numerous substances that
affect the function of other cells, mononuclear phagocytes are thought to play very important roles in RA
(2,28,30). Among the important macrophage-derived
mediators are chemotactic factors (e.g., macrophage-
colony-stimulating factor [313 and interleukin-8 [32]),
complement components, growth factors (macrophage
[platelet]-derived growth factor, interleukin- 1, tumor
necrosis factor [TNF], T cell growth factor p), angiogenesis factors, arachidonic acid metabolites, reactive
oxygen species, and various hydrolases and proteinases (including collagenases) (30). In addition to this
array of important mediators, macrophages also produce various factors that can modulate the overall
clotting process (the formation and dissolution of
fibrin). Monocytes and/or macrophages have been
shown to produce TF (14), factor VII (33), factor V
(34), a prothrombinase complex (15), factor XIII (16),
TTG (16), uPA (17), and a,-macroglobulin (35). Also,
other cells in the synovium (fibroblasts and endothelial
cells) can produce TF, TTG, and plasminogen activators. Because of the increased vascular permeability in
the inflamed tissue, there are high tissue levels of
various plasma proteins in synovial tissues.
Increased levels of fibrin and fibrin-like materials are present in synovial fluid and synovial tissue of
RA patients (3,4). The “rice bodies” seen in RA
synovial fluid are composed of fibrin (3). Anderson and
Gormsen noted that the fibrin found in RA synovium
WEINBERG ET AL
was insoluble in urea, signifying that it had probably
been chemically cross-linked by a transglutaminase
(36). Different investigators have shown that synovial
tissues from arthritis patients have fibrinolytic activities (37), and that synovial macrophages and fibroblasts
display plasminogen activator/plasmin activity (38).
Extravascular coagulation is a prominent feature in immunologically induced inflammation (e.g.,
delayed-type hypersensitivity reactions, Arthus reactions, and experimental glomerulonephritides), in
wound healing, and in tumors (5,39). In these conditions, a variety of factors may be operative in causing
the fibrin formation. In tumors, the neoplastic cells can
supply procoagulant factors (most prominently T F
[39,40]), while in immunologically induced inflammation and in healing wounds, macrophages, fibroblasts,
and/or endothelial cells may supply procoagulants (5).
Products of the coagulation reactions can amplify the
inflammation-thrombin and fibrin(ogen) degradation
products are chemotactic and may modify the function
of inflammatory cells (5,12,13), transglutaminases may
chemically cross-link bioactive molecules (e.g., a,-PI
or fibronectin [9,11]) to biomatrix, and plasmin may
modify the biomatrix and activate proteinases, including collagenase (41). Furthermore, fibrin contributes to
the mass (swelling) of the inflammatory tissue, and
serves as an important part of the provisional matrix
onto which fibroblasts and inflammatory cells attach
and migrate (5,39).
Our work definitively demonstrates that inflammatory synovium from humans with RA has much
fibrin accumulation. This could result from increased
formation and/or decreased dissolution. Tissue factor
in the trauma and OA tissues was seen in small
amounts, being restricted primarily to the endothelial
cell areas, but in RA tissues, it was dramatically
increased, being seen in all areas. Because of the
distribution of T F in the RA synovia, it appears that
T F is increased in macrophages, fibroblasts, and endothelial cells. Others have noted that TF is usually
not expressed in normal endothelial cells (42,43),
except for small amounts in placental vessels (44). We
did see TF in endothelial cells in the synovial samples
from trauma patients, as well as in those from OA and
RA patients. It should be noted, however, that these
trauma patients could not be considered actually normal because of various degrees of tissue damage and
hemarthrosis in these subjects. It has been found that
RA synovial fluid and synovium contain increased
amounts of T N F (45); this may be important in ex-
plaining the increased levels that we demonstrate,
since T N F can increase T F expression in endothelial
cells and in mononuclear phagocytes (46,47).
Previous immunohistologic studies of RA synovium characterizing fibrin have not used antibodies
that could clearly distinguish between fibrinogen and
fibrin (4), but the antibody against fibrin D dimer
demonstrates well that true fibrin is being formed in
the synovial tissue, is being cross-linked, and is being
acted upon (to a limited degree) by plasmin (24). The
RA tissues contained high levels of fibrin D dimer, as
compared with trauma and OA tissues. Remarkably,
the transglutaminases TTG and factor XI11 were also
increased in the RA tissues, providing the ability to
cross-link the fibrin. We have noted before that tissue
macrophages have more transglutaminase activity
than do blood monocytes, and that blood monocytes,
after in vitro “differentiation,” have more transglutaminase activity (16). The finding of increased levels
of TTG and factor XI11 in the RA synovial tissues may
reflect the degree of cellular “differentiation” that has
taken place in the RA synovial tissue.
While tPA levels were not appreciably different
in the synovia of trauma, OA, and RA patients, uPA
was dramatically increased in all areas of the RA
synovial tissue. This finding of increased plasminogen
activator activity in RA tissues correlates with that
noted previously by other investigators (37,38). Cytokines (most notably, interferon- y [48]) have been
shown to increase plasminogen activator levels in
blood monocytes. Interferon-y (protein or messenger
RNA) has been noted to be increased in RA synovial
fluid and synovium (30,49). Other cytokines in the fluid
(e.g., the colony-stimulating factors [SO]) may also
play a role in controlling the expression of plasminogen activator. The significance of the rather selective
increase in uPA compared with levels of TPA is not
known.
The enzymes of the coagulation and fibrinolytic
pathways are regulated by several proteinase inhibitors. Alpha,-macroglobulin, a high molecular weight
proteinase inhibitor of broad specificity, has been
noted in RA synovial fluid and synovial tissue (51,52).
Studies from our laboratory confirm increased levels
in RA synovium (Hoffman M, Weinberg J: unpublished observations). Likewise, we show here that
a,-PI, the most potent plasmin inhibitor (29), is increased in RA synovium. Thus, we have demonstrated
that in the inflamed synovial tissue of RA patients,
there is evidence of increased expression of procoag-
FIBRIN FORMATION/DISSOLUTION IN RA SYNOVIUM
ulant molecules (fibrinogen, TF, TTG, and factor
XIII), increased cross-linked and plasmin-modified
fibrin (fibrin D dimer), and increased anticoagulant
molecules (uPA and q-PI). The remarkable coagulation/anticoagulation, fibrin formatioddegradation activity noted in RA synovium likely contributes to the
local pathology and, through the actions of various
generated enzymes, lymphokines, monokines, and fibrin
degradatory products, perpetuates the inflammation.
This extravascular coagulation/fibrinolysis in
RA represents a target for therapeutic intervention. It
has been noted that anticoagulant therapy can modify
immunologically mediated inflammation in experimental animals and in humans. Warfarin and heparin
anticoagulant treatments have been shown to diminish
delayed-type hypersensitivity reactions ( 3,5) and experimental nephritis in animals (53,54). Defibrination
with the snake venom enzyme ancrod has been noted
to diminish the degree of experimental nephritis in
animals ( 5 3 , systemic lupus erythematosus in animals
(56), and glomerulonephritis in humans (57), disorders
characterized by prominent extravascular fibrin deposition. Belch et a1 noted that the androgen stanolozol
improved the inflammation in RA, and that this reduction of inflammation was accompanied by an increase
in the plasma fibrinolytic activity (58). It is possible
that agents capable of decreasing extravascular fibrin
formation and dissolution might be useful in ameliorating or diminishing the synovitis in RA.
ACKNOWLEDGMENT
We thank Dr. Frederick Rickles for the anti-tissue
factor antibody A1-3.
REFERENCES
Edwards JCW, Sedgwick AD, Willoughby DA: Membrane properties and esterase activity of synovial lining
cells: further evidence for a mononuclear phagocyte
subpopulation. Ann Rheum Dis 41 :282-286, 1982
Krane SM, Simon LS: Rheumatoid arthritis: clinical
features and pathogenic mechanisms. Med Clin North
Am 70:263-284, 1986
Jasani MK: Fibrin: metabolism, immunopathogenesis
and significance in rheumatoid arthritis, Immunopathogenesis of Rheumatoid Arthritis. Edited by GS Panayi,
PM Johnson. Surrey, UK, Reedbooks, Ltd., 1978
Clemmensen I, Hglund B, Andersen RB: Fibrin and
fibronectin in rheumatoid synovial membrane and rheumatoid synovial fluid. Arthritis Rheum 26:479485, 1983
1003
5. Colvin RB: Wound healing processes in hemostasis and
thrombosis, Vascular Endothelium in Hemostasis and
Thrombosis. Edited by MA Gimbrone Jr. New York,
Churchill Livingstone, 1986
6. Bach R: Initiation of coagulation by tissue factor. CRC
Crit Rev Biochem 23:339-368, 1988
7. Edwards RL, Ewan VA, Rickles FR: Macrophage procoagulants, fibrin deposition, and the inflammatory response, The Reticuloendothelial System, Vol. 9. Edited
by SM Phillips, MR Escobar. New York, Plenum Press,
1986
8. Lorand L, Conrad SM: Transglutaminases. Mol Cell
Biochem 58:9-35, 1984
9. Sakata J, Aoki N: Cross-linking of alpha 2-plasmin
inhibitor to fibrin by fibrin-stabilizing factor. J Clin
Invest 65:29&297, 1980
10. Mosher DF, Schad PE, Kleinman HK: Cross-linking of
fibronectin to collagen by blood coagulation factor XIIIa. J Clin Invest 64:781-787, 1979
11. Lijnen HR, Collen D: Interaction of plasminogen activators and inhibitors with plasminogen and fibrin. Semin
Thromb Hemost 8:2-10, 1982
12. Bar-Shavit R, Kahn A, Wilner GD: Monocyte chemotaxis: stimulation by specific exosite region in thrombin.
Science 220:728-73 1, 1983
13. Richardson DL, Pepper DS, Kay AB: Chemotaxis for
human monocytes by fibrinogen-derived peptides. Br J
Haematol 32507-513, 1976
14. Edwards RL, Rickles FR: Macrophage procoagulants.
Prog Hemost Thromb 7: 183-209, 1984
15. Lindahl U, Pejler G, Bggwald A, Seljelid R: A prothrombinase complex of mouse peritoneal macrophages.
Arch Biochem Biophys 273:18&188, 1989
16. Conkling PR, Achyuthan KE, Greenberg CS, Newcomb
TF, Weinberg JB: Human mononuclear phagocyte
transglutaminase activity cross-links fibrin. Thromb Res
5557-68, 1989
17. Vassalli J-D, Dayer J-M, Wohlwend A, Belin D: Concomitant secretion of prourokinase and of a plasminogen
activator-specific inhibitor by cultured human monocytes-macrophages. J Exp Med 159:1653-1668, 1984
18. Ropes MW, Bennett GA, Cobb S, Jacox R, Jessar RA:
19.58 revision of diagnostic criteria for rheumatoid arthritis. Bull Rheum Dis 9:175-176, 1958
19. Hale LP, Martin ME, McCollum DE, Nunley JA,
Springer TA, Singer KH, Haynes BF: Immunohistologic
analysis of the distribution of cell adhesion molecules
within the inflammatory synovial microenvironment.
Arthritis Rheum 32:22-30, 1989
20. McCachren SS, Haynes BF, Niedel JE: Localization of
collagenase in mRNA in rheumatoid arthritis synovium
by in situ hybridization histochemistry. J Clin Immunol
10: 19-27, 1990
21. Dimitriu-Bona A, Burmester R, Waters SJ, Winchester
WEINBERG ET AL
1004
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
RJ: Human mononuclear phagocyte differentiation antigens. J Immunol 130:145-152, 1983
Ewan VA, Cieplinski W, Hancock WW, Boyd AW,
Godschneider IG, Rickles FR: Production and characterization of a monoclonal antibody (Al-3) that binds
selectively to activated monocytes and inhibits monocyte procoagulant activity. J Immunol 136:2416-2420,
1986
Birchbichler PJ, Upchurch HF, Patterson MK, Conway
E: A monoclonal antibody to cellular transglutaminase.
Hybridoma 4: 179-186, 1984
Rylatt DB, Blake AS, Cottis LE, Massingham DA,
Fletcher WA, Masci PP, Whitaker AN, Elms M, Bunce
I, Webber AJ, Wyatt D, Bundesen PG: An immunoassay for human D dimer using monoclonal antibodies.
Thromb Res 31:767-768, 1983
Berger H Jr, Tuttle PR: Comparative properties of six
human plasminogen activators. Prog Fibrinolysis 6:2935, 1982
Hattey E, Wojta J, Binder BR: Monoclonal antibodies
against plasminogen and alpha-2-antiplasmin: binding to
native and modified antigens. Thromb Res 45:485495,
1987
Burmester GR, Dimitriu-Bona A, Waters SJ, Winchester RJ: Identification of three major synovial lining cell
populations by monoclonal antibodies directed to Ia
antigens and antigens associated with monocytesl
macrophages and fibroblasts. Scand J Immunol 17:6982, 1983
Weinberg JB, Wortham TS, Patton KL, Chitneni SR:
Synovial mononuclear phagocytes in rheumatoid arthritis and osteoarthritis: quantitative and functional aspects. Submitted for publication
Lijnen HR, Collen D: Alpha-2 antiplasmin. J Med 16:
225-284, 1985
Lipsky PE, Davis LS, Cush JJ, Oppenheimer-Marks N:
The role of cytokines in the pathogenesis of rheumatoid
arthritis. Springer Semin Immunopathol 11:123-162,
1989
Wang JM, Griffin JD, Rambaldi A, Chen ZG, Mantovani
A: Induction of monocyte migration by recombinant
macrophage colony-stimulating factor. J Immunol 141:
575-579, 1988
Matsushima K , Oppenheim JJ: Interleukin 8 and
MCAF: novel inflammatory cytokines inducible by IL- 1
and TNF. Cytokine 1:2-13, 1989
Van Dam-Mieras MCE, Muller AD, van Deijk WA,
Hemker HC: Clotting factors secreted by monocytes
and macrophages: analytical considerations. Thromb
Res 37:9-19, 1985
Rothberger H, McGee MP: Generation of coagulation
factor V activity by cultured rabbit alveolar macrophages. J Exp Med 160:1880-1890, 1984
Hovi T, Moshe D, Vaheri A: Cultured human mono-
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
cytes synthesize and secrete a2-macroglobulin. J Exp
Med 145:1580-1589, 1977
Anderson B, Gormsen J: Fibrinolytic and fibrin stabilizing activity of synovial membranes. Ann Rheum Dis
29:287-293, 1970
Van de Putte LBA, Hegt VN, Overbeek TE: Activators
and inhibitors of fibrinolysis in rheumatoid and nonrheumatoid synovial membranes: a histochemical study.
Arthritis Rheum 20:671-677, 1977
Medcalf RL, Hamilton JA: Human synovial fibroblasts
produce urokinase-type plasminogen activator. Arthritis
Rheum 29:1397-1401, 1986
Dvorak HF: Tumors: wounds that do not heal. N Engl J
Med 315:165&1659, 1986
Rickles FR, Edwards RL: Activation of blood coagulation in cancer: Trousseau's syndrome revisited. Blood
62:1&31, 1983
Werb Z, Mainardi CL, Vater CA, Harris ED Jr: Endogenous activation of latent collagenase by rheumatoid
synovial cells: evidence for a role of plasminogen activator. N Engl J Med 296:1017-1023, 1977
Drake TA, Morrissey JH, Edgington TS: Selective
expression of tissue factor in human tissues: implications for disorders of hemostasis and thrombosis. Am J
Pathol 134:1087-1097, 1989
Wilcox JN, Smith KM, Schwartz SM, Gordon D: Localization of tissue factor in the normal vessel wall and
in the atherosclerotic plaque. Proc Natl Acad Sci USA
86:2839-2843, 1989
Faulk WP, Labarrere CA, Carson SD: Tissue factor:
identification and characterization of cell types in human
placentae. Blood 76:86-96, 1990
Husby G, Williams RC Jr: Synovial localization of
tumor necrosis factor in patients with rheumatoid arthritis. J Autoimmun 1:363-371, 1988
Bevilacqua MP, Pober JS, Majeua GR, Fiers W, Cotran
RS, Gimbrone MA: Recombinant tumor necrosis factor
induces procoagulant activity in human vascular endothelium: characterization and comparison with the actions of interleukin-1. Proc Natl Acad Sci USA 83:45334537, 1986
Conkling PR, Greenberg CS, Weinberg JB: Tumor necrosis factor induces tissue factor-like activity in human
leukemia cell line U937 and peripheral blood monocytes.
Blood 72: 128-133, 1988
Weinberg JB, Hobbs MM, Misukonis MA: Recombinant
human gamma-interferon induces human monocyte
polykaryon formation. Proc Natl Acad Sci USA 81:
4554-4557, 1984
Degre M, Mellbye 0, Clarke-Jenssen 0: Immune interferon in serum and synovial fluid in rheumatoid arthritis
and related disorders. Ann Rheum Dis 42:672-676, 1983
Xu WD, Firestein GS, Taetle R, Kaushansky K, Zvaifler
NJ: Cytokines in chronic inflammatory arthritis. 11.
Granulocyte-macrophage colony-stimulating factor in
FIBRIN FORMATION/DISSOLUTION IN RA SYNOVIUM
51.
52.
53.
54.
55.
rheumatoid synovial effusions. J Clin Invest 832376882,
1989
Borth W: Alpha 2-macroglobulin in connective tissue
matrix metabolism. Coll Relat Res 4:83-95, 1984
Borth W, Dunky A, Kleesiek K: a,-macroglobulinproteinase complexes as correlated with a,-proteinase
inhibitor-elastase in synovial fluids of rheumatoid arthritis patients. Arthritis Rheum 29:319-325, 1986
Halpern B, Milliez P, Lagrue G, Fray A, Morad JC:
Protective action of heparin in experimental immune
nephritis. Nature 205:257-259, 1965
Vassalli P, McCluskey RT: The pathogenic role of fibrin
deposition in immunologically induced glomerulonephritis. Ann N Y Acad Sci 116: 1052-1062, 1964
Naish P, Penn GB, Evans DJ, Peters DK: The effect of
1005
detibrination on nephrotoxic serum in nephritis in rabbits. Clin Sci 42:643-646, 1972
56. Cole EH, Glynn MF, Laskin CA, Sweet J , Mason N,
Levy GA: Ancrod improves survival in murine systemic
lupus erythematosus. Kidney Int 37:29-35, 1990
57. Kim S, Wadhwa NK, Kant KS, Pollak VE, GlasGreenwalt P, Weiss MA, Hong CG: Fibrinolysis in
glomerulonephritis treated with ancrod: renal functional, immunologic and histopathologic effects. Q J
Med 69: 879-905, 1988
58. Belch JJF, Madhok R, McArdls B, McLaughlin K, Kluft
C, Forbes CD, Sturrock A: The effect of increasing
fibrinolysis in patients with rheumatoid arthritis: a double blind study of stanozolol. Q J Med 58:19-27, 1986
Документ
Категория
Без категории
Просмотров
2
Размер файла
2 613 Кб
Теги
fibrin, patients, extravascular, formation, arthritis, osteoarthritis, tissue, synovial, dissolution, rheumatoid
1/--страниц
Пожаловаться на содержимое документа