Pathways of coagulation activation in situ in rheumatoid synovial tissue

Zacharski, Leo R.; Brown, Forst E.; Memoli, Vincent A.; Kisiel, Walter; Kudryk, Bohdan J.; Rousseau, Sandra M.; Hunt, Jane; Dunwiddie, Christopher T.; Nutt, Elka M.

doi:10.1016/0090-1229(92)90008-c

Cited by 52 publications

(39 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Extravascular coagulation accompanies many Th1-associated diseases, including autoimmune neuropathologies, 1-4 glomerulonephritis, 5,6 rheumatoid arthritis, [7][8][9] Crohn's disease, 10,11 and allograft rejection. 12,13 As our studies indicate that thrombin and fibrin(ogen) function to stimulate cytokine/chemokine production and macrophage adhesion in vivo, extravascular coagulation likely exacerbates Th1-associated chronic inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…The ensuing coagulation cascade culminates with the generation of thrombin, a protease that cleaves extravasated fibrinogen, prompting its polymerization and deposition as fibrin. Accordingly, localized extravascular fibrin deposition accompanies many type 1 T helper cell (Th1)-associated responses, including autoimmune neuropathologies, [1][2][3][4] glomerulonephritis, 5,6 rheumatoid arthritis, [7][8][9] Crohn's disease, 10,11 allograft rejection, 12,13 delayed-type hypersensitivity, [14][15][16][17][18][19] and viral infections. 20,21 For some time, it has been appreciated that such Th1-associated coagulation has physiologic consequences, as the swelling that accompanies delayed-type hypersensitivity responses is suppressed in anticoagulated or fibrinogen-deficient subjects.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Roles for thrombin and fibrin(ogen) in cytokine/chemokine production and macrophage adhesion in vivo

Szaba

Smiley

2002

Blood

288

224

View full text Add to dashboard Cite

Extravascular coagulation leading to fibrin deposition accompanies many immune and inflammatory responses. Although recognized by pathologists for decades, and probably pathologic under certain conditions, the physiologic functions of extravascular coagulation remain to be fully defined. This study demonstrates that thrombin can activate macrophage adhesion and prompt interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) production in vivo. Peritoneal macrophages were elicited with thioglycollate (TG) and then activated in situ, either by intraperitoneal injection of lipopolysaccharide (LPS) or by injection of antigen into mice bearing antigen-primed T cells. Others previously established that such treatments stimulate macrophage adhesion to the mesothelial lining of the peritoneal cavity. The present study demonstrates that thrombin functions in this process, as macrophage adhesion was suppressed by Refludan, a highly specific thrombin antagonist, and induced by direct peritoneal administration of purified thrombin. Although recent studies established that protease activated receptor 1 (PAR-1) mediates some of thrombin's proinflammatory activities macrophage adhesion occurred normally in PAR-1-deficient mice. However, adhesion was suppressed in fibrin(ogen)-deficient mice, suggesting that fibrin formation stimulates macrophage adhesion in vivo. This study also suggests that fibrin regulates chemokine/cytokine production in vivo, as direct injection of thrombin stimulated peritoneal accumulation of IL-6 and MCP-1 in a fibrin(ogen)-dependent manner. Given that prior studies have clearly established inflammatory roles for PAR-1, thrombin probably has pleiotropic functions during inflammation, stimulating vasodilation and mast cell degranulation via PAR-1, and activating cytokine/chemokine production and macrophage adhesion via fibrin(ogen). IntroductionVasodilation and increased vascular permeability are among the earliest signs of inflammation. These events stimulate the extravasation of inactive coagulant precursors, which become activated upon exposure to extravascular tissues. The ensuing coagulation cascade culminates with the generation of thrombin, a protease that cleaves extravasated fibrinogen, prompting its polymerization and deposition as fibrin. Accordingly, localized extravascular fibrin deposition accompanies many type 1 T helper cell (Th1)-associated responses, including autoimmune neuropathologies, 1-4 glomerulonephritis, 5,6 rheumatoid arthritis, 7-9 Crohn's disease, 10,11 allograft rejection, 12,13 delayed-type hypersensitivity, 14-19 and viral infections. 20,21 For some time, it has been appreciated that such Th1-associated coagulation has physiologic consequences, as the swelling that accompanies delayed-type hypersensitivity responses is suppressed in anticoagulated or fibrinogen-deficient subjects. [14][15][16][17][18][19] However, the full significance of immune-associated extravascular coagulation remains to be defined.Recent studies suggest that thrombin is a physiologic m...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Roles for thrombin and fibrin(ogen) in cytokine/chemokine production and macrophage adhesion in vivo

Szaba

Smiley

2002

Blood

288

224

View full text Add to dashboard Cite

show abstract

“…Even though FGN incubation with the synovial cells was performed using serum-free medium to lessen the chances of FGN degradation and polymerization, it was possible that factors such as thrombin-like proteases, known to be released from synovial cells (29), could have caused small amounts of polymerization to occur close to the cell surface. Thus it was possible that nonspecific "matrix"-associated effects such as mechanical pressure, gel contraction, and impaired diffusion of metabolites and/or oxygen could be responsible for the increased ICAM-1 expression of the cells.…”

Section: Addition Of Thrombin To Fgn Does Not Influence the Inductionmentioning

confidence: 99%

Fibrin(ogen)-Induced Expression of ICAM-1 and Chemokines in Human Synovial Fibroblasts

Liu

Piela-Smith

2000

The Journal of Immunology

View full text Add to dashboard Cite

It has long been recognized that in most inflamed arthritic joints the coagulation system is activated, leading to the local generation of fibrin, and it has long been hypothesized that the local fibrin deposition promotes inflammation and tissue destruction. However, only recently has the direct effect of fibrin on the inflammatory process been seriously investigated, and specific roles assigned to fibrin or its products as mediators of the inflammatory process. Although fibrin and/or fibrinogen (fibrin(ogen)) is abundantly present in inflamed tissues and joints rich in fibroblastic cells, no significant data on fibrin(ogen)-induced gene expression by fibroblasts have been published. We now demonstrate that coculture of human synovial fibroblasts with fibrin(ogen) results in the up-regulation of ICAM-1 as well as increased production of the chemokines IL-8 and growth-related oncogene-α. Increased ICAM-1 expression was fibrin(ogen) dose-dependent and was demonstrated by ELISA, flow cytometry, and functional adhesion assays. Levels of ICAM-1 induced by fibrin(ogen) were comparable to those that could be induced by cytokine stimulation. Fibrin(ogen) stimulation of ICAM-1 could be suppressed by pyrrolidinedithiocarbamate, an inhibitor of NF-κB activation. Chemokine production was induced by fibrin(ogen) in cell culture supernatants >100-fold as compared with controls. Thus, through its activation of synovial fibroblasts, fibrin(ogen) deposition may promote the recruitment (via chemokines) and retention (via adhesion molecules) of lymphocytes within the arthritic joint.

show abstract

“…Fibrin deposition is one of the most conspicuous and consistent features of both human RA and experimental animal models of arthritic disease, documented in areas of synovial hemorrhage and necrosis and more broadly in areas of synovial inflammation and hyperplasia and along articular surfaces (16,18,19). Furthermore, fibrin(ogen) is a key component of particulate "rice bodies" within synovial fluid (18).…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, fibrin(ogen) is a key component of particulate "rice bodies" within synovial fluid (18). Fibrin(ogen), a classic acute phase reactant, appears to be a key bridging molecule between the hemostatic and inflammatory systems.…”

Section: Introductionmentioning

confidence: 99%

Fibrin(ogen) exacerbates inflammatory joint disease through a mechanism linked to the integrin αMβ2 binding motif

Flick

LaJeunesse²,

Talmage³

et al. 2007

J. Clin. Invest.

155

148

View full text Add to dashboard Cite

Fibrin deposition within joints is a prominent feature of arthritis, but the precise contribution of fibrin(ogen) to inflammatory events that cause debilitating joint damage remains unknown. To determine the importance of fibrin(ogen) in arthritis, gene-targeted mice either deficient in fibrinogen (Fib -) or expressing mutant forms of fibrinogen, lacking the leukocyte receptor integrin α M β 2 binding motif (Fibγ 390-396A ) or the α IIb β 3 platelet integrin-binding motif (Fibγ Δ5 ), were challenged with collagen-induced arthritis (CIA). Fib -mice exhibited fewer affected joints and reduced disease severity relative to controls. Similarly, diminished arthritis was observed in Fibγ 390-396A mice, which retain full clotting function. In contrast, arthritis in Fibγ Δ5 mice was indistinguishable from that of controls. Fibrin(ogen) was not essential for leukocyte trafficking to joints, but appeared to be involved in leukocyte activation events. Fib -and Fibγ 390-396A mice with CIA displayed reduced local expression of TNF-α, IL-1β, and IL-6, which suggests that α M β 2 -mediated leukocyte engagement of fibrin is mechanistically upstream of the production of proinflammatory mediators. Supporting this hypothesis, arthritic disease driven by exuberant TNF-α expression was not impeded by fibrinogen deficiency. Thus, fibrin(ogen) is an important, but context-dependent, determinant of arthritis, and one mechanism linking fibrin(ogen) to joint disease is coupled to α M β 2 -mediated inflammatory processes.

show abstract

Pathways of coagulation activation in situ in rheumatoid synovial tissue

Cited by 52 publications

References 47 publications

Roles for thrombin and fibrin(ogen) in cytokine/chemokine production and macrophage adhesion in vivo

Roles for thrombin and fibrin(ogen) in cytokine/chemokine production and macrophage adhesion in vivo

Fibrin(ogen)-Induced Expression of ICAM-1 and Chemokines in Human Synovial Fibroblasts

Fibrin(ogen) exacerbates inflammatory joint disease through a mechanism linked to the integrin αMβ2 binding motif

Contact Info

Product

Resources

About