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Molecular Medicine

, Volume 17, Issue 5–6, pp 568–573 | Cite as

Novel Aspects of Fibrin(ogen) Fragments during Inflammation

  • Carla Jennewein
  • Nguyen Tran
  • Patrick Paulus
  • Peter Ellinghaus
  • Johannes Andreas Eble
  • Kai Zacharowski
Open Access
Review Article

Abstract

Coagulation is fundamental for the confinement of infection and/or the inflammatory response to a limited area. Under pathological inflammatory conditions such as arthritis, multiple sclerosis or sepsis, an uncontrolled activation of the coagulation system contributes to inflammation, microvascular failure and organ dysfunction. Coagulation is initiated by the activation of thrombin, which, in turn, triggers fibrin formation by the release of fibrinopeptides. Fibrin is cleaved by plasmin, resulting in clot lysis and an accompanied generation of fibrin fragments such as D and E fragments. Various coagulation factors, including fibrinogen and/or fibrin (fibrin(ogen)) and also fibrin degradation products, modulate the inflammatory response by affecting leukocyte migration and cytokine production. Fibrin fragments are mostly proinflammatory, however, Bβ15–42 in particular possesses potential antiinflammatory effects. Bβ15–42 inhibits Rho-kinase activation by dissociating Fyn from Rho and, hence prevents stress-induced loss of endothelial barrier function and also leukocyte migration. This article summarizes the state-of-the-art in inflammatory modulation by fibrin(ogen) and fibrin fragments. However, further research is required to gain better understanding of the entire role fibrin fragments play during inflammation and, possibly, disease development.

Introduction

Inflammation is a complex response to infection or injury with the aim to (i) confine inflammation and/or infection to a limited area, (ii) eliminate noxious stimuli and (iii) restore homeostasis. However, this process is associated with the activation of the coagulation cascade. A wide range of inflammatory conditions including sepsis (1), rheumatoid arthritis (2), Alzheimer disease (3), and multiple sclerosis (4) are not only attributed to an uncontrolled inflammatory response, but also to the disturbance of coagulation. Thus, when coagulation is compromised, it can contribute to the pathogenesis of various inflammatory conditions via fibrin deposition and microvascular failure; as well as by enhancing the inflammatory response (5,6). The contribution of fibrinogen and/or fibrin [fibrin(ogen)] to inflammation has been recognized, while the role of fibrin degradation products is still under investigation. However, in septic patients with organ dysfunction serum levels of fibrin(ogen) degradation products, D-dimers, Bβ15–42-related peptides and soluble fibrin are increased (7,8). The entire cross-talk of inflammation and coagulation is reviewed extensively (1,6,9,10). This article will highlight some aspects of the interaction between inflammation and coagulation while focusing on the inflammatory potential of fibrin(ogen) and their degradation products.

Cross-talk between Coagulation and Inflammation

An inflammatory response shifts the hemostatic system toward a prothrombotic state, while coagulation also affects inflammation. Two coagulation factors stand out during this cross-talk: tissue factor (TF) and thrombin. TF, the initiator of the coagulation cascade, is strongly induced during inflammation in endothelial cells (ECs) and leukocytes (11), which in turn activates thrombin. Blocking TF using neutralizing antibodies abrogates the inflammatory and coagulopathic response in two experimental in vivo models of sepsis (12) and ischemia/reperfusion (13). When TF is blocked, thrombin generation is also compromised. This is associated with less activation of the inflammatory and coagulation system, suggesting that thrombin is one of the major players in this process. Thrombin activates endothelial and immune cells by binding mainly to protease-activated receptor (PAR)-1, -3 and -4. It induces a strong inflammatory response by enhancing cytokine and chemokine expression as well as by increasing leukocyte recruitment, mainly via PAR-1, but also PAR-4 signaling (6,14, 15, 16).

Fibrinogen and Fibrin Structure

Fibrinogen is a 340 kDa glycoprotein synthesized in the liver with corresponding plasma levels of 1.5–3 g/L. The protein complex consists of two sets of three polypeptide chains, namely the Aα, Bβ and γ chains. The chains are joined together by disulfide bridges of their N-termini forming the central E globule, whereas the C-termini of Bβ and γ form the two outer D domains connected to the E domain by coil-coiled rod-like structure of the three polypeptide chains.

Coagulation is initiated by conversion of fibrinogen to fibrin. Thrombin cleaves within the N-termini of the Aα and Bβ chains releasing the fibrinopeptides A (FpA, Aα1–16) and B (Bβ1–15), thereby exposing polymerization sites. The activated fibrin monomers polymerize by binding the exposed polymerization sites to complementary binding pockets within the D domains, therewith forming protofibrils. Finally, thrombin activates coagulation factor XIIIa (FXIIIa) and stabilizes the fibrin clot by catalyzing the formation of isopeptide bonds between the γ chains of two fibrin molecules (reviewed in 17,18).

Fibrinolysis is facilitated by plasmin. It is synthesized as plasminogen and activated by proteolysis via tissue-type (t) or urokinase-type (u) plasminogen activator (tPA or uPA). Activated plasmin in turn cleaves fibrin at various cleavage sites resulting in X and Y fragments, D-dimers, D and E fragments, Bβ15–42 and smaller fragments mostly derived from the α chain (19, 20, 21). Figure 1 schematically depicts fibrinogen, fibrin, its domains, cleavage sites and the resulting plasmic derivatives.
Figure 1

Structure of fibrin(ogen) and its cleavage sites. During coagulation, thrombin cleaves fibrinogen releasing the fibrinopeptides A and B (Aα1–16, Bβ1–14) therewith triggering fibrin polymerization. Following proteolysis of fibrin by plasmin generates various fibrin fragments such as D-dimers, D and E fragments, Bβ15–42 and α chain fragments. The scissors mark plasmin cleavage sites, while the knife marks thrombin cleavage sites.

Inflammatory Potential of Fibrinogen and Fibrin

During the 1960–70s the first evidence of a potential inflammatory role of fibrin(ogen) in vivo was found. It was demonstrated that fibrinogen and fibrin contribute to inflammation by inducing leukocyte migration (22, 23, 24). Later, in vitro and in vivo studies demonstrated that fibrin(ogen) alters inflammation not only by affecting leukocyte migration, but also by directly modulating the inflammatory response of leukocytes and ECs via an increased cytokine/chemokine response. Exposure of ECs to fibrin induces the expression of interleukin (IL)-8 mRNA and protein (25). Fibrin(ogen) has been shown to cause an inflammatory response in peripheral blood mononuclear cells (PBMCs) induced by high levels of reactive oxygen species (ROS) (26), increased cytokine (for example, tumor necrosis factor-α, IL-1β and IL-6) (27,28) and chemokine expression (for example, macrophage inflammatory protein-1 and -2 [MIP-1 and -2] and macrophage chemoattractant protein-1 [MCP-1]) (29). Fibrin(ogen)-induced chemokine expression was associated with toll-like receptor 4 (TLR-4) signaling, since this effect was absent in C3H/HeJ mice, which express a TLR-4 (29) mutant. In contrast, others have excluded the involvement of TLR-4 signaling pathway in response to a fibrin(ogen) challenge (4). Kaneider et al. showed that fibrinogen reduces clotting time in monocytes and induces matrix metalloproteinase-9 (MMP-9) (30). Analysis of underlying mechanisms revealed that fibrin(ogen) modulates mitogen-activated protein kinase (MAPK) signaling, protein kinase C (PKC) and nuclear factor kB (NFkB) (30, 31, 32, 33), a key transcription factor during inflammation (34).

Fibrin(ogen) also binds to various integrins and adhesion molecules such as αVβ3 or αxβ2 (CD11c/CD18) (35,36). Current data suggest that the integrin αMβ2 is the “main” fibrin(ogen) receptor involved in (i) ROS production (26), (ii) cytokine expression (28,30, 31, 32, 33) and (iii) leukocyte migration. αMβ2 interacts with fibrin(ogen) by recognizing specific sequences (so called P1:γ190–202 and P2:γ377–395 and P2 core recognition motif P2-C:γ383–395) within the γ chain of the D nodule (37, 38, 39, 40, 41). Recently, the role of αMβ 2 and fibrin(ogen) interaction was addressed under in vivo inflammatory conditions. Converting the αMβ2-binding motif of fibrinogen (fibrinogen-γ390–396A) abolished leukocyte adhesion in vitro, while migration in response to S. aureus-induced peritonitis was not affected. However, bacterial clearance in fibrinogen-γ390–396A knock-in mice was impaired significantly, indicating the importance of fibrinogen (42). This is further supported by the fact that fibrinogen deficiency and also fibrinogen-γ390–396A knock-in significantly reduced disease severity in a mouse collagen-induced arthritis model. Interestingly, this effect was associated with lower cytokine expression, whereas leukocyte trafficking was unchanged (2). Adams et al. demonstrated that fibrinogen activates microglia via αMβ2 but not the TLR-4 pathway. In an experimental autoimmune encephalomyelitis model, inhibition of fibrin(ogen)–αMβ2 interaction with the peptide γ377–395 reduced microglia activation, coagulation was not affected (4). In summary, fibrinogen-αMβ2 interaction strongly modulates the inflammatory response by leukocytes, while trafficking seems to be compensated by other integrins and adhesion molecules.

The intercellular adhesion molecule-1 (ICAM-1) of ECs is another important fibrinogen receptor. By binding to ICAM-1, fibrinogen acts as a bridging molecule enhancing leukocyte-endothelium interaction (43). This interaction is augmented by the vascular endothelial-cadherin (VE-cadherin)-dependent induction of ICAM-1. The exposed Bβ15–42 sequence was essential for VE-cadherin binding, since blocking FpB release also prevents binding and ICAM-1 induction (44). Even though there is lot of evidence for fibrin(ogen)-dependent leukocyte adhesion, in vivo studies revealed that leukocytes and platelets do not readily accumulate in fibrin clots (45,46).

Undoubtedly, fibrin(ogen) plays a major role during inflammation. The thrombin inhibitor refludan reduced macrophage adhesion, while fibrinogen knock-out additionally reduced MCP-1 and IL-6 expression in response to thioglycolate (TG) (47). Cunningham et al. demonstrated in a mouse crescentic glomerulonephritis model that administration of the thrombin inhibitor hirudin afforded greater protection against renal injury and inflammation than did PAR-1 deficiency (14). This might indicate the involvement of fibrin fragments inducing inflammation, although, hirudin also inhibits thrombin-dependent activation of PAR-4. Therefore, it cannot be excluded that some protective effects of hirudin in this animal model are due to abrogated PAR-4 signaling. Moreover, platelet PAR-4 plays an essential role in TF-mediated inflammation (16).

Depleting fibrinogen with ancrod showed similar results in a TF-induced inflammation model; TF increased IL-6 levels. This effect was abolished completely when thrombin or FVIIa were blocked or when fibrinogen was depleted by ancrod (16). In a myocardial ischemia/reperfusion model, fibrinogen knock-out mice showed a significant reduction in infarct sizes, when compared with littermates (48). Fibrin deposition seems to contribute to the pathogenesis of Alzheimer disease by increasing blood brain-barrier (BBB) damage and neuroinflammation (3).

In conclusion, fibrin(ogen) augments the severity of various inflammatory conditions. Even though fibrinogen depletion reduces inflammation, it remains unclear if this is solely due to fibrin or also to fibrin(ogen) degradation products. We hypothesize that fibrin fragments also contribute to the pathophysiology of inflammation.

Fibrin Fragments

Various fibrin(ogen) degradation products are generated during coagulation and fibrinolysis. Initiation of clotting involves the release of FpA and B. Plasmin leads to the generation of D-dimers, D and E fragments and also smaller fragments such as the peptide Bβ15–42. These fragments, and especially D-dimers, are used as biomarkers for increased fibrin(ogen) turnover. Under various inflammatory conditions, such as sepsis or rheumatoid arthritis, fibrin degradation product levels are increased (7,49), therefore assuming the important role of the coagulation/ fibrinolysis system under these conditions. Besides fibrin fragments, fibrinogen degradation products also seem to modulate inflammation. In 1989, Kazura et al. reported an inhibitory effect of fibrinogen degradation products on the oxidative burst and concomitant bactericidal activity of peripheral mononuclear cells, probably by inhibiting PKC activation (50).

Fibrinopeptides A and B. Various groups reported proinflammatory effects of fibrinopeptides, in particular its function as a chemoattractant for neutrophils, monocytes and macrophages (51, 52, 53). Analysis of exudates from animals injected with purified FpA and FpB revealed that the numbers of leukocytes and MCP-1 levels were increased in rat air pouches. Since both fibrinopeptides have been injected in combination, single effects of each peptide remains to be elucidated (54). In contrast, one study revealed opposite effects of fibrinopeptides. In a carrageenan-induced inflammatory rat model, FpA and FpB reduced paw swelling, suggesting anti-inflammatory potential. In this particular study, thrombin-dependent effects were abolished by the use of heparin (55). Since Singh et al. showed that FpB but not FpA attracts macrophages (53), involvement of thrombin to the proinflammatory response could be excluded. As a result of these conflicting reports, further investigation is warranted.

D fragments. d-dimers generated by plasmin digestion of fibrin are used as markers for fibrinolysis and disseminated intravascular coagulation (DIC) in man. Exposure of D-dimers or D monomers on the human promonocytic leukemia cell line, NOMO-1, increased the levels of IL-1α and β, uPA, TF and plasminogen activator inhibitor-2 (PAI-2) (56). In addition, D-dimers triggered the release of IL-1 β, IL-6 and PAI in peripheral blood monocytes (57). Others have shown that D fragments have neither pro- nor antiinflammatory effects on monocytes/macrophages (58,59).

Fibrin fragment E (FnE). So far, little is known regarding the inflammatory potential of FnE. Various groups reported that FnE has angiogenic activity (60, 61, 62), while fibrinogen fragment E (FgnE) inhibits angiogenesis (62,63). In rat peritoneal macrophages, FnE as well as FgnE induced IL-6 production, which was supposed to be mediated by binding to CD11c (58). In the human monocytic cell line, THP-1-induced IL-1β production was increased by adherent FnE, but not by fragment D or FgnE (59). In additon to the studies on physiological FnE, the biological activity of FnE is often associated with a fragment named NDSKII (N-terminal disulfide knot II). NDSKII is generated synthetically via the cleavage of fibrinogen by cyanogen bromide and thrombin digestion. The resulting product is similar—but not identical—to the physiological FnE (FnE: Aα17–78, Bβ15–122 and γ1–62; NDSKII: Aα17–51, Bβ15–118, γ1–78) (19,64). Bach et al. studied the interaction of NDSKII using human umbilical vein endothelial cells (HUVECs). Binding assays demonstrated that the interaction of NDSKII is dependent on the Bβ15–42 region, since NDSK (generated after cyanogen bromide digestion without thrombin cleavage) does not expose Bβ15–42 and therefore did not show any affinity to HUVECs. Moreover, NDSKII binds to VE-cadherin but not to PECAM-1, ICAM-1 or various integrins (65) and facilitates leukocyte migration (48). In detail, lymphocyte migration depends on VE-cadherin and is inhibited by Bβ15–42, while monocyte and neutrophil migration is mediated by the binding of the α chain (NDSKII to CD11c). ICAM-1 antibody only partially inhibited migration of all three cell types (48).

Bβ15–42. Bβ15–42, a fragment of the N-terminal β chain, is generated by plasmin cleavage of fibrin. In contrast to later studies, Skogen et al. demonstrated that the fragment Bβ1–42 is a potent chemoat-tractant for neutrophils and fibroblasts, independent of the FpB sequence (66). Bβ15–42 also was capable of inducing IL-8 expression in human oral squamous cell carcinoma cells. Antibodies against Bβ15–42 inhibited fibrin-induced IL-8 expression, while a peptide representing a sequence of the N terminus of the region (GHRP) mimicked fibrin exposure (67). However, later studies mainly reported the immunosuppressive potential of Bβ15–42 being protective in various pathologic conditions such as ischemiareperfusion injury.

Thus, Bβ15–42 protects the myocardium against ischemia-reperfusion injury by reducing infarct size and leukocyte accumulation. Interestingly, the protective effect was abrogated in fibrinogendeficient mice, suggesting that Bβ15–42 reduces fibrinogen-dependent inflammation. Furthermore, Bβ15–42 reduced NDSK II-induced leukocyte recruitment by competing with it for binding to VE-cadherin (48). This work has been translated into a multicenter phase IIa clinical trial investigating the effects of Bβ15–42 (FX06) on myocardial infarct size. In summary, Bβ15–42 significantly reduced the size of the necrotic core zone of infarcts while total late enhancement was not significantly different between control and Bβ15–42-treated groups (68).

In a pig model of hemorrhagic shock, Bβ15–42-treated animals showed improved pulmonary and circulatory function. Bβ15–42 reduced plasma IL-6 and neutrophil influx into the myocardium, liver and small intestine, protecting these organs from shock (69). Moreover, Bβ15–42 functions as a signaling molecule. In two different shock models—Dengue shock syndrome and LPS-induced shock model, Bβ15–42 preserved endothelial barrier function by inhibiting stress-induced opening of EC adherens junctions (70). Cell-to-cell contact between ECs is formed mainly by VE-cadherin, which in turn is under the control of RhoGTPases regulating actin dynamics and junction stability. Rho-kinase is activated in response to stress, and causes loss of function of the endothelial barrier. Bβ15–42 prevented Rho-kinase activation by dissociating Fyn from VE-cadherin, which in turn associates to p190RhoGAP. Bβ15–42-treated animals had improved survival rates and reduced hemoconcentration and fibrinogen consumption (70). In a cardiac transplant model, Bβ15–42 also attenuated the ischemia-reperfusion injury (71). Thus, Bβ15–42 is a promising therapeutic agent; however, the full mechanism of action is still under investigation.

Other fragments. Staton et al. proposed a potential role for a 24-amino acid fragment derived from the N terminus of the α chain of FgnE named alphastatin. This peptide exhibited antiangiogenic effects by inhibiting growth factor-mediated migration, proliferation and tubule formation of human dermal microvascular ECs. In a syngeneic tumor model, alphastatin disrupted endothelium layers, caused widespread thrombosis and attenuated tumor growth (72).

Recently, a novel fragment of the Bβ chain (Bβ43–63) was identified. The fragment released after plasmin cleavage of fibrin had no effect on EC proliferation or migration, but inhibited tubule formation partly owing to cytotoxic effects on ECs. Moreover, Bβ43–63 reduced adhesion of ECs to the extracellular matrix by binding to and blocking integrin αVβ 3, exhibiting antiangiogenic and antitumor properties (73).

However, further fragments such as α chain fragments are generated during fibrinolysis while their function still remains elusive. Figure 2 depicts a schematic overview of the inflammatory effects of fibrin(ogen) and fibrin degradation products.
Figure 2

Modulation of inflammation by fibrin(ogen) and their degradation products. Following trauma and/or infection, tissue factor is released and induces coagulation. Fibrinogen is converted to fibrin, which in turn is degraded by plasmin. Fibrin(ogen) modulates the inflammatory response by affecting leukocyte migration, but also by induction of cytokine/chemokine expression mostly via Mac-1 signaling. Fibrin fragment E also induces cytokine expression and leukocyte recruitment/migration by binding to VE-cadherin, which is inhibited by Bβ15–42. Furthermore, Bβ15–42 preserves stress- induced endothelial barrier function by inhibiting Rho-kinase activation and subsequent junction opening. NO, nitric oxide; Mac-1, macrophage antigen 1; PI3K, phosphoinositide-3-kinase; TNFα, tumor necrosis factor-α.

Conclusion

It is undisputed that inflammation activates the coagulation system and vice versa. Our current knowledge suggests that most players within the coagulation cascade have proinflammatory properties. In contrast, the peptide Bβ15–42 mediates potent antiinflammatory effects. Therefore, any modulation of the coagulation system may reduce inflammation on one side, but on the other side may induce bleeding. Thus, targeting the proinflammatory aspects of coagulation, without affecting coagulation itself, might represent a novel therapeutic strategy within the treatment of inflammatory conditions.

High levels of fibrin fragments in septic patients with organ dysfunction suggest an increased fibrin turnover. Disease severity and outcome have not been correlated with fibrin fragments. Therefore, it might be of further interest to evaluate potential implications of fibrin degradation products as biomarkers of inflammatory conditions.

Disclosure

The authors declare that they have no competing interests as defined by Molecular Medicine, or other interests that might be perceived to influence the results and discussion reported in this paper.

Notes

Acknowledgment

This work is supported by the Deutsche Forschungsgesellschaft (SFB834, project B4). DISCLOSURE

References

  1. 1.
    Levi M. (2010) The coagulant response in sepsis and inflammation. Haemostaseologie. 30:10–6.CrossRefGoogle Scholar
  2. 2.
    Flick MJ, et al. (2007) Fibrin(ogen) exacerbates inflammatory joint disease through a mechanism linked to the integrin alphaMbeta2 binding motif. J.Clin. Invest. 117:3224–35.CrossRefPubMedGoogle Scholar
  3. 3.
    Paul J, Strickland S, Melchor JP. (2007) Fibrin deposition accelerates neurovascular damage and neuroinflammation in mouse models of Alzheimer’s disease. J.Exp. Med. 204:1999–2008.CrossRefPubMedGoogle Scholar
  4. 4.
    Adams RA, et al. (2007) The fibrin-derived gamma377–395 peptide inhibits microglia activation and suppresses relapsing paralysis in central nervous system autoimmune disease. J. Exp. Med. 204:571–82.CrossRefPubMedGoogle Scholar
  5. 5.
    Boos CJ, Goon PK, Lip GY. (2006) The endothelium, inflammation, and coagulation in sepsis. Clin. Pharmacol. Ther. 79:20–2.CrossRefPubMedGoogle Scholar
  6. 6.
    Levi M, van der Poll T, Buller HR. (2004) Bidirectional relation between inflammation and coagulation. Circulation. 109:2698–704.CrossRefGoogle Scholar
  7. 7.
    Iba T, et al. (2005) Association between the severity of sepsis and the changes in hemostatic molecular markers and vascular endothelial damage markers. Shock. 23:25–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Fareed J, et al. (1998) Useful laboratory tests for studying thrombogenesis in acute cardiac syndromes. Clin. Chem. 44:1845–53.PubMedGoogle Scholar
  9. 9.
    Medcalf RL. (2007) Fibrinolysis, inflammation, and regulation of the plasminogen activating system. J.Thromb. Haemost. 5 Suppl 1:132–42.CrossRefPubMedGoogle Scholar
  10. 10.
    Knoebl P. (2010) Blood coagulation disorders in septic patients. Wien. Med. Wochenschr. 160:129–38.CrossRefPubMedGoogle Scholar
  11. 11.
    Pawlinski R, Mackman N. (2010) Cellular sources of tissue factor in endotoxemia and sepsis. Thromb. Res. 125 Suppl 1:S70–3.CrossRefPubMedGoogle Scholar
  12. 12.
    Levi M, et al. (1994) Inhibition of endotoxin-induced activation of coagulation and fibrinolysis by pentoxifylline or by a monoclonal anti-tissue factor antibody in chimpanzees. J. Clin. Invest. 93:114–20.CrossRefPubMedGoogle Scholar
  13. 13.
    Erlich JH, et al. (2000) Inhibition of the tissue factor-thrombin pathway limits infarct size after myocardial ischemia-reperfusion injury by reducing inflammation. Am. J. Pathoi. 157:1849–62.CrossRefGoogle Scholar
  14. 14.
    Cunningham MA, et al. (2000) Protease-activated receptor 1 mediates thrombin-dependent, cellmediated renal inflammation in crescentic glomerulonephritis. J. Exp. Med. 191:455–62.CrossRefPubMedGoogle Scholar
  15. 15.
    Yang YH, et al. (2005) Reduction of arthritis severity in protease-activated receptor-deficient mice. Arthritis Rheum. 52:1325–32.CrossRefPubMedGoogle Scholar
  16. 16.
    Busso N, et al. (2008) Essential role of platelet activation via protease activated receptor 4 in tissue factor-initiated inflammation. Arthritis Res. Ther. 10:R42.CrossRefPubMedGoogle Scholar
  17. 17.
    Mosesson MW. (2005) Fibrinogen and fibrin structure and functions. J. Thromb. Haemost. 3:1894–904.CrossRefPubMedGoogle Scholar
  18. 18.
    Lord ST. (2007) Fibrinogen and fibrin: scaffold proteins in hemostasis. Curr. Opin. Hematol. 14:236–41.CrossRefPubMedGoogle Scholar
  19. 19.
    Olexa SA, Budzynski AZ, Doolittle RF, Cottrell BA, Greene TC. (1981) Structure of fragment E species from human cross-linked fibrin. Biochemistry. 20:6139–5.CrossRefPubMedGoogle Scholar
  20. 20.
    Smith EB, Keen GA, Grant A, Stirk C. (1990) Fate of fibrinogen in human arterial intima. Arteriosclerosis. 10:263–75.CrossRefPubMedGoogle Scholar
  21. 21.
    Walker JB, Nesheim ME. (1999) The molecular weights, mass distribution, chain composition, and structure of soluble fibrin degradation products released from a fibrin clot perfused with plasmin. J. Biol. Chem. 274:5201–12.CrossRefPubMedGoogle Scholar
  22. 22.
    Hurley JV. (1964) Substances promoting leukocyte emigration. Ann. N. Y. Acad. Sci. 116:918–35.CrossRefPubMedGoogle Scholar
  23. 23.
    Colvin RB, Johnson RA, Mihm MC Jr, Dvorak HF. (1973) Role of the clotting system in cell-mediated hypersensitivity. I. Fibrin deposition in delayed skin reactions in man. J. Exp. Med. 138:686–98.CrossRefPubMedGoogle Scholar
  24. 24.
    Barnhart MI, Riddle JM, Bluhm GB, Quintana C. (1967) Fibrin promotion and lysis in arthritic joints. Ann. Rheum. Dis. 26:206–18.CrossRefPubMedGoogle Scholar
  25. 25.
    Qi J, Goralnick S, Kreutzer DL. (1997) Fibrin regulation of interleukin-8 gene expression in human vascular endothelial cells. Blood. 90:3595–602.PubMedGoogle Scholar
  26. 26.
    Trezzini C, Schuepp B, Maly FE, Jungi TW. (1991) Evidence that exposure to fibrinogen or to antibodies directed against Mac-1 (CD11b/CD18; CR3) modulates human monocyte effector functions. Br. J. Haematol. 77:16–24.CrossRefPubMedGoogle Scholar
  27. 27.
    Jensen T, et al. (2007) Fibrinogen and fibrin induce synthesis of proinflammatory cytokines from isolated peripheral blood mononuclear cells. Thromb. Haemost. 97:822–9.CrossRefPubMedGoogle Scholar
  28. 28.
    Fan ST, Edgington TS. (1993) Integrin regulation of leukocyte inflammatory functions. CD11b/CD18 enhancement of the tumor necrosis factor-alpha responses of monocytes. J. Immunol. 150:2972–80.PubMedGoogle Scholar
  29. 29.
    Smiley ST, King JA, Hancock WW. (2001) Fibrinogen stimulates macrophage chemokine secretion through toll-like receptor 4. J. Immunol. 167:2887–94.CrossRefPubMedGoogle Scholar
  30. 30.
    Kaneider NC, Mosheimer B, Gunther A, Feistritzer C, Wiedermann CJ. (2010) Enhancement of fibrinogen-triggered pro-coagulant activation of monocytes in vitro by matrix metallo-proteinase-9. Thromb. J. 8:2.CrossRefPubMedGoogle Scholar
  31. 31.
    Kreuzer J, et al. (1996) Fibrinogen promotes monocyte adhesion via a protein kinase C dependent mechanism. J. Mol. Med. 74:161–5.CrossRefPubMedGoogle Scholar
  32. 32.
    Perez RL, Roman J. (1995) Fibrin enhances the expression of IL-1 beta by human peripheral blood mononuclear cells. Implications in pulmonary inflammation. J. Immunol. 154:1879–87.PubMedGoogle Scholar
  33. 33.
    Sitrin RG, Pan PM, Srikanth S, Todd RF 3rd. (1998) Fibrinogen activates NF-kappa B transcription factors in mononuclear phagocytes. J. Immunol. 161:1462–70.PubMedGoogle Scholar
  34. 34.
    Li Q, Verma IM. (2002) NF-kappaB regulation in the immune system. Nat. Rev. Immunol. 2:725–34.CrossRefPubMedGoogle Scholar
  35. 35.
    Hynes RO. (1992) Integrins: versatility, modulation, and signaling in cell adhesion. Cell. 69:11–25.CrossRefGoogle Scholar
  36. 36.
    Altieri DC. (1999) Regulation of leukocyte-endothelium interaction by fibrinogen. Thromb. Haemost. 82:781–6.CrossRefPubMedGoogle Scholar
  37. 37.
    Altieri DC, et al. (1990) A unique recognition site mediates the interaction of fibrinogen with the leukocyte integrin Mac-1 (CD11b/CD18). J. Biol. Chem. 265:12119–22.PubMedGoogle Scholar
  38. 38.
    Ugarova TP, et al. (1998) Identification of a novel recognition sequence for integrin alphaM beta2 within the gamma-chain of fibrinogen. J. Biol. Chem. 273:22519–27.CrossRefPubMedGoogle Scholar
  39. 39.
    Yakovlev S, Zhang L, Ugarova T, Medved L. (2005) Interaction of fibrin(ogen) with leukocyte receptor alpha M beta 2 (Mac-1): further characterization and identification of a novel binding region within the central domain of the fibrinogen gamma-module. Biochemistry. 44:617–26.CrossRefPubMedGoogle Scholar
  40. 40.
    Forsyth CB, Solovjov DA, Ugarova TP, Plow EF. (2001) Integrin alpha(M)beta(2)-mediated cell migration to fibrinogen and its recognition pep- tides. J. Exp. Med. 193:1123–33.CrossRefPubMedGoogle Scholar
  41. 41.
    Altieri DC, Plescia J, Plow EF. (1993) The structural motif glycine 190-valine 202 of the fibrinogen gamma chain interacts with CD11b/CD18 integrin (alpha M beta 2, Mac-1) and promotes leukocyte adhesion. J. Biol. Chem. 268:1847–53.PubMedGoogle Scholar
  42. 42.
    Flick MJ, et al. (2004) Leukocyte engagement of fibrin(ogen) via the integrin receptor alphaM-beta2/Mac-1 is critical for host inflammatory response in vivo. J. Clin. Invest. 113:1596–606.CrossRefPubMedGoogle Scholar
  43. 43.
    Languino LR, et al. (1993) Fibrinogen mediates leukocyte adhesion to vascular endothelium through an ICAM-1-dependent pathway. Cell. 73:1423–34.CrossRefPubMedGoogle Scholar
  44. 44.
    Harley SL, Sturge J, Powell JT. (2000) Regulation by fibrinogen and its products of intercellular adhesion molecule-1 expression in human saphenous vein endothelial cells. Arterioscler. Thromb. Vasc. Biol. 20:652–8.CrossRefPubMedGoogle Scholar
  45. 45.
    Lishko VK, Burke T, Ugarova T. (2007) Antiadhesive effect of fibrinogen: a safeguard for thrombus stability. Blood. 109:1541–9.CrossRefPubMedGoogle Scholar
  46. 46.
    Lishko VK, Yermolenko IS, Ugarova TP. (2010) Plasminogen on the surfaces of fibrin clots prevents adhesion of leukocytes and platelets. J. Thromb. Haemost. 8:799–807.CrossRefPubMedGoogle Scholar
  47. 47.
    Szaba FM, Smiley ST. (2002) Roles for thrombin and fibrin(ogen) in cytokine/chemokine production and macrophage adhesion in vivo. Blood. 99:1053–9.CrossRefPubMedGoogle Scholar
  48. 48.
    Petzelbauer P, et al. (2005) The fibrin-derived pep-tide Bbeta15-42 protects the myocardium against ischemia-reperfusion injury. Nat. Med. 11:298–304.CrossRefPubMedGoogle Scholar
  49. 49.
    Ichikawa Y, Yamada C, Horiki T, Hoshina Y, Uchiyama M. (1998) Serum matrix metallopro-teinase-3 and fibrin degradation product levels correlate with clinical disease activity in rheumatoid arthritis. Clin. Exp. Rheumatol. 16:533–40.PubMedGoogle Scholar
  50. 50.
    Kazura JW, Wenger JD, Salata RA, Budzynski AZ, Goldsmith GH. (1989) Modulation of polymor-phonuclear leukocyte microbicidal activity and oxidative metabolism by fibrinogen degradation products D and E. J. Clin. Invest. 83:1916–24.CrossRefPubMedGoogle Scholar
  51. 51.
    Richardson DL, Pepper DS, Kay AB. (1976) Chemotaxis for human monocytes by fibrinogen-derived peptides. Br. J. Haematol. 32:507–13.CrossRefPubMedGoogle Scholar
  52. 52.
    Senior RM, Skogen WF, Griffin GL, Wilner GD. (1986) Effects of fibrinogen derivatives upon the inflammatory response. Studies with human fibrinopeptide B. J. Clin. Invest. 77:1014–9.CrossRefPubMedGoogle Scholar
  53. 53.
    Singh TM, Kadowaki MH, Glagov S, Zarins CK. (1990) Role of fibrinopeptide B in early atherosclerotic lesion formation. Am. J. Surg. 160:156–9.CrossRefPubMedGoogle Scholar
  54. 54.
    Persson K, Russell W, Morgelin M, Herwald H. (2003) The conversion of fibrinogen to fibrin at the surface of curliated Escherichia coli bacteria leads to the generation of proinflammatory fibrinopeptides. J. Biol. Chem. 278:31884–90.CrossRefPubMedGoogle Scholar
  55. 55.
    Ruhenstroth-Bauer G, Scherer R, Hornberger M, Tongendorff G. (1981) Demonstration of anti-inflammatory activity of fibrinogen and fibrinopeptides in rats. Inflammation. 5:343–51.CrossRefPubMedGoogle Scholar
  56. 56.
    Hamaguchi M, et al. (1991) FDP D-dimer induces the secretion of interleukin-1, urokinase-type plasminogen activator, and plasminogen activator inhibitor-2 in a human promonocytic leukemia cell line. Blood. 77:94–100.PubMedGoogle Scholar
  57. 57.
    Robson SC, Shephard EG, Kirsch RE. (1994) Fibrin degradation product D-dimer induces the synthesis and release of biologically active IL-1 beta, IL-6 and plasminogen activator inhibitors from monocytes in vitro. Br. J. Haematol. 86:322–6.CrossRefPubMedGoogle Scholar
  58. 58.
    Lee ME, Rhee KJ, Nham SU. (1999) Fragment E derived from both fibrin and fibrinogen stimulates interleukin-6 production in rat peritoneal macrophages. Mol. Cells. 9:7–13.PubMedGoogle Scholar
  59. 59.
    Lee ME, Kweon SM, Ha KS, Nham SU. (2001) Fibrin stimulates microfilament reorganization and IL-1beta production in human monocytic THP-1 cells. Mol. Cells. 11:13–20.PubMedGoogle Scholar
  60. 60.
    Thompson WD, et al. (1992) Angiogenic activity of fibrin degradation products is located in fibrin fragment E. J. Pathol. 168:47–53.CrossRefPubMedGoogle Scholar
  61. 61.
    Bootle-Wilbraham CA, Tazzyman S, Thompson WD, Stirk CM, Lewis CE. (2001) Fibrin fragment E stimulates the proliferation, migration and differentiation of human microvascular endothelial cells in vitro. Angiogenesis. 4:269–75.CrossRefPubMedGoogle Scholar
  62. 62.
    Naito M, Stirk CM, Smith EB, Thompson WD. (2000) Smooth muscle cell outgrowth stimulated by fibrin degradation products. The potential role of fibrin fragment E in restenosis and atherogenesis. Thromb. Res. 98:165–74.CrossRefPubMedGoogle Scholar
  63. 63.
    Bootle-Wilbraham CA, Tazzyman S, Marshall JM, Lewis CE. (2000) Fibrinogen E-fragment inhibits the migration and tubule formation of human dermal microvascular endothelial cells in vitro. Cancer Res. 60:4719–24.PubMedGoogle Scholar
  64. 64.
    Vali Z, Scheraga HA. (1988) Localization of the binding site on fibrin for the secondary binding site of thrombin. Biochemistry. 27:1956–63.CrossRefPubMedGoogle Scholar
  65. 65.
    Bach TL, Barsigian C, Yaen CH, Martinez J. (1998) Endothelial cell VE-cadherin functions as a receptor for the beta15-42 sequence of fibrin. J. Biol. Chem. 273:30719–28.CrossRefPubMedGoogle Scholar
  66. 66.
    Skogen WF, Senior RM, Griffin GL, Wilner GD. (1988) Fibrinogen-derived peptide B beta 1–42 is a multidomained neutrophil chemoattractant. Blood. 71:1475–9.PubMedGoogle Scholar
  67. 67.
    Lalla RV, Tanzer ML, Kreutzer DL. (2003) Identification of a region of the fibrin molecule involved in upregulation of interleukin-8 expression from human oral squamous cell carcinoma cells. Arch. Oral Biol. 48:263–71.CrossRefPubMedGoogle Scholar
  68. 68.
    Atar D, et al. (2009) Effect of intravenous FX06 as an adjunct to primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction results of the F.I.R.E. (Efficacy of FX06 in the Prevention of Myocardial Reperfusion Injury) trial. J. Am. Coll. Cardiol. 53:720–9.CrossRefPubMedGoogle Scholar
  69. 69.
    Roesner JP, et al. (2009) Bbeta15-42 (FX06) reduces pulmonary, myocardial, liver, and small intestine damage in a pig model of hemorrhagic shock and reperfusion. Crit. Care Med. 37:598–605.CrossRefPubMedGoogle Scholar
  70. 70.
    Gröger M, et al. (2009) Peptide Bbeta(15–42) preserves endothelial barrier function in shock. PLoS One. 4:e5391.CrossRefPubMedGoogle Scholar
  71. 71.
    Wiedemann D, et al. (2010) The fibrin-derived peptide Bbeta(15–42) significantly attenuates ischemia-reperfusion injury in a cardiac transplant model. Transplantation. 89:824–9.CrossRefPubMedGoogle Scholar
  72. 72.
    Staton CA, et al. (2004) Alphastatin, a 24-amino acid fragment of human fibrinogen, is a potent new inhibitor of activated endothelial cells in vitro and in vivo. Blood. 103:601–6.CrossRefPubMedGoogle Scholar
  73. 73.
    Krajewska E, et al. (2010) A novel fragment derived from the beta chain of human fibrinogen, beta43-63, is a potent inhibitor of activated endothelial cells in vitro and in vivo. Br. J. Cancer. 102:594–601.CrossRefPubMedGoogle Scholar

Copyright information

© The Feinstein Institute for Medical Research 2011

Authors and Affiliations

  • Carla Jennewein
    • 1
  • Nguyen Tran
    • 1
  • Patrick Paulus
    • 1
  • Peter Ellinghaus
    • 2
  • Johannes Andreas Eble
    • 3
  • Kai Zacharowski
    • 1
  1. 1.Clinic of Anesthesiology, Intensive Care Medicine and Pain TherapyJW-Goethe-University Hospital FrankfurtFrankfurt am MainGermany
  2. 2.Bayer Schering Pharma AGWuppertalGermany
  3. 3.Center of Molecular Medicine, Excellence Cluster Cardio-Pulmonary SystemGoethe-University Hospital FrankfurtFrankfurt am MainGermany

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