novel aspects of fibrin(ogen) fragments during inflammation · 2018. 10. 9. · novel aspects of...

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INTRODUCTIONInflammation is a complex response

to infection or injury with the aim to(i) confine inflammation and/or infectionto a limited area, (ii) eliminate noxiousstimuli and (iii) restore homeostasis.However, this process is associated withthe activation of the coagulation cascade.A wide range of inflammatory conditionsincluding sepsis (1), rheumatoid arthritis(2), Alzheimer disease (3), and multiplesclerosis (4) are not only attributed to anuncontrolled inflammatory response, butalso to the disturbance of coagulation.Thus, when coagulation is compromised,it can contribute to the pathogenesis ofvarious inflammatory conditions via fib-rin deposition and microvascular failure;

as well as by enhancing the inflamma-tory response (5,6). The contribution offibrinogen and/or fibrin [fibrin(ogen)] toinflammation has been recognized, whilethe role of fibrin degradation products isstill under investigation. However, inseptic patients with organ dysfunctionserum levels of fibrin(ogen) degradationproducts, D-dimers, Bβ15–42–relatedpeptides and soluble fibrin are increased(7,8). The entire cross-talk of inflamma-tion and coagulation is reviewed exten-sively (1,6,9,10). This article will high-light some aspects of the interactionbetween inflammation and coagulationwhile focusing on the inflammatory po-tential of fibrin(ogen) and their degrada-tion products.

Cross-talk between Coagulation andInflammation

An inflammatory response shifts thehemostatic system toward a prothrom-botic state, while coagulation also affectsinflammation. Two coagulation factorsstand out during this cross-talk: tissuefactor (TF) and thrombin. TF, the initiatorof the coagulation cascade, is strongly in-duced during inflammation in endothe-lial cells (ECs) and leukocytes (11), whichin turn activates thrombin. Blocking TFusing neutralizing antibodies abrogatesthe inflammatory and coagulopathic re-sponse in two experimental in vivo models of sepsis (12) and ischemia/reperfusion (13). When TF is blocked,thrombin generation is also compro-mised. This is associated with less activa-tion of the inflammatory and coagulationsystem, suggesting that thrombin is oneof the major players in this process.Thrombin activates endothelial and immune cells by binding mainly to protease-activated receptor (PAR)-1, -3and -4. It induces a strong inflammatory

Novel Aspects of Fibrin(ogen) Fragments duringInflammation

Carla Jennewein,1 Nguyen Tran,1 Patrick Paulus,1 Peter Ellinghaus,2 Johannes Andreas Eble,3

and Kai Zacharowski1

1Clinic of Anesthesiology, Intensive Care Medicine and Pain Therapy, Goethe-University Hospital Frankfurt, Frankfurt am Main,Germany; 2Bayer Schering Pharma AG, Wuppertal, Germany; and 3Center of Molecular Medicine, Excellence Cluster Cardio-Pulmonary System, Goethe-University Hospital Frankfurt, Frankfurt am Main, Germany

Coagulation is fundamental for the confinement of infection and/or the inflammatory response to a limited area. Under patho-logical inflammatory conditions such as arthritis, multiple sclerosis or sepsis, an uncontrolled activation of the coagulation systemcontributes 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 anaccompanied generation of fibrin fragments such as D and E fragments. Various coagulation factors, including fibrinogen and/orfibrin [fibrin(ogen)] and also fibrin degradation products, modulate the inflammatory response by affecting leukocyte migrationand cytokine production. Fibrin fragments are mostly proinflammatory, however, Bβ15–42 in particular possesses potential antiin-flammatory effects. Bβ15–42 inhibits Rho-kinase activation by dissociating Fyn from Rho and, hence prevents stress-induced loss ofendothelial barrier function and also leukocyte migration. This article summarizes the state-of-the-art in inflammatory modulationby fibrin(ogen) and fibrin fragments. However, further research is required to gain better understanding of the entire role fibrin frag-ments play during inflammation and, possibly, disease development.© 2011 The Feinstein Institute for Medical Research, www.feinsteininstitute.orgOnline address: http://www.molmed.orgdoi: 10.2119/molmed.2010.00146

Address correspondence and reprint requests to Kai Zacharowski, Clinic of Anesthesiol-

ogy, Intensive Care Medicine and Pain Therapy, JW-Goethe-University Hospital Frankfurt,

Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. Phone: +49-69-6301-5998; Fax:

+49-69-6301-5881; E-mail: [email protected].

Submitted August 11, 2010; Accepted for publication January 3, 2011; Epub

(www.molmed.org) ahead of print January 4, 2011.

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response by enhancing cytokine andchemokine expression as well as by in-creasing leukocyte recruitment, mainlyvia PAR-1, but also PAR-4 signaling(6,14–16).

Fibrinogen and Fibrin StructureFibrinogen is a 340 kDa glycoprotein

synthesized in the liver with correspon-ding plasma levels of 1.5–3 g/L. The pro-tein complex consists of two sets of threepolypeptide chains, namely the Aα, Bβand γ chains. The chains are joined to-gether by disulfide bridges of theirN-termini forming the central E globule,

whereas the C-termini of Bβ and γ formthe two outer D domains connected tothe E domain by coil-coiled rod-likestructure of the three polypeptide chains.

Coagulation is initiated by conversionof fibrinogen to fibrin. Thrombin cleaveswithin the N-termini of the Aα and Bβchains releasing the fibrinopeptides A(FpA, Aα1–16) and B (Bβ1–15), therebyexposing polymerization sites. The acti-vated fibrin monomers polymerize bybinding the exposed polymerization sitesto complementary binding pocketswithin the D domains, therewith formingprotofibrils. Finally, thrombin activatescoagulation factor XIIIa (FXIIIa) and sta-bilizes the fibrin clot by catalyzing theformation of isopeptide bonds betweenthe γ chains of two fibrin molecules (re-viewed in 17,18).

Fibrinolysis is facilitated by plasmin. Itis synthesized as plasminogen and acti-vated by proteolysis via tissue-type (t) orurokinase-type (u) plasminogen activator(tPA or uPA). Activated plasmin in turncleaves fibrin at various cleavage sites re-sulting in X and Y fragments, D-dimers, Dand E fragments, Bβ15–42 and smallerfragments mostly derived from the α chain(19–21). Figure 1 schematically depicts fib-rinogen, fibrin, its domains, cleavage sites andthe resulting plasmic derivatives.

Inflammatory Potential of Fibrinogenand Fibrin

During the 1960–70s the first evidenceof a potential inflammatory role of fib-rin(ogen) in vivo was found. It wasdemonstrated that fibrinogen and fibrincontribute to inflammation by inducingleukocyte migration (22–24). Later, in vitroand in vivo studies demonstrated that fib-rin(ogen) alters inflammation not only byaffecting leukocyte migration, but also bydirectly modulating the inflammatory re-sponse of leukocytes and ECs via an in-creased cytokine/chemokine response.Exposure of ECs to fibrin induces the ex-pression of interleukin (IL)-8 mRNA andprotein (25). Fibrin(ogen) has been shownto cause an inflammatory response in peripheral blood mononuclear cells(PBMCs) induced by high levels of

reactive oxygen species (ROS) (26), in-creased cytokine (for example, tumornecrosis 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 macrophagechemoattractant protein-1 [MCP-1]) (29).Fibrin(ogen)-induced chemokine expres-sion was associated with toll-like receptor4 (TLR-4) signaling, since this effect wasabsent in C3H/HeJ mice, which express aTLR-4 (29) mutant. In contrast, othershave excluded the involvement of TLR-4signaling pathway in response to a fib-rin(ogen) challenge (4). Kaneider et al.showed that fibrinogen reduces clottingtime in monocytes and induces matrixmetalloproteinase-9 (MMP-9) (30). Analy-sis of underlying mechanisms revealedthat fibrin(ogen) modulates mitogen- activated protein kinase (MAPK) signal-ing, protein kinase C (PKC) and nuclearfactor κB (NFκB) (30–33), a key transcrip-tion factor during inflammation (34).

Fibrin(ogen) also binds to various inte-grins and adhesion molecules such asαVβ3 or αxβ2 (CD11c/CD18) (35,36). Cur-rent data suggest that the integrin αMβ2

is the “main” fibrin(ogen) receptor in-volved in (i) ROS production (26), (ii) cytokine expression (28,30–33) and(iii) leukocyte migration. αMβ2 interactswith fibrin(ogen) by recognizing specificsequences (so called P1:γ190–202 andP2:γ377–395 and P2 core recognition motifP2-C:γ383–395) within the γ chain of theD nodule (37–41). Recently, the role ofαMβ2 and fibrin(ogen) interaction was ad-dressed under in vivo inflammatory con-ditions. Converting the αMβ2-bindingmotif 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 fibrino-gen-γ390–396A knock-in mice was impairedsignificantly, indicating the importanceof fibrinogen (42). This is further sup-ported by the fact that fibrinogen defi-ciency and also fibrinogen-γ390–396A

knock-in significantly reduced diseaseseverity in a mouse collagen-inducedarthritis model. Interestingly, this effect

Figure 1. Structure of fibrin(ogen) and itscleavage sites. During coagulation, throm-bin cleaves fibrinogen releasing the fib-rinopeptides A and B (Aα1–16, Bβ1–14)therewith triggering fibrin polymerization.Following proteolysis of fibrin by plasmingenerates various fibrin fragments such asD-dimers, D and E fragments, Bβ15–42 andα chain fragments. The scissors mark plas-min cleavage sites, while the knife marksthrombin cleavage sites.


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was associated with lower cytokine ex-pression, whereas leukocyte traffickingwas unchanged (2). Adams et al. demon-strated that fibrinogen activates mi-croglia via αMβ2 but not the TLR-4 path-way. In an experimental autoimmuneencephalomyelitis model, inhibition offibrin(ogen)–αMβ2 interaction with thepeptide γ377–395 reduced microglia activa-tion, coagulation was not affected (4). Insummary, fibrinogen–αMβ2 interactionstrongly modulates the inflammatory re-sponse by leukocytes, while traffickingseems to be compensated by other inte-grins and adhesion molecules.

The intercellular adhesion molecule-1(ICAM-1) of ECs is another important fib-rinogen receptor. By binding to ICAM-1,fibrinogen acts as a bridging molecule en-hancing leukocyte–endothelium interac-tion (43). This interaction is augmentedby the vascular endothelial–cadherin(VE-cadherin)-dependent induction ofICAM-1. The exposed Bβ15–42 sequencewas essential for VE-cadherin binding,since blocking FpB release also preventsbinding and ICAM-1 induction (44). Eventhough there is lot of evidence forfibrin(ogen)-dependent leukocyte adhe-sion, in vivo studies revealed that leuko-cytes and platelets do not readily accu-mulate in fibrin clots (45,46).

Undoubtedly, fibrin(ogen) plays a majorrole during inflammation. The thrombininhibitor refludan reduced macrophageadhesion, while fibrinogen knock-out ad-ditionally reduced MCP-1 and IL-6 expres-sion in response to thioglycolate (TG) (47).Cunningham et al. demonstrated in amouse crescentic glomerulonephritismodel that administration of the thrombininhibitor hirudin afforded greater protec-tion against renal injury and inflammationthan did PAR-1 deficiency (14). This mightindicate the involvement of fibrin frag-ments inducing inflammation, although,hirudin also inhibits thrombin-dependentactivation of PAR-4. Therefore, it cannot beexcluded that some protective effects ofhirudin in this animal model are due toabrogated PAR-4 signaling. Moreover,platelet PAR-4 plays an essential role inTF-mediated inflammation (16).

Depleting fibrinogen with ancrodshowed similar results in a TF-inducedinflammation model; TF increased IL-6levels. This effect was abolished com-pletely when thrombin or FVIIa wereblocked or when fibrinogen was de-pleted by ancrod (16). In a myocardial ischemia/reperfusion model, fibrinogenknock-out mice showed a significant re-duction in infarct sizes, when comparedwith littermates (48). Fibrin depositionseems to contribute to the pathogenesisof Alzheimer disease by increasing bloodbrain-barrier (BBB) damage and neuroin-flammation (3).

In conclusion, fibrin(ogen) augmentsthe severity of various inflammatoryconditions. Even though fibrinogen de-pletion reduces inflammation, it remainsunclear if this is solely due to fibrin oralso to fibrin(ogen) degradation prod-ucts. We hypothesize that fibrin frag-ments also contribute to the pathophysi-ology of inflammation.

Fibrin FragmentsVarious fibrin(ogen) degradation

products are generated during coagula-tion and fibrinolysis. Initiation of clot-ting involves the release of FpA and B.Plasmin leads to the generation ofD-dimers, D and E fragments and alsosmaller fragments such as the peptideBβ15–42. These fragments, and espe-cially D-dimers, are used as biomarkersfor increased fibrin(ogen) turnover.Under various inflammatory conditions,such as sepsis or rheumatoid arthritis,fibrin degradation product levels are in-creased (7,49), therefore assuming theimportant role of the coagulation/fibrinolysis system under these condi-tions. Besides fibrin fragments, fibrino-gen degradation products also seem to modulate inflammation. In 1989,Kazura et al. reported an inhibitory ef-fect of fibrinogen degradation productson the oxidative burst and concomitantbactericidal activity of peripheralmononuclear cells, probably by inhibit-ing PKC activation (50).

Fibrinopeptides A and B. Variousgroups reported proinflammatory effects

of fibrinopeptides, in particular its func-tion as a chemoattractant for neutrophils,monocytes and macrophages (51–53).Analysis of exudates from animals in-jected with purified FpA and FpB re-vealed that the numbers of leukocytesand MCP-1 levels were increased in ratair pouches. Since both fibrinopeptideshave been injected in combination, singleeffects of each peptide remains to be elu-cidated (54). In contrast, one study re-vealed opposite effects of fibrinopep-tides. In a carrageenan-inducedinflammatory rat model, FpA and FpBreduced paw swelling, suggesting anti -inflammatory potential. In this particularstudy, thrombin-dependent effects wereabolished by the use of heparin (55).Since Singh et al. showed that FpB butnot FpA attracts macrophages (53), in-volvement of thrombin to the proinflam-matory response could be excluded. As aresult of these conflicting reports, furtherinvestigation is warranted.

D fragments. D-dimers generated byplasmin digestion of fibrin are used asmarkers for fibrinolysis and dissemi-nated intravascular coagulation (DIC) in man. Exposure of D-dimers or D monomers on the human promono-cytic leukemia cell line, NOMO-1, in-creased the levels of IL-1α and β, uPA,TF and plasminogen activator inhibitor-2(PAI-2) (56). In addition, D-dimers trig-gered the release of IL-1β, IL-6 and PAIin peripheral blood monocytes (57). Oth-ers have shown that D fragments haveneither pro- nor antiinflammatory effectson monocytes/macrophages (58,59).

Fibrin fragment E (FnE). So far, little isknown regarding the inflammatory po-tential of FnE. Various groups reportedthat FnE has angiogenic activity (60–62),while fibrinogen fragment E (FgnE) in-hibits angiogenesis (62,63). In rat peri-toneal macrophages, FnE as well as FgnEinduced IL-6 production, which was sup-posed to be mediated by binding toCD11c (58). In the human monocytic cellline, THP-1–induced IL-1β productionwas increased by adherent FnE, but notby fragment D or FgnE (59). In additonto the studies on physiological FnE, the



biological activity of FnE is often associ-ated with a fragment named NDSKII(N-terminal disulfide knot II). NDSKII isgenerated synthetically via the cleavageof fibrinogen by cyanogen bromide andthrombin digestion. The resulting prod-uct is similar—but not identical—to thephysiological FnE (FnE: Aα17–78,Bβ15–122 and γ1–62; NDSKII: Aα17–51,Bβ15–118, γ1–78) (19,64). Bach et al. stud-ied the interaction of NDSKII usinghuman umbilical vein endothelial cells(HUVECs). Binding assays demonstratedthat the interaction of NDSKII is depen-dent on the Bβ15–42 region, since NDSK(generated after cyanogen bromide diges-tion without thrombin cleavage) does notexpose Bβ15–42 and therefore did notshow any affinity to HUVECs. Moreover,NDSKII binds to VE-cadherin but not toPECAM-1, ICAM-1 or various integrins(65) and facilitates leukocyte migration(48). In detail, lymphocyte migration de-pends on VE-cadherin and is inhibited byBβ15–42, while monocyte and neutrophilmigration is mediated by the binding ofthe α chain (NDSKII to CD11c). ICAM-1antibody only partially inhibited migra-tion of all three cell types (48).

Bβ15–42. Bβ15–42, a fragment of theN-terminal β chain, is generated by plas-min cleavage of fibrin. In contrast to laterstudies, Skogen et al. demonstrated thatthe fragment Bβ1–42 is a potent chemoat-tractant for neutrophils and fibroblasts,independent of the FpB sequence (66).Bβ15–42 also was capable of inducingIL-8 expression in human oral squamouscell carcinoma cells. Antibodies againstBβ15–42 inhibited fibrin-induced IL-8 ex-pression, while a peptide representing asequence of the N terminus of the region(GHRP) mimicked fibrin exposure (67).However, later studies mainly reportedthe immunosuppressive potential ofBβ15–42 being protective in variouspathologic conditions such as ischemia-reperfusion injury.

Thus, Bβ15–42 protects the myocar -dium against ischemia-reperfusion injuryby reducing infarct size and leukocyteaccumulation. Interestingly, the protec-tive effect was abrogated in fibrinogen-

deficient mice, suggesting that Bβ15–42reduces fibrinogen- dependent inflamma-tion. Furthermore, Bβ15–42 reducedNDSK II–induced leukocyte recruitmentby competing with it for binding toVE-cadherin (48). This work has beentranslated into a multicenter phase IIaclinical trial investigating the effects ofBβ15–42 (FX06) on myocardial infarctsize. In summary, Bβ15–42 significantlyreduced the size of the necrotic core zoneof infarcts while total late enhancementwas not significantly different betweencontrol and Bβ15–42–treated groups (68).

In a pig model of hemorrhagic shock,Bβ15–42–treated animals showed improvedpulmonary and circulatory function.Bβ15–42 reduced plasma IL-6 and neu-trophil influx into the myocardium, liverand small intestine, protecting these organsfrom shock (69). Moreover, Bβ15–42 func-tions as a signaling molecule. In two dif-ferent shock models—Dengue shock syn-drome and LPS- induced shock model,Bβ15–42 preserved endothelial barrierfunction by inhibiting stress- inducedopening of EC adherens junctions (70).Cell-to-cell contact between ECs is formed

Figure 2. Modulation of inflammation by fibrin(ogen) and their degradation products. Fol-lowing 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) modu-lates the inflammatory response by affecting leukocyte migration, but also by induction ofcytokine/chemokine expression mostly via Mac-1 signaling. Fibrin fragment E also inducescytokine expression and leukocyte recruitment/migration by binding to VE- cadherin,which is inhibited by Bβ15–42. Furthermore, Bβ15–42 preserves stress- induced endothelialbarrier function by inhibiting Rho-kinase activation and subsequent junction opening. NO,nitric oxide; Mac-1, macrophage antigen 1; PI3K, phosphoinositide-3-kinase; TNFα, tumornecrosis factor-α.


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mainly by VE-cadherin, which in turn isunder the control of RhoGTPases regulat-ing actin dynamics and junction stability.Rho-kinase is activated in response tostress, and causes loss of function of theendothelial barrier. Bβ15–42 preventedRho-kinase activation by dissociating Fynfrom VE-cadherin, which in turn associ-ates to p190RhoGAP. Bβ15–42–treated ani-mals had improved survival rates and re-duced hemoconcentration and fibrinogenconsumption (70). In a cardiac transplantmodel, Bβ15–42 also attenuated the ischemia-reperfusion injury (71). Thus,Bβ15–42 is a promising therapeutic agent;however, the full mechanism of action isstill under investigation.

Other fragments. Staton et al. proposeda potential role for a 24-amino acid frag-ment derived from the N terminus of theα chain of FgnE named alphastatin. Thispeptide exhibited antiangiogenic effectsby inhibiting growth factor-mediated mi-gration, proliferation and tubule forma-tion of human dermal microvascularECs. In a syngeneic tumor model, al-phastatin disrupted endothelium layers,caused widespread thrombosis and at-tenuated tumor growth (72).

Recently, a novel fragment of the Bβ chain (Bβ43–63) was identified. Thefragment released after plasmin cleavageof fibrin had no effect on EC prolifera-tion or migration, but inhibited tubuleformation partly owing to cytotoxic ef-fects on ECs. Moreover, Bβ43–63 reducedadhesion of ECs to the extracellular ma-trix by binding to and blocking integrinαVβ3, exhibiting antiangiogenic and anti-tumor properties (73).

However, further fragments such as α chain fragments are generated duringfibrinolysis while their function still remains elusive. Figure 2 depicts aschematic overview of the inflammatoryeffects of fibrin(ogen) and fibrin degra-dation products.

CONCLUSIONIt is undisputed that inflammation acti-

vates the coagulation system and viceversa. Our current knowledge suggeststhat most players within the coagulation

cascade have proinflammatory properties.In contrast, the peptide Bβ15–42 mediatespotent antiinflammatory effects. There-fore, any modulation of the coagulationsystem may reduce inflammation on oneside, but on the other side may inducebleeding. Thus, targeting the proinflam-matory aspects of coagulation, without af-fecting coagulation itself, might representa novel therapeutic strategy within thetreatment of inflammatory conditions.

High levels of fibrin fragments in sep-tic patients with organ dysfunction sug-gest an increased fibrin turnover. Diseaseseverity and outcome have not been cor-related with fibrin fragments. Therefore,it might be of further interest to evaluatepotential implications of fibrin degrada-tion products as biomarkers of inflam-matory conditions.

ACKNOWLEDGMENTThis work is supported by the

Deutsche Forschungsgesellschaft(SFB834, project B4).

DISCLOSUREThe authors declare that they have no

competing interests as defined by Molecu-lar Medicine, or other interests that mightbe perceived to influence the results anddiscussion reported in this paper.

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