The effects of plasma proteins on controlling the activity of matrix metalloproteinases (MMPs, matrixins) have been the focus of numerous studies, although only a few have examined the influence of matrixins on plasma proteins. Recently, it has been shown that MMPs may play a role in the degradation of fibrin. We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system. Our data demonstrate that the catalytic domains of MMP-8, MMP-12, MMP-13, and MMP-14 can proteolytically process fibrinogen and, with the exception of MMP-8, also inactivate Factor XII (Hageman factor). We have identified the amino termini of the major protein fragments. Cleavage of fibrinogen occurred in all chains and resulted in significantly impaired clotting. Moreover, rapid proteolytic inactivation of Factor XII (Hageman factor) by MMP-12, MMP-13, and MMP-14 was noted. These results support the hypothesis of an impaired thrombolytic potential of MMP-degraded Factor XII in vivo. MMPinduced degradation of fibrinogen supports a plasminindependent fibrinolysis mechanism. Consequently, degradation of these proteins may be important in inflammation, atherosclerosis, and angiogenesis, all of which are known to be influenced by MMP activity.The matrix metalloproteinases, MMPs 1 and matrixins, form a family of structurally and functionally related zinc-containing endopeptidases. Together they are able to degrade most of the constituents of the extracellular matrix such as basement membrane, collagens, proteoglycans, fibronectin, and laminin (1). Thus, they are implicated in connective tissue remodeling processes associated with embryonic development, pregnancy, growth, and wound repair (2). The deleterious potential of the MMPs is normally controlled by the endogenous and specific tissue inhibitors of metalloproteinases or the more general nonspecific ␣ 2 -macroglobulin (3). Disturbance of the well balanced equilibrium of MMPs and tissue inhibitors of metalloproteinases results in pathological situations such as rheumatoid and osteoarthritis, atherosclerosis, tumor growth, metastasis, and fibrosis (4-8). In addition to degradation of extracellular matrix constituents, plasma proteins such as serpins (9) or fibrinogen and cross-linked fibrin (10-12) are also cleaved.Fibrinogen is a 340-kDa dimeric glycoprotein consisting of a pair of three polypeptide chains A␣, B␤, and ␥ that are interconnected by 29 disulfide bonds. The amino termini of these chains are joined together in a central domain that can be isolated as a single fragment from a plasmin digestion of fibrinogen (13). During blood coagulation, fibrinogen participates in both the cellular phase and the fluid phase of blood clot formation (14, 15). Fibrinogen can be converted into an insoluble fibrin clot as a consequence of thrombin-catalyzed removal of fibrinopeptides A (FpA, A␣-(20 -35)) 2 and B (FpB...

A relationship was sought between the tissue concentrations of interleukin (IL)-8, matrix metalloproteinase (MMP)-8 and MMP-9, and the numbers of the various leukocytes infiltrating the lower uterine segment stroma during parturition. Biopsy specimens of the lower uterine segment were obtained from 63 women undergoing Caesarean section at various stages of cervical dilatation at term. The concentrations of IL-8, MMP-8 and MMP-9 were determined with enzyme-linked immunosorbent assays, and the leukocytes were quantified immunohistochemically. The median IL-8 concentration (pg/mg total protein) rose significantly from 17.2 at < 2 cm dilatation, to 26.5 at 2 to < 4 cm dilatation, and 1954.0 at 4-6 cm dilatation, and remained at approximately this concentration at > 6 cm dilatation. The median MMP-8 concentration (ng/mg total protein) increased significantly from 32.2 at < 2 cm dilatation to 114.2 at > 6 cm dilatation. The median MMP-9 concentration (ng/mg total protein) rose significantly from 15.4 at < 2 cm dilatation to 102.1 at > 6 cm dilatation. The number of neutrophils was significantly higher at 4-6 cm and > 6 cm dilatation than at > 2 cm, reaching maximum values at > 6 cm dilatation. The findings in this study support the hypothesis that IL-8-induced infiltration of the cervical stroma by neutrophils and subsequent release of proteinases may play a key role in parturition.

No abstract

Degranulation of polymorphonuclear leukocytes (PMNL) occurs during extracorporeal circulation. A degranulation-inhibiting protein identical to angiogenin was recently isolated from high-flux dialyzer ultrafiltrate. This protein inhibits the release of lactoferrin and metalloproteinases from PMNL in vitro. In the present study, we investigated end-stage renal disease patients undergoing regular hemodialysis treatment with either high-flux dialyzers (n = 51) or low-flux dialyzers (n = 44), and chronically uremic patients undergoing hemodiafiltration (n = 30). Hemodialysis therapy with low-flux polysulfone or cellulose triacetate membranes caused no or only minimal reduction (≤8%) of plasma angiogenin levels within 2 h of dialysis treatment associated with a 1.6-fold lactoferrin release from PMNL. Hemodialysis therapy with high-flux membranes (e.g. cellulose triacetate, polymethylmethacrylate) or hemodiafiltration resulted in a reduction of plasma angiogenin levels by 20–40% after 2 h associated with a nearly 4-fold PMNL lactoferrin release. The release of PMNL elastase was not affected by the different treatment modalities used. We conclude that high angiogenin plasma levels protect against lactoferrin release from PMNL during extracorporeal circulation in chronically uremic patients. A decrease of plasma angiogenin between 20 and 40% during extracorporeal circulation, however, results in marked PMNL lactoferrin release. This novel mechanism may explain, at least in part, PMNL degranulation also in non complement activating high-flux membranes.

No abstract