Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0155339 (Brown)
 12,436 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A number of species respond to bacterial endotoxin (lipopolysaccharide [LPS]) wherein cells of the monocyte-macrophage lineage are rapidly induced either directly or via T-cell collaboration to initiate the extrinsic coagulation protease pathway. This results in fibrin formation and deposition as well as consumption of plasma coagulation proteins. It has been claimed that this cellular response, basic to the Shwartzman reaction, is lacking in rats and may account for the more limited severity of the Shwartzman reaction in this species. We examined the in vitro lymphoid procoagulant response in Fischer 344, Brown Norway, and Lewis rats. When peripheral blood mononuclear cells (PBM) were stimulated in vitro with LPS, a procoagulant activity (PCA) response was observed when assayed by acceleration of clotting of recalcified human or rat platelet-poor plasma. The response was rapid, with a maximum achieved at 4 h. PCA was not physically dissociated from viable PBM by 5 mM EDTA, which is consistent with the presence of an intrinsic plasma membrane initiator molecule rather than calcium-bound gamma-carboxylated glutamic acid-containing proteases. The induction of monocyte PCA was prevented by incubation of cells with cycloheximide or actinomycin D, implicating a new biosynthetic requirement. Cultivation of PBM with warfarin did not diminish the function of the effector PCA, nor did vitamin K augment the function of the endotoxin-induced PCA, indicating that the functional activity was not attributable to gamma-carboxylated glutamic acid-containing proteins. No inhibition of the cellular PCA molecule was produced by serine protease inhibitors. The LPS-induced PCA appeared to involve a tissue factor-like molecule since both factors X and VII were required in mediating PCA. Isolation of monocytes and T lymphocytes from LPS-stimulated PBM demonstrated that PCA was present in the monocyte-rich fraction. When isolated rat T lymphocytes and monocytes were separately exposed to LPS, PCA was not induced. In contrast, when the cells were combined, LPS induced PCA, indicating that the PCA response involved cellular collaboration between cells present in T lymphocyte and monocyte populations.
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PMID:Lymphoid procoagulant response to bacterial endotoxin in the rat. 384 Jul 72

Coagulation factor Xa is a plasma serine protease that catalyzes prothrombin to thrombin conversion, which, in turn, leads to the generation of the fibrin clot. Of the several parameters that govern the plasma level of factor Xa, control of its catabolism is of crucial importance. However, little is known regarding the mechanisms by which factor Xa is catabolized. In the present study we examine the cellular basis for the uptake and degradation of factor Xa. 125I-Factor Xa was degraded by hepatoma cells and embryonic fibroblasts via a process which required cell surface-bound tissue factor pathway inhibitor (TFPI), a potent inhibitor of factor Xa. Uptake and degradation of cell surface-bound 125I-TFPI was also markedly stimulated in response to factor Xa binding. The intracellular kinetics of 125I-factor Xa and cell surface-bound 125I-TFPI display a strikingly similar pattern, suggesting that factor Xa and cell surface-bound TFPI are taken up as a bimolecular complex. Using cell lines either deficient in low density lipoprotein receptor-related protein, an endocytic receptor that mediates the degradation of uncomplexed TFPI (Warshawsky, I., Broze, G.J., Jr., and Schwartz, A.L. (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 6664-6668), or deficient in tissue factor (TF), an integral membrane protein capable of forming quarternary complexes with factor Xa, TFPI, and factor VIIa, we demonstrated that the receptor that mediates the uptake and degradation of factor Xa-TFPI complex was neither low density lipoprotein receptor-related protein nor TF. As the vascular endothelial cell surface retains a substantial pool of TFPI (Sandset, P.M., Alildgaard, U., and Larsen, M.L. (1988) Thromb. Res. 50, 803-813; Novotny, W.F., Brown, S.G., Miletich, J.P., Rader, D.J., and Broze, G.J., Jr. (1991) Blood 78, 387-393), our data suggest that endothelial cell surface TFPI may be actively involved in the clearance of factor Xa from the circulation via mediated uptake and degradation.
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PMID:Receptor-mediated endocytosis of coagulation factor Xa requires cell surface-bound tissue factor pathway inhibitor. 862 21

Tissue-factor-pathway inhibitor (TFPI) is a multivalent inhibitor with three tandemly arranged Kunitz- type-protease-inhibitor (KPI) domains. Previous studies [Girard, Y. J., Warren, L. A., Novotny , W. F., Likert, K. M., Brown, S. G., Miletich, J. R & Broze, G. J. (1989) Nature 338, 518-520] by means of site-directed mutagenesis indicated that KPI domain 1 interacts with factor VIIa, that KPI domain 2 interacts with factor Xa, and that KPI domain 3 is apparently without inhibitory function. To elucidate the reaction mechanism of this complex inhibitor, we followed a different approach and studied the inhibitory properties of fragments of TFPI obtained by expression in yeast. Results obtained with TFPI-(1-161)-peptide and separate recombinant TFPI-KPI domains 1, 2 and 3 showed that KPI domain 1 inhibited factor VIIa/tissue factor (Ki = 250 nM), KPI domain 2 inhibited factor Xa (Ki = 90 nM), and that KPI domain 3 was without detectable inhibitory function. Studies with separate KPI domains also showed that KPI domain 2 was mainly responsible for inhibition of trypsin (Ki = 0.1 nM) and chymotrypsin (Ki = 0.75 nM), whereas KPI domain 1 inhibited plasmin (Ki = 26 nM) and cathepsin G (Ki = 200 nM). The structural basis for the interaction between serine proteases and KPI domains is discussed in terms of putative three-dimensional models of the proteins derived by comparative molecular-modelling methods. Studies of factor Xa inhibition by intact TFPI (Ki approximately 0.02 nM) suggested that regions other than the contact area of the KPI domain, interacted strongly with factor Xa. Secondary-site interactions were crucial for TFPI inhibition of factor Xa but was of little or no importance for its inhibition of trypsin.
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PMID:Inhibitory properties of separate recombinant Kunitz-type-protease-inhibitor domains from tissue-factor-pathway inhibitor. 863 47