Effect of fibrinogenolytic products D and E on fibrinogen and albumin synthesis in the rat.

Franks, John; Kirsch, Ralph E.; Frith, L.; Purves, Langley R.; Franks, W T; Franks, Jonathon; Mason, Philip J.; Saunders, S. J.

doi:10.1172/jci110069

Cited by 37 publications

(16 citation statements)

References 26 publications

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“…It has been suggested that the plasminolytic fragments of fibrinogen, specifically fragment D, only stimulated an increased synthesis of fibrinogen because no increase in either haptoglobin or albumin was detected after infusion of fragment D into rabbits (6) and rats (5). Our data demonstrate that fragment D or E has no direct effect on the hepatocyte's production offibrinogen-rather that the stimulation comes through the action of fragment D or E or the leukocyte.…”

Section: Resultsmentioning

confidence: 55%

Regulation of fibrinogen synthesis by plasmin-derived fragments of fibrinogen and fibrin: an indirect feedback pathway.

Ritchie¹,

Levy²,

Adams³

et al. 1982

Proc. Natl. Acad. Sci. U.S.A.

102

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The effect of plasmin-derived fibrinogen fragments on the biosynthesis of fibrinogen was investigated in cultured monolayers ofrat hepatocytes. Incubating the cells with several concentrations of either fibrinogen or fibrin fragment D or E had no effect on the synthesis and secretion of fibrinogen by these cells. However, if the fragments were incubated with isolated peripheral blood leukocytes, they caused these cells to secrete a factor that when added to the hepatocytes caused an increase in fibrinogen synthesis 4-to 6-fold over controls. Moreover, the hepatocyte-stimulating factor also affected the production of several other proteins produced by the hepatocyte. These results demonstrate that both fragments D and E can stimulate hepatic fibrinogen synthesis via an indirect leukocyte-mediated pathway.When fibrinogen or fibrin is acted upon by plasmin, a series of well-defined proteolytic cleavages occur that ultimately result in the formation of two different molecular species that come from different parts of the molecule. The fragments are designated E, which is derived from the amino-terminal region of the molecule and has a Mr of 40,000, and D, which is derived from the carboxy-terminal region and has a Mr of 80,000 (1, 2). Slightly more than a decade ago, Barnhardt et al (3) infused fibrinolytic fragments into dogs and found a significant increase in fibrinogen synthesis as judged by an increased immunofluorescence of liver slices taken several hours after the infusion. The observation that some of the plasminolytic fragments derived from fibrinogen or fibrin maybe involved in the regulation of fibrinogen synthesis was suggestive of a novel regulatory pathway that could be an important part of the inflammatory response.A number of reports has appeared (4-8) which seem to verify and expand the study of Barnhardt et al.-that is, they suggest that either fibrinogen degradation products or fibrin degradation products (FDP or fdp, respectively) play an important role in regulating fibrinogen synthesis. On the other hand, several other studies (9)(10)(11)(12) have been unable to demonstrate any effects of FDP on fibrinogen production. Unfortunately there is no consistent explanation for these conflicting observations. Thus, whether FDP play any significant role in regulating fi--brinogen is still unresolved.In this report we have characterized a role that FDP play in regulating fibrinogen synthesis by exposing cultured hepatocytes to purified fragments offibrinogen and fibrin. We provide evidence that the fragments, do not stimulate fibrinogen synthesis by direct interaction with the hepatocyte. However, the fragments do affect fibrinogen synthesis by stimulating leukocytes to produce a potent hepatocyte-stimulating factor (HSF), which then acts on the hepatocytes to increase fibrinogen synthesis. We also demonstrate that both fragments are equally potent in causing the production of HSF. These results show the pathway by which FDP stimulate fibrinogen production. MATERIALS AND METHODSPreparation of R...

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Section: Resultsmentioning

confidence: 55%

Regulation of fibrinogen synthesis by plasmin-derived fragments of fibrinogen and fibrin: an indirect feedback pathway.

Ritchie¹,

Levy²,

Adams³

et al. 1982

Proc. Natl. Acad. Sci. U.S.A.

102

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“…For this particular molecule, the occurrence of a pseudo-cyclic form, stabilized by an intramolecular hydrogen bond, has been speculated (3). Such a conformation would meet the spatial dequirements postulated (3,4) for the ring dimension (5.15 A) to fit into the hydrophobic portion of the cellulose macromolecule. Moreover, detailed crystallographic investigations on MMNO (6)(7)(8) coupled with computer simulation (9) have underlined that the solvent molecule should possess an hydrophobic end, in order to prevent any segmental recombination of the cellulose chains.…”

Section: Introductionmentioning

confidence: 87%

“…In the search for new cellulose organic solvents, tertiary amine oxide molecules have particularly attracted attention (1)(2)(3)(4)(5). In the patents, a claim for tertiary amine oxide to be a solvent is to be cyclic, as for example N-methylmorpholine N-oxide (abbreviated MMNO).…”

Section: Introductionmentioning

confidence: 99%

Cellulose organic solvents: V. Conformational aspects of N,N-dimethyl ethanolamine N-oxide in its crystalline and diluted states

Maia¹,

Péguy²,

Pérez³

1984

Can. J. Chem.

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Can. J. Chem. 62, 6 (1984). N,N-Dimethyl ethanolamine N-oxide (DMEAO) belongs to the class of tertiary amine oxide molecules that are good solvents for cellulose, although not being cyclic. Crystallographi: investigation shows that anhydrous DMEAO is monoclinic, space group Cc, a = 25.725(9), b = 7.023(4), c = 9.483(5) A, P = 101.16(10)", Z = 12. The crystal structure has been solved by direct methods and refined to a final R value of 0.063 for 575 observed reflexions. Threc independent molecules are found within the asymmetric unit; one of these displays a pseudo-cyclic form dictated by the occurrence of a strong intramolecular hydrogen bond. Conformational investigation of DMEAO in solution, using ir and nmr spectroscopy shows that this pseudocyclic form is more likely to occur in diluted states. These findings are related to the ability of this tertiary amine oxide to act as a good solvent, up to a watcr content of onc water molecule per DMEAO molecule. E. R. MAIA, A. PEGUY et S. PEREZ. Can. J . Chcm. 62, 6 (1984). Bien que ne possidant pas de structure cyclique, le N-oxyde de N,N-dimkthyl ethanolamine (DMEAO) appartient h cette nouvelle classe de solvants organiques de la cellulose, que constituent les oxydes d'amines tertiaires. A 1'Ctat cristallin, la forme anhydre du DMEAO cristallise dans le group: d'espace Cc du systkme n~onoclinique, caractCrisC par les paramktres suivants: a = 25.725(9), 6 = 7.023(4), c = 9.483(5) A, P = 101.16(10)", Z = 12. La structure cristalline a CtC rCsolue par niCthodes directes et affinCe jusqu'h un facteur de reliabilitC final R = 0.063 calcult pour 575 rkflexions indkpendantes. La resolution de cette structure permet dc mettre en Cvidence l'existence de 3 molCcules cristallographiquement indkpendantes, parmi lesquelles apparait une molecule dans une conformation pseudo-cyclique stabiliske par une forte liaison hydrogkne intramolCculaire. Les Ctudes de spectroscopie ir et rmn en milieu diluC permettent de conclure que l'existence de cette conformation est aussi privilCgiCe cn solution. Ccs diffkrcnts ClCments permettent d'expliquer pourquoi cet oxyde d'amine tertiaire non cyclique agit comme un bon solvant de la cellulose et ce jusqu'a unc valeur limite correspondant a un Ctat monohydratk du DMEAO.

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“…In these studies, stimulation of fibrinogen synthesis by FDP fragment D (FDP-D) was 3-to 5-fold higher than by FDP fragment E (FDP-E) (4). A similar effect of FDP-D was subsequently seen in rats (5,6). In vitro perfusion of isolated rat liver (7) has also identified FDP-D ability to stimulate fibrinogen synthesis.…”

mentioning

confidence: 89%

Stimulation of fibrinogen synthesis in cultured rat hepatocytes by fibrinogen degradation product fragment D.

LaDuca

Tinsley

Dang³

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

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The direct stimulation of fibrinogen biosynthesis by fibrinogen degradation produces (FDPs) was studied in rat hepatocyte cultures. Pure rat FDP fragment D (FDP-D) (Mr 90,000) and FDP fragment E (FDP-E) (Mr 40,000) and mixtures of the two (FDP-DE) were added to rat hepatocytes cultured in serum-free hormonally defined medium. Hydrocortisone (20 Fibrinogen, the central component ofthe coagulation system, is synthesized in the liver. The plasma level of fibrinogen has been suggested to be an independent risk factor for coronary (1) and cerebral occlusive arterial diseases (2). Hence, it is extremely important to understand the molecular mechanisms controlling fibrinogen synthesis. Plasmin digestion of fibrinogen and fibrin results in generation of fibrinogen degradation products (FDPs) and fibrin degradation products, respectively. Our studies have previously shown that i.v. infusion of homologous FDPs into rabbits stimulates fibrinogen synthesis (3,4). In these studies, stimulation of fibrinogen synthesis by FDP fragment D (FDP-D) was 3-to 5-fold higher than by FDP fragment E (FDP-E) (4). A similar effect of FDP-D was subsequently seen in rats (5, 6). In vitro perfusion of isolated rat liver (7) has also identified FDP-D ability to stimulate fibrinogen synthesis.Studies of FDP effects on fibrinogen synthesis in hepatocyte culture have produced discrepant results (8-11). Both direct (8) and indirect (9) effects of FDPs on fibrinogen synthesis have been reported. These discrepancies are difficult to resolve, due, in part, to a diversity of cell culture conditions. Because a sound understanding of the regulatory mechanisms of fibrinogen synthesis is of important physiologic and clinical value, we have further studied the direct role of FDPs in fibrinogen synthesis. These studies evaluate the effect of homologous rat FDP preparations of fibrinogen biosynthesis in rat hepatocytes cultured in a serum-free, hormonally defined medium. Animals. Adult male Sprague-Dawley rats (200-250 g) were used (Charles River Breeding Laboratories) for preparation of hepatocytes and rat tail collagen. MATERIALS AND METHODSPreparation of Hepatocytes. Rat hepatocytes were prepared by a modification (12) of the collagenase perfusion method of Seglen (13). The isolated cells were washed and prepared for culture by the method described (14). Hepatocyte viability was->90% in all cultures used as determined by trypan blue exclusion and lactic dehydrogenase released into the medium.Culture Conditions. Hepatocytes were cultured in serumfree hormonally defined (SFHD) medium as described (15). SFHD medium consisted of RPMI 1640 supplemented with copper (0.1 mM), selenium (3.0 nM), zinc (50 pM), and penicillin/streptomycin (100 units/ml). Fungizone (2.5 mg/ ml) was included during the first day of culture. SFHD was further supplemented with either insulin (10 pg/ml) and epidermal growth factor (50 ng/ml) and referred to as SFHD-IE or with insulin, epidermal growth factor, and hydrocortisone (20 AuM) and referred to as SFHD-ICE. Cells (2 x...

show abstract

Effect of fibrinogenolytic products D and E on fibrinogen and albumin synthesis in the rat.

Cited by 37 publications

References 26 publications

Regulation of fibrinogen synthesis by plasmin-derived fragments of fibrinogen and fibrin: an indirect feedback pathway.

Regulation of fibrinogen synthesis by plasmin-derived fragments of fibrinogen and fibrin: an indirect feedback pathway.

Cellulose organic solvents: V. Conformational aspects of N,N-dimethyl ethanolamine N-oxide in its crystalline and diluted states

Stimulation of fibrinogen synthesis in cultured rat hepatocytes by fibrinogen degradation product fragment D.

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