Pharmacological Approaches and Strategies for Therapeutic Modulation of Fibrinogen

Handley, Dean A.; Hughes, Thomas E.

doi:10.1016/s0049-3848(97)00091-1

Cited by 20 publications

(12 citation statements)

References 191 publications

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“…We observed dose-dependent elevation of [Ca 2ϩ ] i when hFbg was added to purified PMN. The higher concentration of hFbg used (2 mg/ml), which is within the normal range of Fbg concentration in plasma (23), caused a rapid and transient rise in cytosolic calcium, similar to that induced by FMLP (10 Ϫ7 M; Fig. 1) or 20 g of immune complexes (not shown), two well-known Ca 2ϩ -mobilizing stimuli.…”

Section: Human Fbg Induces Transient Rise In [Ca 2ϩ ] I In Purified Nmentioning

confidence: 57%

“…We hypothesize that during an inflammatory process, chemoattractants, early adhesion, or cytokines could prime neutrophils in circulation or in extravascular sites, turning them into sensitive targets for fibrinogen. On the other hand, during the fibrinolytic cascade, fibrinogen is rapidly converted into cleavage products (23), limiting the activation potential of Fbg-PMN interactions. In this regard, we have also described that thrombin completely abrogated the hFbg effect on neutrophil degranulation.…”

Section: Discussionmentioning

confidence: 99%

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Fibrinogen Promotes Neutrophil Activation and Delays Apoptosis

Rubel

Fernández

Dran

et al. 2001

The Journal of Immunology

122

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The acute phase of the inflammatory response involves an increase in the concentrations of different plasma proteins that include fibrinogen (Fbg) and multiple proinflammatory mediators. In parallel, neutrophil activation is thought to play a crucial role in several inflammatory conditions, and it has been recently demonstrated that Fbg specifically binds to the α-subunit of CD11b/CD18 on neutrophil surface. Although several reports have shown that CD11b engagement modulates neutrophil responses, the effect of human Fbg (hFbg), one of CD11b physiologic ligands, has not been exhaustively investigated. We have now shown that incubation of purified neutrophils with hFbg induces a transient and rapid elevation of free intracellular Ca2+. This early intracellular signal is accompanied by changes in the expression of neutrophil activation markers, including enhancement of CD11b and CD66b, and down-regulation of FcγRIII. In addition, we have evaluated the effect of hFbg on two functional events related to expression and resolution of inflammation: cytotoxic capacity and rate of neutrophil apoptosis. We have found that activation of neutrophils by hFbg resulted in both enhancement of phagocytosis and Ab-dependent cellular cytotoxicity, and delay of apoptosis. We conclude that during inflammatory processes, soluble Fbg could influence neutrophil responses, increasing and prolonging their functional capacity.

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Section: Human Fbg Induces Transient Rise In [Ca 2ϩ ] I In Purified Nmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Fibrinogen Promotes Neutrophil Activation and Delays Apoptosis

Rubel

Fernández

Dran

et al. 2001

The Journal of Immunology

122

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“…No drugs are known that have a specific effect on plasma fibrinogen levels, but several drugs influence plasma fibrinogen levels as an additional effect (see Table 2). 40–45 The most studied drugs are platelet aggregation inhibiting drugs such as ticlopidine and the lipid lowering fibrates. Both types of drugs decrease the plasma fibrinogen level by about 10%, and bezafibrate lowers fibrinogen levels even more in patients with diabetes 40,46,47.…”

Section: Effect Of Drugs On Fibrinogenmentioning

confidence: 99%

Effects of Diet, Drugs, and Genes on Plasma Fibrinogen Levels

Maat¹

2001

Annals of the New York Academy of Sciences

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Plasma levels of fibrinogen have been identified as independent risk predictors of cardiovascular disease. This has greatly increased interest in the regulation of plasma fibrinogen levels. Many demographic and environmental factors are known to affect fibrinogen levels, such as diet, use of several drugs, age, smoking, body mass, gender, physical exercise, race, and season. Additionally, it is also known that genetic factors determine the fibrinogen levels, and also that they determine the response of fibrinogen levels to environmental factors. Estimates, based on twin studies, suggest that 30–50% of the plasma fibrinogen level is genetically determined. The effect of dietary components on plasma fibrinogen levels is modest. Several components have been identified as factors that influence fibrinogen levels. Among those are fish oil, other lipids, and fibers. Dietary components that were expected to have an effect on fibrinogen, but for which no association was observed are black and green tea. Several drugs are known to influence fibrinogen levels, the most studied of which are platelet aggregation inhibiting drugs, such as ticlopidine, and the lipid lowering fibric acid derivatives (fibrates). Both types of drugs decreased the plasma fibrinogen level by about 10%, and bezafibrate lowers fibrinogen even more in patients with diabetes. No clear effect was observed for the HMG‐CoA reductase inhibitors (statins). In the Bezalip study, fibrinogen levels decreased in patients treated with bezafibrate, but this had no clear effect on the risk of cardiovascular disease. This suggests that several mechanisms influence the fibrinogen level and that these mechanisms may contribute differently to cardiovascular disease. Several variations in the fibrinogen genes have been described and especially variations in the promoter region of the fibrinogen β‐gene are interesting, because the synthesis of the fibrinogen Bβ chain is considered to be the rate limiting step in the fibrinogen biosynthesis. In many studies the fibrinogen β‐gene polymorphisms (−455G/A, −148C/T, and BclI) are found to be associated with the plasma levels of fibrinogen. However, they are not associated with the risk of cardiovascular events, although in several studies an association with the severity and progression of atherosclerosis has been reported. It has also been observed frequently that the fibrinogen β‐gene promoter polymorphisms are associated with the response of fibrinogen levels to environmental factors, such as exercise and trauma. In conclusion, plasma fibrinogen levels are regulated by an interesting and complex interplay between environmental and genetic factors.

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“…Hyperfibrinogenaemia is commonly observed in cows with increased hepatocellular production of this acute phase protein in response to moderate or marked systemic inflammation (Welles et al, 1993). Handley and Hughes (1997) underlined that hepatic fibrinogen synthesis is enhanced by thrombin. The plasma concentration of fibrinogen directly influences both the rate of fibrin formation and the fluidity of blood, so it can lead to hypercoagulation in the blood and abnormal fibrin deposition.…”

Section: Discussionmentioning

confidence: 99%

Crosstalk between coagulation and inflammation in mastitis and metritis in dairy cows

Bobowiec

Wessely-Szponder

Hola³

2009

Acta Veterinaria Hungarica

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Coagulation and inflammation are closely related as part of the mechanisms of host defence during a severe infection. The aim of this study was to investigate the relation between thrombin as a factor in both the coagulative and inflammatory processes and neutrophil secretory function on the basis of lactoferrin (LF), elastase and myeloperoxidase release in the course of mastitis and metritis in cows. Thrombin generation was measured on the basis of hydrolysis of SAR-PRO-ARG-pNA and lactoferrin concentration was estimated by an ELISA method. The greatest thrombin generation was observed in the metritis group (1.18 ± 0.62 IU). The level of LF was the highest in the group of cows with mastitis (0.74 ± 0.55 mg/ml) in the first phase of the disease. In the second phase of the diseases the level of serum LF in cows with mastitis diminished to the value of 0.41 ± 0.16 mg/ml, whereas in cows with metritis the level of LF increased to 0.51 ± 0.17 mg/ml. This study reveals that the excessive production of thrombin not only causes hypercoagulatory disorders but also exaggerates neutrophil function by the release of some enzymes which may play a destructive role during disseminated intravascular coagulation (DIC). These enzymes also inhibit anticoagulative systems, thus potentially worsening the course of the disease.

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Pharmacological Approaches and Strategies for Therapeutic Modulation of Fibrinogen

Cited by 20 publications

References 191 publications

Fibrinogen Promotes Neutrophil Activation and Delays Apoptosis

Fibrinogen Promotes Neutrophil Activation and Delays Apoptosis

Effects of Diet, Drugs, and Genes on Plasma Fibrinogen Levels

Crosstalk between coagulation and inflammation in mastitis and metritis in dairy cows

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