RESUMO
Leptospirosis is a widespread zoonosis caused by pathogenic Leptospira spp. It is an important infectious disease that affects humans and animals. The disease causes economic losses as it affects livestock, with decreased milk production and death. Our group is investigating the genome sequences of L. interrogans targeting surface-exposed proteins because, due to their location, these proteins are capable to interact with several host components that could allow establishment of the infection. These interactions may involve adhesion of the bacteria to extracellular matrix (ECM) components and, hence, help bacterial colonization. The bacteria could also react with the host fibrinolytic system and/or with the coagulation cascade components, such as, plasminogen (PLG) and fibrinogen (Fg), respectively. The binding with the first system generates plasmin (PLA), increasing the proteolytic power of the bacteria, while the second interferes with clotting in a thrombin-catalyzed reaction, which may promote hemorrhage foci and increase bacterial dissemination. Interaction with the complement system negative regulators may help bacteria to evade the host immune system, facilitating the invasion. This work compiles the main described leptospiral proteins that could act as adhesins, as PLG and fibrinogen receptors and as complement regulator binding proteins. We present models in which we suggest possible mechanisms of how leptospires might colonize and invade host tissues, causing the disease. Understanding leptospiral pathogenesis will help to identify antigen candidates that would contribute to the development of more effective vaccines and diagnostic tests.
Assuntos
Interações Hospedeiro-Patógeno , Leptospira/patogenicidade , Adesinas Bacterianas/fisiologia , Animais , Proteínas do Sistema Complemento/fisiologia , Proteínas da Matriz Extracelular/metabolismo , Fibrinogênio/fisiologia , Humanos , Evasão da Resposta Imune , Leptospira/imunologia , Plasminogênio/metabolismoRESUMO
INTRODUCTION: During the fluid phase of hemostasis, fibrinogen is converted into fibrin, but other hemostatic factors are required. Reference values of hemostatic factors are established by manufacturers producing reagents using individuals with a specific genetic background. OBJECTIVE: To establish reference values for hemostatic factors in the Mexican indigenous and Mestizo populations. MATERIAL AND METHODS: We carried out a cross-sectional, descriptive study of healthy adult Mexicans. Clotting activity was evaluated using coagulometric assays. Blood donors were informed about the nature of the study and informed consent was obtained prior to blood being drawn. The protocol was approved by the Ethics Committee of our institution. RESULTS: One hundred and twenty samples were assayed (60 females and 60 males). Fibrinogen was higher in mestizos and in females. Reference values for factor XII ranged from 40-170% in indigenous subjects and from 36-159% in mestizos. Factor VIII ranged from 57-160% in indigenous subjects and from 51-209% in mestizo subjects. Reference values for the other hemostatic factors were also clearly different from the commercial reference values. Reference values for hemostatic factors in the Mexican population are different from traditionally used commercial reference values. There were significant differences between indigenous and mestizo Mexicans in the concentration of hemostatic factors with a tendency among mestizos to have higher factor concentrations. Low levels of plasma factor XII are frequent and perhaps may represent a risk factor for thrombotic events. Using these reference values may individualize the reposition of factors in Mexican hemophiliac patients.
Assuntos
Fatores de Coagulação Sanguínea/fisiologia , Testes de Coagulação Sanguínea , Hemostasia/fisiologia , Adulto , Doadores de Sangue , Estudos Transversais , Etnicidade , Fator VIII/fisiologia , Fator XII/fisiologia , Feminino , Fibrinogênio/fisiologia , Humanos , Masculino , México , Valores de ReferênciaRESUMO
AIMS: Excessive production of nitric oxide (NO) and reactive oxygen species (ROS) in sepsis modulates different cell functions. Since the sepsis severity is associated with the degree of platelet activation, we decided to investigate the role of systemic generation of NO and ROS in modulating the platelet adhesion of lipopolysaccharide (LPS)-treated rats. MAIN METHODS: Platelet adhesion was evaluated using fibrinogen-coated 96-well microtiter plates. Cyclic GMP levels were measured using enzyme immunoassay kit. KEY FINDINGS: Treatment of rats with LPS significantly increased spontaneous platelet adhesion, but reduced the thrombin-activated platelet adhesion when compared with control rats. Chronic treatment of rats with the NO synthase inhibitor L-NAME (20 mg/rat/day, 7 days) prior to LPS injection normalized the increased adhesion in non-activated platelets, but failed to affect the adhesion in thrombin-activated platelets. The cGMP levels were modified neither in non-activated nor in thrombin-activated platelets of LPS-treated rats when compared with control rats. The incubation of non-activated platelets with the O2- scavenger PEG-SOD reversed the stimulatory effect of LPS on spontaneous adhesion, but had no effect in stimulated-platelet adhesion of non-treated or LPS-treated groups. Moreover, pretreatment of rats with the antioxidant N-acetylcysteine (NAC; 150 mg/kg) prevented the increase of non-activated platelet adhesion, and significantly reduced the inhibitory effect of LPS on thrombin-stimulated adhesion. SIGNIFICANCE: Our findings suggest that in LPS-treated rats, NO plays an important modulatory role only in non-stimulated platelet adhesion through cGMP-independent mechanisms, while ROS, directly or by affecting the redox state of the animals, modulates both non-activated and thrombin-activated platelet adhesion.
Assuntos
Plaquetas/efeitos dos fármacos , Fibrinogênio/fisiologia , Lipopolissacarídeos/farmacologia , Adesividade Plaquetária/efeitos dos fármacos , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Acetilcisteína/farmacologia , Animais , GMP Cíclico/metabolismo , Inibidores Enzimáticos/farmacologia , Sequestradores de Radicais Livres/farmacologia , Técnicas In Vitro , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Polietilenoglicóis/farmacologia , Ratos , Superóxido Dismutase/farmacologia , Trombina/farmacologiaRESUMO
The chronic and immediate post-exercise responses in the hemostatic and fibrinolytic systems have been shown to be variable and reflect differing adaptations with ageing and responses to exercise protocols. This study investigated the effects of acute and exhaustive exercise on the amplitude and duration of hemostatic and fibrinolytic responses in young adolescent males. The sample comprised 10 sedentary boys (13.2+/-0.5 years, 55.8+/-11.3kg, 165.7+/-7.4cm), who had not exercised or received any medication for at least 2 weeks before the experiments. The subjects performed exhaustive stepping exercise, consisting of 1s up and down cycles to fatigue. When the subjects were unable to maintain the required stepping rhythm, they were given a 30s recovery period. Following each 30s recovery participants recommenced the stepping cadence until fatigue prevented them continuing. Venous blood samples were drawn before and immediately, 1 and 24h after exercise to assess the following coagulation and fibrinolytic parameters: Platelet counts, activated partial thromboplastin time (aPTT), prothrombin time (PT), coagulation factor VIII (FVIII:C), von Willebrand factor (vWF), fibrinogen concentration, thrombin-antithrombin complex (TAT), D-dimer, plasminogen activator inhibitor (PAI-1), and tissue-type plasminogen activator (t-PA). Immediately following exercise, platelet counts, aPTT, FVIII, vWF and t-PA were significantly elevated in contrast to PAI-1, which decreased significantly until 1h after exercise. FVIII and platelet counts were elevated at 1 and 24h after exercise, respectively. Only the parameters FVIII and PAI-1 did not return to baseline values during the first hour after physical exercise. When compared to adults the results revealed different rates and ranges of coagulation and fibrinolysis parameters being activated by exhaustive exercise in this group of adolescents.
Assuntos
Fatores de Coagulação Sanguínea/análise , Exercício Físico/fisiologia , Hemostasia/fisiologia , Fadiga Muscular/fisiologia , Adolescente , Análise de Variância , Testes de Coagulação Sanguínea , Plaquetas , Criança , Ensaio de Imunoadsorção Enzimática , Teste de Esforço , Fibrinogênio/fisiologia , Humanos , MasculinoRESUMO
Endothelial dysfunction and inflammation play a crucial role in all stages of atherosclerosis, from the beginning, during progression, and, finally, in its highest clinical expression: acute coronary syndromes. In this process, fibrinogen, an acute phase reactant with active participation in endothelial function, thrombosis and inflammation has proved to be an independent variable to cardiovascular risk together with its participation in resistance phenomena to different antithrombotic approaches. The reasons by which fibrinogen is elevated in cardiovascular disease and atherosclerosis are, in general, only incompletely understood; but all cells involved in the atherogenetic process are able to produce cytokines, which induce an acute phase reaction that increases fibrinogen levels in plasma. The potential pathophysiological mechanisms by which elevated fibrinogen levels mediate cardiovascular risk are multiple. Fibrinogen forms the substrate for thrombin an represents the final step in the coagulation cascade, it is essential for platelet aggregation, it modulates endothelial function, it promotes smooth muscle cell proliferation and migration, it interacts with the binding of plasmin with its receptor and, finally, it represents a major acute phase protein. Epidemiological studies have established sufficient evidence to consider fibrinogen as a strong, consistent, and independent cardiovascular risk marker or factor. Based on all these implications, the target of this review is an analysis of physiopathogenic and epidemiologic evidence searching for guidelines to establish whether fibrinogen as a risk factor or marker is the lost link between cardiovascular disease and classic risk factors. CONCLUSION: Analyses of the respective studies suggest that fibrinogen is an important and independent cardiovascular risk factor, clearly associated with conventional risk factors and genetic polymorphisms. Whether or not fibrinogen is causally involved in atherothrombogenesis still remains to be determined and despite of unsolved issues that are waiting conclusive answers, fibrinogen has emerged as an important additional marker of cardiovascular risk.
Assuntos
Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Cardiovasculares , Fibrinogênio/fisiologia , Fatores Etários , Aspirina , Aterosclerose/sangue , Aterosclerose , Aterosclerose , Biomarcadores , Estudos Cross-Over , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares , Doença das Coronárias/sangue , Doença das Coronárias , Doença das Coronárias , Exercício Físico , Seguimentos , Fibrinogênio , Fibrinogênio , Fibrinolíticos , Hipolipemiantes , Inflamação/sangue , Estudos Longitudinais , Polimorfismo Genético , Inibidores da Agregação Plaquetária , Fatores de Risco , Fatores Socioeconômicos , Fumar/efeitos adversosRESUMO
UNLABELLED: Endothelial dysfunction and inflammation play a crucial role in all stages of atherosclerosis, from the beginning, during progression, and, finally, in its highest clinical expression: acute coronary syndromes. In this process, fibrinogen, an acute phase reactant with active participation in endothelial function, thrombosis and inflammation has proved to be an independent variable to cardiovascular risk together with its participation in resistance phenomena to different antithrombotic approaches. The reasons by which fibrinogen is elevated in cardiovascular disease and atherosclerosis are, in general, only incompletely understood; but all cells involved in the atherogenetic process are able to produce cytokines, which induce an acute phase reaction that increases fibrinogen levels in plasma. The potential pathophysiological mechanisms by which elevated fibrinogen levels mediate cardiovascular risk are multiple. Fibrinogen forms the substrate for thrombin an represents the final step in the coagulation cascade, it is essential for platelet aggregation, it modulates endothelial function, it promotes smooth muscle cell proliferation and migration, it interacts with the binding of plasmin with its receptor and, finally, it represents a major acute phase protein. Epidemiological studies have established sufficient evidence to consider fibrinogen as a strong, consistent, and independent cardiovascular risk marker or factor. Based on all these implications, the target of this review is an analysis of physiopathogenic and epidemiologic evidence searching for guidelines to establish whether fibrinogen as a risk factor or marker is the lost link between cardiovascular disease and classic risk factors. CONCLUSION: Analyses of the respective studies suggest that fibrinogen is an important and independent cardiovascular risk factor, clearly associated with conventional risk factors and genetic polymorphisms. Whether or not fibrinogen is causally involved in atherothrombogenesis still remains to be determined and despite of unsolved issues that are waiting conclusive answers, fibrinogen has emerged as an important additional marker of cardiovascular risk.
Assuntos
Doenças Cardiovasculares/epidemiologia , Fibrinogênio/fisiologia , Adulto , Fatores Etários , Idoso , Aspirina/uso terapêutico , Aterosclerose/sangue , Aterosclerose/epidemiologia , Aterosclerose/prevenção & controle , Biomarcadores , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/prevenção & controle , Doença das Coronárias/sangue , Doença das Coronárias/epidemiologia , Doença das Coronárias/prevenção & controle , Estudos Cross-Over , Exercício Físico , Feminino , Fibrinogênio/análise , Fibrinogênio/genética , Fibrinolíticos/uso terapêutico , Seguimentos , Humanos , Hipolipemiantes/uso terapêutico , Inflamação/sangue , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/uso terapêutico , Polimorfismo Genético , Fatores de Risco , Fumar/efeitos adversos , Fatores SocioeconômicosRESUMO
The aim of this study was to investigate the blood viscosity profile and to evaluate the influence of plasmatic (fibrinogen) and cellular (erythrocyte aggregation) factors in a group of hypertensive patients, compared with a normotensive group. We worked with anticoagulated blood of both non diabetic hypertensive patients (n=31), and healthy individuals (n=40). The plasmatic viscosity and whole blood determination were obtained with a cone-plate viscometer. Erythrocyte aggregation was studied by microscopical observation and quantified by an Aggregate Shape Parameter (ASP), defined as the relation projected area/perimeter. Fibrinogen was determined by the Clauss method with a coagulometer. A comparison between these groups led us to assert that whole blood viscosity was significantly higher in hypertensive patients than in the controls at all shear rates. Plasma viscosity values only showed significant differences between both groups at low shear rate (1.15 a 11.56 seg(-1)). The hypertensive patients showed irregular and amorphous aggregates so that ASP appeared significantly higher (p< 0.001) in patients with hypertension (0.69 +/- 0.11) than in healthy subjects (0.25 +/- 0.12). Fibrinogen appeared slightly higher (p<0.01) in the hypertensive group than in the normal group. Several hemorheological parameters play important roles in the pathogenesis of hypertension. Among these factors, several hemorheological parameters could be altered in hypertension (hematocrit, plasma fibrinogen level, erythrocyte deformability and aggregability, plasma and whole blood viscosity). An increased RBC aggregation has been identified as an important factor responsible for disturbing blood rheological behavior in the microcirculation. The present study demonstrates an abnormal erythrocyte aggregation, which was detected by increased ASP values that could be responsible for vascular complications in hypertension.
Assuntos
Hemorreologia , Hipertensão/sangue , Adulto , Idoso , Viscosidade Sanguínea/fisiologia , Agregação Eritrocítica/fisiologia , Feminino , Fibrinogênio/fisiologia , Humanos , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-IdadeRESUMO
El objetivo de este trabajo fue investigar el perfil de viscosidad sanguínea y evaluar la influencia de factores plasmáticos ( fibrinógeno) y celulares ( agregación eritrocitaria ) en un grupo de pacientes hipertensos comparados con un grupo de paciente normotensos. Se trabajó con sangre anticoagulada de pacientes hipertensos no diabéticos (n=3) e indivíduos sanos (n=40). La viscosidad plasmática y de sangre entera se determinaron con un viscosímetro cono-plato. La agregación eritrocitaria se estudió por observación microscopia de los agregados y cuantificación a través de un parâmetro de forma denominado ASP ( Aggregation Shape Parameter), definido como la relación de área proyectada respecto al perímetro. El fibrinógeno se determino con un coagulómetro por el método de Clauss. Los valores de viscosidad de sangre entera resultaron significativamente aumentados en los pacientes hipertensos respecto de los normales para todas las velicidades estudiadas. Los valores de viscosidad plasmática solo presentaron diferencia significativas a bajas velocidades de corte (1.15 a 11.56 seg 1) . Los pacientes hipertensos presentaron agregados amorfos e irregulares, lo que se refleja en los valores alterados de ASP, significativamente mayores (p<0.001) en paciente hipertensos (0.69± 0.11) respecto de los indivíduos normales ( 0.25± 0.12). Los valores de fibrinógeno resultaron ligeramente superiores en los pacientes hipertensos respecto del grupo control (p< 0.01). Numerosos parámetros hemorreológicos juegan un papel importante en la patogénesis de la hipertensión. Entre estos factores hemorreológicos, valores parâmetros podrían estar en la hipertensión ( hematrocito, fibrinógeno plasmático, deformabilidad y agragación eritrocitaria , viscosidad sanguínea y plasmática). En este trabajo, se pudo demostrar anormalidades en la agregación eritrocitaria, detectada por los valores de ASP que podría estar involucrado en las complicaciones vasculares de la hipertensión.
Assuntos
Adulto , Pessoa de Meia-Idade , Humanos , Masculino , Feminino , Hemorreologia , Hipertensão/sangue , Viscosidade Sanguínea/fisiologia , Agregação Eritrocítica/fisiologia , Fibrinogênio/fisiologia , Hipertensão/fisiopatologiaRESUMO
El objetivo de este trabajo fue investigar el perfil de viscosidad sanguínea y evaluar la influencia de factores plasmáticos ( fibrinógeno) y celulares ( agregación eritrocitaria ) en un grupo de pacientes hipertensos comparados con un grupo de paciente normotensos. Se trabajó con sangre anticoagulada de pacientes hipertensos no diabéticos (n=3) e indivíduos sanos (n=40). La viscosidad plasmática y de sangre entera se determinaron con un viscosímetro cono-plato. La agregación eritrocitaria se estudió por observación microscopia de los agregados y cuantificación a través de un parÔmetro de forma denominado ASP ( Aggregation Shape Parameter), definido como la relación de área proyectada respecto al perímetro. El fibrinógeno se determino con un coagulómetro por el método de Clauss. Los valores de viscosidad de sangre entera resultaron significativamente aumentados en los pacientes hipertensos respecto de los normales para todas las velicidades estudiadas. Los valores de viscosidad plasmática solo presentaron diferencia significativas a bajas velocidades de corte (1.15 a 11.56 seg ò1) . Los pacientes hipertensos presentaron agregados amorfos e irregulares, lo que se refleja en los valores alterados de ASP, significativamente mayores (p<0.001) en paciente hipertensos (0.69± 0.11) respecto de los indivíduos normales ( 0.25± 0.12). Los valores de fibrinógeno resultaron ligeramente superiores en los pacientes hipertensos respecto del grupo control (p< 0.01). Numerosos parámetros hemorreológicos juegan un papel importante en la patogénesis de la hipertensión. Entre estos factores hemorreológicos, valores parÔmetros podrían estar en la hipertensión ( hematrocito, fibrinógeno plasmático, deformabilidad y agragación eritrocitaria , viscosidad sanguínea y plasmática). En este trabajo, se pudo demostrar anormalidades en la agregación eritrocitaria, detectada por los valores de ASP que podría estar involucrado en las complicaciones vasculares de la hipertensión. (AU)
Assuntos
Adulto , Pessoa de Meia-Idade , Idoso , Humanos , Masculino , Feminino , Hemorreologia , Hipertensão/sangue , Hipertensão/fisiopatologia , Viscosidade Sanguínea/fisiologia , Agregação Eritrocítica/fisiologia , Fibrinogênio/fisiologiaRESUMO
A biologia molecular evolui de forma vertiginosa e atualmente é tida como ferramenta indispensável na compreensão de doenças complexas e multifatoriais como a doença arterial coronariana. Tal abordagem gera uma nova forma de avaliação de doenças conhecidas e propicia a criação de novas técnicas, novos métodos diagnósticos e possíveis abordagens terapêuticas, interferindo diariamente no desfecho clínico final do paciente. O número de publicações em genética cardiovascular aumentou cinco vezes nos últimos 20 anos e a descoberta de novos polimorfismos e mutações bem como marcadores de inflamação, coagulação e genes relacionados ao metabolismo lipídico contribuem para se conhecer cada vez mais os aspectos intrínsecos envolvidos na aterosclerose. Este artigo irá abordar os principais avanços nessa área, identificando os polimorfismos mais comuns e sua relevância clínica segundo grandes ensaios e meta-análises,bem como fazer um breve racional acerca do desenho atual dos ensaios clínicos em biologia molecular
Assuntos
Humanos , Arteriosclerose/fisiopatologia , Arteriosclerose/genética , Biologia Molecular/métodos , Biologia Molecular/tendências , Doença das Coronárias/fisiopatologia , Doença das Coronárias/genética , Genética/tendências , Polimorfismo Genético/fisiologia , Polimorfismo Genético/genética , Fibrinogênio/fisiologia , Fibrinogênio/genética , Selectina-P/fisiologia , Selectina-P/genéticaRESUMO
Fibrinogen secretion is mediated by prostaglandin biosynthesis and is considered a risk factor for cardiovascular disease. Since meloxicam produces inhibition of prostaglandin biosynthesis it may help to normalize hyperfibrinogenemia. We investigated the pharmacological effect of meloxicam on fibrinogen levels and the possible regression of histopathological lesions of thoracic aorta. Rats were subjected to multiple injuries (MI) in the form of laparotomies (Lx) during a 30 day period (1/week). Meloxicam 0.065 mg/kg/day (per rat) was administered orally immediately after the third Lx in multiple injury animals during a ten day period. Blood was obtained 72 hours after the last injury in all groups. Fibrinogen was measured by spectrophotometry and the values were expressed in mg/dL. A statistically significant increment of fibrinogen was observed when comparing uninjured animals (control) (208.7+/-6.0) with the multiple injury group (336.6+/-7.5) (P<0.001). Fibrinogen decreased to the control value in the meloxicam group (198+/-8.7). Histopathological lesions were similar in the MI and meloxicam groups, showing endothelial denudation and intima enlargement from the thoracic aorta in 96% of the slices studied. The decrease in fibrinogen in the meloxicam group would be due to cyclooxygenase-2 (Cox-2) selective inhibition, even though the histopathological lesions did not regress.
Assuntos
Inibidores de Ciclo-Oxigenase/farmacologia , Endotélio Vascular/fisiopatologia , Fibrinogênio/metabolismo , Tiazinas/farmacologia , Tiazóis/farmacologia , Doenças Vasculares/prevenção & controle , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Fibrinogênio/fisiologia , Masculino , Meloxicam , RatosRESUMO
The adsorption of thrombin to fibrin during clotting defines "Antithrombin I" activity. We confirmed that thrombin generation in afibrinogenemic or in Reptilase defibrinated normal plasma was higher than in normal plasma. Repletion of these fibrinogen-deficient plasmas with fibrinogen 1 (gamma A/gamma A), whose fibrin has two "low affinity" non-substrate thrombin binding sites, resulted in moderately reduced thrombin generation by 29-37%. Repletion with fibrinogen 2 (gamma'/gamma A), which in addition to low affinity thrombin-binding sites in fibrin, has a "high affinity" non-substrate thrombin binding site in the carboxy-terminal region of its gamma' chain, was even more effective and reduced thrombin generation by 57-67%. Adding peptides that compete for thrombin binding to fibrin [S-Hir53-64 (hirugen) or gamma'414-427] caused a transient delay in the onset of otherwise robust thrombin generation, indicating that fibrin formation is necessary for full expression of Antithrombin I activity. Considered together, 1) the increased thrombin generation in afibrinogenemic or fibrinogen-depleted normal plasma that is mitigated by fibrinogen replacement; 2) evidence that prothrombin activation is increased in afibrinogenemia and normalized by fibrinogen replacement; 3) the severe thrombophilia that is associated with defective thrombin-binding in dysfibrinogenemias Naples I and New York I, and 4) the association of afibrinogenemia or hypofibrinogenemia with venous or arterial thromboembolism, indicate that Antithrombin I (fibrin) modulates thromboembolic potential by inhibiting thrombin generation in blood.
Assuntos
Fibrina/biossíntese , Fibrinogênio/fisiologia , Hirudinas/análogos & derivados , Trombina/antagonistas & inibidores , Afibrinogenemia , Antitrombinas/farmacologia , Hirudinas/farmacologia , Humanos , Fragmentos de Peptídeos/farmacologia , Ligação Proteica , Protrombina/metabolismo , Trombina/biossíntese , TrombofiliaRESUMO
The integrin family not only mediates the recruitment of polymorphonuclear leukocytes (PMN) to sites of inflammation but also regulates several effector functions by binding to specific ligands. We have recently demonstrated that soluble fibrinogen (sFbg) is able to trigger an activating signal in PMN through an integrin-dependent mechanism. This activation results in degranulation, phagocytosis enhancement, and apoptosis delay. The aim of the present work was to further elucidate the molecular events that follow sFbg interaction with CD11b in human PMN, and the participation of this signaling pathway in the regulation of neutrophil functionality. We demonstrate that sFbg triggers a cascade of intracellular signals that lead to focal adhesion kinase and extracellular signal-regulated kinase 1/2 tyrosine phosphorylation. The activation of this mitogen-activated protein kinase pathway plays a central role in the sFbg modulation of secondary granule degranulation, Ab-dependent phagocytosis, and apoptosis. However, fibrinogen-induced secretory vesicle degranulation occurs independently of the signaling transduction pathways investigated herein. In the context of an inflammatory process, the intracellular signal pathway activated by sFbg may be an early event influencing the functionality of PMN.
Assuntos
Fibrinogênio/fisiologia , Sistema de Sinalização das MAP Quinases/imunologia , Neutrófilos/imunologia , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Benzoquinonas , Degranulação Celular/efeitos dos fármacos , Degranulação Celular/imunologia , Grânulos Citoplasmáticos/efeitos dos fármacos , Grânulos Citoplasmáticos/imunologia , Grânulos Citoplasmáticos/metabolismo , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/imunologia , Inibidores Enzimáticos/farmacologia , Fibrinogênio/farmacologia , Flavonoides/farmacologia , Quinase 1 de Adesão Focal , Proteína-Tirosina Quinases de Adesão Focal , Genisteína/farmacologia , Humanos , Imidazóis/farmacologia , Cinética , Lactamas Macrocíclicas , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/enzimologia , Neutrófilos/metabolismo , Fosforilação/efeitos dos fármacos , Fosfotirosina/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Piridinas/farmacologia , Quinonas/farmacologia , Rifabutina/análogos & derivados , SolubilidadeRESUMO
This paper demonstrate that plasmatic fibrinogen is a risk factor for ischaemic cardiovascular disease. Apart from its hemostatic functions, it has an important role in the atherothrombotic process. Prospective studies in a normal population and on patients with pre-existent cardiovascular disease demonstrate that fibrinogen is a predictor of cardiovascular events, either as first episode or recurrence. It is also reviewed a epidemiological study which is been carried out in Venezuela as a pilot study for Latinamerica because our population is different from those where the studies have been performed up to now. It is also mentioned the factors that influence the fibrinogen levels, some of them can be modified which could be useful for the prevention of the disease. It is considered the necessity of further studies to evaluate the benefit of the control of the fibrinogen level.
Assuntos
Doenças Cardiovasculares/etiologia , Fibrinogênio/fisiologia , Arteriosclerose/etiologia , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Fibrinogênio/análise , Humanos , Fatores de Risco , Trombose/etiologiaRESUMO
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 alpha-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 FcgammaRIII. 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.
Assuntos
Adjuvantes Imunológicos/fisiologia , Apoptose/imunologia , Fibrinogênio/fisiologia , Ativação de Neutrófilo , Neutrófilos/citologia , Neutrófilos/metabolismo , Antígenos CD/biossíntese , Antígenos de Diferenciação/biossíntese , Cálcio/metabolismo , Moléculas de Adesão Celular , Degranulação Celular/imunologia , Membrana Celular/imunologia , Membrana Celular/metabolismo , Separação Celular , Humanos , Antígeno de Macrófago 1/biossíntese , Neutrófilos/imunologia , Receptores de IgG/biossíntese , Solubilidade , Regulação para Cima/imunologiaRESUMO
Epidemiological studies have shown that the haemostatic parameters Fibrinogen (Fg), Factor VII (F VII), Factor VIII (F VIII), von Willebrand factor (vWF), Tissue Plasminogen Activator (t-PA), Plasminogen Activator Inhibitors (PAI) are risk factors/markers of ischemic cardiovascular disease. Ferritin (sFER) and Leukocytosis have also been implicated. In the present study we have followed the levels of fibrinogen, von Willebrand factor and thrombomodulin in relation to lipids, iron and the appearance of atherosclerotic lesions in New Zealand rabbits fed with a cholesterol enriched diet for a two-month period compared with a group of control rabbits. Hematocrit and white blood cell count (WBC) were measured in parallel. In hyperchlesterolemic rabbits the levels of fibrinogen and von Willebrand factor increased progressively, showing a positive correlation with the increasing cholesterol levels. There was an increase in soluble thrombomodulin beginning at the eighth week of study. In addition, these animals showed gross intimal atherosclerotic lesions in the whole extension of their aortas. Immunohistochemical studies showed the presence of fibrin(ogen) related antigen throughout the arterial wall and in the central portions of the atheromas. In the control group there was no formation of atherosclerotic plaques and all haemostatic, haematological and biochemical parameters were within the normal range. WBC and sFER levels were unaffected in both groups. Our results show that increased levels of fibrinogen and von Willebrand factor, known coronary risk factors, are strongly associated with the formation of atherosclerotic plaques in rabbits. The plaques contain a considerable amount of fibrinogen related antigen.
Assuntos
Arteriosclerose/complicações , Fibrinogênio/fisiologia , Hemostasia , Trombose/metabolismo , Fator de von Willebrand/metabolismo , Animais , Arteriosclerose/metabolismo , Arteriosclerose/patologia , Dieta Aterogênica , Ferritinas/análise , Hematócrito , Hipercolesterolemia/sangue , Contagem de Leucócitos , Coelhos , Fatores de Risco , Trombomodulina/metabolismo , Trombose/etiologia , Triglicerídeos/sangue , Túnica Íntima/metabolismo , Túnica Íntima/patologiaRESUMO
No protocolo de avaliaçäo clínico-laboratorial de pacientes com acidente vascular cerebral (AVC) aterotrombótico dosamos e analisamos níveis de fibrinogênio plasmático (técnica de Clauss automatizada), para determinar seu possível papel como fator de risco trombogênico em 29 pacientes (20 homens e 9 mulheres) com idades entre 25 a 79 anos (mediana=55); todos tinham tido AVC aterotrombótico. Eles foram classificados em 2 grupos segundo alteraçöes de fluxo nas carótidas: g1 - sem alteraçäo de fluxo (n=19) e g2 - com alteraçöes de fluxo (n=10). Resultados- A média das dosagens de fibrinogênio no g1 foi de 269 e no g2 de 353 mg/dl. Quarenta e sete por cento dos pacientes do g1 e 80 por cento do g2, apresentaram medidas >300 mg/dl. As diferenças obtidas entre os grupos neste estudo foram significante. Conclusäo- Considerando o nível de risco epidemiológico de 300 mg/dl, nossos resultados sugerem que o fibrinogênio é um fator de risco independente para AVC aterotrombótico, especialmente naqueles com alteraçäo de fluxo carotídeo.