RESUMEN
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.
Asunto(s)
Fibrinógeno/fisiología , Sistema de Señalización de MAP Quinasas/inmunología , Neutrófilos/inmunología , Apoptosis/efectos de los fármacos , Apoptosis/inmunología , Benzoquinonas , Degranulación de la Célula/efectos de los fármacos , Degranulación de la Célula/inmunología , Gránulos Citoplasmáticos/efectos de los fármacos , Gránulos Citoplasmáticos/inmunología , Gránulos Citoplasmáticos/metabolismo , Activación Enzimática/efectos de los fármacos , Activación Enzimática/inmunología , Inhibidores Enzimáticos/farmacología , Fibrinógeno/farmacología , Flavonoides/farmacología , Quinasa 1 de Adhesión Focal , Proteína-Tirosina Quinasas de Adhesión Focal , Genisteína/farmacología , Humanos , Imidazoles/farmacología , Cinética , Lactamas Macrocíclicas , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Neutrófilos/efectos de los fármacos , Neutrófilos/enzimología , Neutrófilos/metabolismo , Fosforilación/efectos de los fármacos , Fosfotirosina/metabolismo , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/metabolismo , Piridinas/farmacología , Quinonas/farmacología , Rifabutina/análogos & derivados , SolubilidadRESUMEN
As HIV seropositive patients with undetectable CSF viral load have a lower likelihood of developing neurologic disease, the determination of CSF viral load levels may be useful to evaluate the efficacy of HAART. We compared plasma viral load levels with HIV-1 RNA CSF levels in 18 hemophilic patients without neurocognitive involvement under HAART. We detected a significant correlation between plasma viral load levels and CSF viral load levels. Fourteen patients with undetectable plasma viral load had undetectable RNA HIV-1 CSF levels as well. Four patients with detectable plasma viral load had detectable HIV-RNA in CSF, but the latter were significantly lower. Viral load is usually lower in non-blood fluids and HAART decreases the viral load in CSF as well as in blood.
Asunto(s)
Humanos , Terapia Antirretroviral Altamente Activa , Hemofilia A , Infecciones por VIH , VIH-1 , ARN Viral , Carga Viral , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Enfermedades del Sistema Nervioso Central , Hemofilia A , Infecciones por VIH , ARN ViralRESUMEN
As HIV seropositive patients with undetectable CSF viral load have a lower likelihood of developing neurologic disease, the determination of CSF viral load levels may be useful to evaluate the efficacy of HAART. We compared plasma viral load levels with HIV-1 RNA CSF levels in 18 hemophilic patients without neurocognitive involvement under HAART. We detected a significant correlation between plasma viral load levels and CSF viral load levels. Fourteen patients with undetectable plasma viral load had undetectable RNA HIV-1 CSF levels as well. Four patients with detectable plasma viral load had detectable HIV-RNA in CSF, but the latter were significantly lower. Viral load is usually lower in non-blood fluids and HAART decreases the viral load in CSF as well as in blood. (Au)