RESUMO
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
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.
Assuntos
Humanos , Terapia Antirretroviral de Alta Atividade , Hemofilia A , Infecções por HIV , HIV-1 , RNA Viral , Carga Viral , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Doenças do Sistema Nervoso Central , Hemofilia A , Infecções por HIV , RNA ViralRESUMO
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)
