RESUMO
Kinase inhibitors are promising drugs to stabilize the endothelial barrier following inflammatory damage. However, our limited knowledge of how kinase signaling activates barrier-restorative pathways and the complexity of multi-target drugs have hindered drug discovery and repurposing efforts. Here, we apply a kinase regression approach that exploits drug polypharmacology to investigate endothelial barrier regulation. A screen of 28 kinase inhibitors identified multiple inhibitors that promote endothelial barrier integrity and revealed divergent barrier phenotypes for BCR-ABL drugs. Target deconvolution predicted 50 barrier-regulating kinases from diverse kinase families. Using gene knockdowns, we identified kinases with a role in endothelial barrier regulation and dissected different mechanisms of action of barrier-protective kinase inhibitors. These results demonstrate the importance of polypharmacology in the endothelial barrier phenotype of kinase inhibitors and provide promising new leads for barrier-strengthening therapies.
Assuntos
Compostos de Anilina/farmacologia , Carbazóis/farmacologia , Alcaloides Indólicos/farmacologia , Nitrilas/farmacologia , Fosfotransferases/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Compostos de Anilina/química , Carbazóis/química , Linhagem Celular , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Humanos , Alcaloides Indólicos/química , Nitrilas/química , Fosfotransferases/genética , Fosfotransferases/metabolismo , Polifarmacologia , Inibidores de Proteínas Quinases/química , Quinolinas/química , Transdução de Sinais/efeitos dos fármacosRESUMO
Recent concepts suggest that both Plasmodium falciparum factors and coagulation contribute to endothelial activation and dysfunction in pediatric cerebral malaria (CM) pathology. However, there is still limited understanding of how these complex inflammatory stimuli are integrated by brain endothelial cells. In this study, we examined how mature-stage P. falciparum infected erythrocytes (IE) interact with tumor necrosis factor α (TNFα) and thrombin in the activation and permeability of primary human brain microvascular endothelial cell (HBMEC) monolayers. Whereas trophozoite-stage P. falciparum-IE have limited effect on the viability of HBMEC or the secretion of pro-inflammatory cytokines or chemokines, except at super physiological parasite-host cell ratios, schizont-stage P. falciparum-IE induced low levels of cell death. Additionally, schizont-stage parasites were more barrier disruptive than trophozoite-stage P. falciparum-IE and prolonged thrombin-induced barrier disruption in both resting and TNFα-activated HBMEC monolayers. These results provide evidence that parasite products and thrombin may interact to increase brain endothelial permeability.
Assuntos
Encéfalo/metabolismo , Células Endoteliais/metabolismo , Eritrócitos/metabolismo , Plasmodium falciparum/metabolismo , Trombina/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Encéfalo/irrigação sanguínea , Encéfalo/parasitologia , Permeabilidade da Membrana Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Células Endoteliais/parasitologia , Eritrócitos/parasitologia , Humanos , Malária Cerebral/metabolismo , Malária Cerebral/parasitologia , Malária Falciparum/metabolismo , Malária Falciparum/parasitologia , Plasmodium falciparum/crescimento & desenvolvimento , Plasmodium falciparum/fisiologia , Proteínas de Protozoários/metabolismo , Esquizontes/metabolismo , Esquizontes/fisiologia , Trombina/farmacologia , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
The diploic veins serve as an important connection between the extracranial and intracranial venous systems. They change in size during growth from adolescence to adulthood. The diploic space has been identified as an additional site of reabsorption of cerebrospinal fluid (CSF). Herein, the anatomy and physiology of the diploic veins are reviewed.
