RESUMO
Hemin, the oxidized prosthetic moiety of hemoglobin, has been implicated in the pathogenesis of acute chest syndrome in patients with sickle cell disease by virtue of its endothelial-activating properties. In this study, we examined whether hemin can cause lung microvascular endothelial barrier dysfunction. By assessing transendothelial resistance using electrical cell impedance sensing, and by directly measuring trans-monolayer fluorescein isothiocyanate-dextran flux, we found that hemin does cause endothelial barrier dysfunction in a concentration-dependent manner. Pretreatment with either a Toll-like receptor 4 inhibitor, TAK-242, or an antioxidant, N-acetylcysteine, abrogated this effect. Increased monolayer permeability was found to be associated with programmed cell death by necroptosis, as evidenced by Trypan blue staining, terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, Western blotting for activated forms of key effectors of cell death pathways, and studies utilizing specific inhibitors of necroptosis and apoptosis. Further studies examining the role of endothelial cell necroptosis in promoting noncardiogenic pulmonary edema during acute chest syndrome are warranted and may open a new avenue of potential treatments for this devastating disease.
Assuntos
Apoptose/efeitos dos fármacos , Células Endoteliais/citologia , Hemina/farmacologia , Pulmão/irrigação sanguínea , Pulmão/fisiopatologia , Microvasos/patologia , Clorometilcetonas de Aminoácidos/farmacologia , Caspase 3/metabolismo , Desferroxamina/farmacologia , Dextranos/metabolismo , Impedância Elétrica , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/metabolismo , Humanos , Imidazóis/farmacologia , Marcação In Situ das Extremidades Cortadas , Indóis/farmacologia , Ferro/metabolismo , Quelantes de Ferro/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Modelos Biológicos , Necrose , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Coloração e Rotulagem , Receptor 4 Toll-Like/metabolismoRESUMO
A term male baby, after delivery, was found to have a 3-centimeter beefy-red mass protruding from the left chest wall, adjacent to the left nipple. Radiological imaging suggested it's origin from the left lateral liver segment. A diagnostic laparoscopy confirmed the isolated connection to the liver, elevated left hemidiaphragm, and protrusion between the ribs. The mass was excised using electrocautery, and pathologic examination showed normal liver tissue.