RESUMO
Elevated serum concentrations of the vasoactive protein endothelin-1 (ET-1) occur in the setting of systemic inflammatory response syndrome and contribute to distal organ hypoperfusion and pulmonary hypertension. Thus, understanding the cellular source and transcriptional regulation of systemic inflammatory stress-induced ET-1 expression may reveal therapeutic targets. Using a murine model of LPS-induced septic shock, we demonstrate that the hepatic macrophage is the primary source of elevated circulating ET-1, rather than the endothelium as previously proposed. Using pharmacologic inhibitors, ET-1 promoter luciferase assays, and by silencing and overexpressing NF-κB inhibitory protein IκB expression, we demonstrate that LPS-induced ET-1 expression occurs via an NF-κB-dependent pathway. Finally, the specific role of the cRel/p65 inhibitory protein IκBß was evaluated. Although cytoplasmic IκBß inhibits activity of cRel-containing NF-κB dimers, nuclear IκBß stabilizes NF-κB/DNA binding and enhances gene expression. Using targeted pharmacologic therapies to specifically prevent IκBß/NF-κB signaling, as well as mice genetically modified to overexpress IκBß, we show that nuclear IκBß is both necessary and sufficient to drive LPS-induced ET-1 expression. Together, these results mechanistically link the innate immune response mediated by IκBß/NF-κB to ET-1 expression and potentially reveal therapeutic targets for patients with Gram-negative septic shock.
Assuntos
Endotelina-1/imunologia , Endotoxemia/imunologia , Regulação da Expressão Gênica/imunologia , Proteínas I-kappa B/imunologia , Fígado/imunologia , Macrófagos/imunologia , NF-kappa B/imunologia , Transdução de Sinais/imunologia , Animais , Linhagem Celular , Endotelina-1/genética , Endotoxemia/genética , Endotoxemia/patologia , Proteínas I-kappa B/genética , Fígado/patologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Camundongos Transgênicos , NF-kappa B/genética , Transdução de Sinais/genéticaRESUMO
We report a case of a 1-month-old infant with spontaneous thymic hemorrhage secondary to severe vitamin K deficiency. He was brought to medical attention due to scrotal bruising and during evaluation was noted to be tachypneic and hypoxemic. Chest X-ray revealed an enlarged cardiothymic silhouette, and a follow-up echocardiogram revealed a mass in the anterior mediastinum. Routine laboratory work-up revealed severe coagulopathy. Further questioning revealed the patient had not received prophylactic vitamin K at birth. The coagulopathy resolved with administration of vitamin K, and a biopsy confirmed the anterior mediastinal mass was due to spontaneous thymic hemorrhage.