Elevated serum concentrations of the vasoactive protein 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 NFκB inhibitory protein IκB expression, we demonstrate that LPS-induced ET-1 expression occurs via an NFκB dependent pathway. Finally, the specific role of the cRel/p65 inhibitory protein IκBβ was evaluated. Although cytoplasmic IκBβ inhibits activity of cRel containing NFκB dimers, nuclear IκBβ stabilizes NFκB/DNA binding and enhances gene expression. Using targeted pharmacologic therapies to specifically prevent IκBβ/NFκB signaling, as well as mice genetically modified to overexpress IκBβ, we show that nuclear IκBβ is both necessary and sufficient to drive LPS-induced ET-1 expression. Together, these results mechanistically link the innate immune response mediated by IκBβ/NFκB to ET-1 expression and potentially reveals therapeutic targets for patients with gram-negative septic shock.
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.
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