American journal of physiology. Heart and circulatory physiology
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Am. J. Physiol. Heart Circ. Physiol. · Jan 2010
Increased death receptor pathway of apoptotic signaling in septic mouse aorta: effect of systemic delivery of FADD siRNA.
Recent evidence suggests that apoptotic cell death plays an important role in the pathophysiology of sepsis. Because there is extensive apoptosis of vascular endothelial cells in sepsis, we examined whether the death receptor pathway of apoptotic signaling is altered in thoracic aortas from mice with polymicrobial sepsis, as produced by cecal ligation and puncture (CLP). In septic aorta, total and surface expression levels of the two death receptors tumor necrosis factor receptor 1 and Fas were highly upregulated. ⋯ Terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling (TUNEL) revealed that the significant appearance of cell apoptosis in aortic endothelium after CLP-induced sepsis was eliminated when FADD siRNA was systemically applied. Light and electron microscopic examinations of septic aorta showed cell swelling, nuclear fragmentation, and partial detachment of endothelial cells from the basal membrane, which were prevented by systemic treatment with FADD siRNA. Finally, FADD siRNA administration dramatically improved survival of CLP mice, supporting the feasibility of this gene-based approach for treating septic shock.
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Am. J. Physiol. Heart Circ. Physiol. · Jan 2010
Maternal glucocorticoid exposure alters tight junction protein expression in the brain of fetal sheep.
We examined the expression of tight junction (TJ) proteins in the cerebral cortex, cerebellum, and spinal cord of fetuses after maternal treatment with single and multiple courses of dexamethasone. Ewes received either single courses of four 6-mg dexamethasone or placebo injections every 12 h for 48 h between 104 and 107 days or the same treatment once a week between 76-78 and 104-107 days of gestation. TJ protein expression was determined by Western immunoblot analysis on tissue harvested at 105-108 days of gestation. ⋯ Linear regression comparing K(i) to TJ proteins showed inverse correlations with claudin-1 and claudin-5 in the cerebral cortex after a single course and ZO-2 in the spinal cord after multiple courses and direct correlations with ZO-1 in the cerebellum and spinal cord after multiple courses. We conclude that maternal glucocorticoid treatment increases the expression of specific TJ proteins in vivo, patterns of TJ protein expression vary after exposure to single and multiple glucocorticoid courses, and decreases in blood-brain barrier permeability are associated with increases in claudin-1, claudin-5, and ZO-2 expression and decreases in ZO-1 expression. In utero glucocorticoid exposure alters the molecular composition of the barrier and affects fetal blood-brain barrier function.
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Am. J. Physiol. Heart Circ. Physiol. · Jan 2010
Inhibition of matrix metalloproteinase activity in vivo protects against vascular hyporeactivity in endotoxemia.
Persistent arterial hypotension is a hallmark of sepsis and is believed to be caused, at least in part, by excess nitric oxide (NO). NO can combine with superoxide to produce peroxynitrite, which activates matrix metalloproteinases (MMPs). Whether MMP inhibition in vivo protects against vascular hyporeactivity induced by endotoxemia is unknown. ⋯ Plasma MMP-2 activities were unchanged by LPS. Specific MMP-2 activity was increased in aortas from LPS-treated rats. This study demonstrates the in vivo protective effect of the MMP inhibitor doxycycline against the development of vascular hyporeactivity in endotoxemic rats.