7. In this study we have shown that MMP-9 transactivates EGFR in brain microvascular ECs with subsequent p38 MAPK/NFκB signaling, resulting in suppressed transcription/translation and protein expression of the TJ protein occludin. These effects were attenuated with specific inhibition of EGFR in brain ECs in vitro. Moreover, we observed EGFR activation, p38 MAPK activation, and the loss of occludin in brains of mice with experimentally induced this website ALF. Together these results suggest that EGFR plays a role in activating the pathobiology of brain injury in ALF. Brain edema in ALF is unique. It occurs in the comatose stages of encephalopathy in ALF. The onset of encephalopathy in ALF patients presages impending brain edema
and a lethal course of the disease. Once liver failure is resolved, either by liver transplantation or by spontaneous recovery of the injured liver, the brain edema is resolved. However, if the brain edema is inadequately controlled, it will ultimately lead to herniation and brain death. Even with significant brain edema, both light and electron microscopic evaluations of these brains reveal that the BBB and its TJs remain relatively intact. However, there are certain subtle changes, including fine perturbations at the endothelial cellular plasma membrane and thickening of the basal lamina.37 In the absence of obvious structural breakdown of the BBB, the prominent and consistent swelling of astrocytic foot processes has led
to the dominant theory that cytotoxic mechanisms cause brain edema in ALF.38 Although vasogenic elements have been implicated,39, 40 evidence for vasogenic edema in ALF has been lacking. Increasing evidence has suggested http://www.selleckchem.com/products/idasanutlin-rg-7388.html that even with a relatively intact BBB, subtle alterations in TJ composition can result in highly selective permeability to small molecules, such as water and ammonia. In mice that are selectively deficient in claudin-5,
a component of TJ proteins, the BBB and TJ appear intact under electron microscopic examination. However, these mice have increased permeability 上海皓元医药股份有限公司 to molecules that are less than 800 Da.8 Similarly, when occludin at the TJ is targeted with a specific peptide or is modified by proteolysis, TJ permeability is significantly increased without any obvious structural change.7, 9, 41 Collectively, these data indicate that altered permeability of the BBB can result from very subtle changes in the BBB and/or TJ composition. We recently observed that there are significant biochemical alterations in occludin, claudin-5, and ZO-1 in brains of mice with experimentally induced ALF5 and that these changes were attenuated when MMP-9 was inhibited.5, 13 We observed similar findings when murine brain EC were exposed to MMP-9 in vitro.5 However, TJs make up only a small part of the brain capillary surface area. The endothelial cellular plasmalemma interacts with MMP-9 or other inciting factors within the capillary circulation to a greater extent than the TJs.
No related posts.