Publications (2)7.44 Total impact
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Article: Albumin causes increased myosin light chain kinase expression in astrocytes via p38 mitogen-activated protein kinase.
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ABSTRACT: Myosin light chain kinase (MLCK) plays an important role in the reorganization of the cytoskeleton, leading to disruption of vascular barrier integrity in multiple organs, including the blood-brain barrier (BBB), after traumatic brain injury (TBI). MLCK has been linked to transforming growth factor (TGF) and rho kinase signaling pathways, but the mechanisms regulating MLCK expression following TBI are not well understood. Albumin leaks into the brain parenchyma following TBI, activates glia, and has been linked to TGF-β receptor signaling. We investigated the role of albumin in the increase of MLCK in astrocytes and the signaling pathways involved in this increase. After midline closed-skull TBI in mice, there was a significant increase in MLCK-immunoreactive (IR) cells and albumin extravasation, which was prevented by treatment with the MLCK inhibitor ML-7. Using immunohistochemical methods, we identified the MLCK-IR cells as astrocytes. In primary astrocytes, exposure to albumin increased both isoforms of MLCK, 130 and 210. Inhibition of the TGF-β receptor partially prevented the albumin-induced increase in both isoforms, which was not prevented by inhibition of smad3. Inhibition of p38 MAPK, but not ERK, JNK, or rho kinase, also prevented this increase. These results are further evidence of a role of MLCK in the mechanisms of BBB compromise following TBI and identify astrocytes as a cell type, in addition to endothelium in the BBB, that expresses MLCK. These findings implicate albumin, acting through p38 MAPK, in a novel mechanism by which activation of MLCK following TBI may lead to compromise of the BBB.Journal of Neuroscience Research 02/2011; 89(6):852-61. · 2.74 Impact Factor -
Article: Albumin activates the canonical TGF receptor-smad signaling pathway but this is not required for activation of astrocytes.
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ABSTRACT: The use of albumin as a resuscitation fluid is considered safe for most critically ill patients. However, clinical data suggest albumin may increase mortality in neurotrauma, but improve outcome after stroke. Albumin has been shown to activate glia, and to play a role in the mechanisms of epileptogenesis via the TGFβ-receptor (TGFβR). We have previously shown that albumin induces the production of inflammatory mediators including IL-1β via activation of MAPK pathways in primary astrocytes and microglia. The extracellular signaling mechanisms leading to the activation of glial cells in response to albumin are not well understood. Here, we investigated the role of the TGFβR and the canonical TGFβ receptor-smad signaling pathway in astrocyte activation by albumin. In primary astrocyte cultures, albumin activated the smad pathway downstream of the TGFβR by increasing the phosphorylation of smad2, and in the level of smad3 and smad4 translocated to the nucleus. Albumin produced an increase in IL-1β which was not dependent on smad activation, but was prevented by blockade of the TGFβR. Increase in the chemokine CX3CL1, and the decrease in S100B produced by albumin were independent of the TGFβR and smad activation. Albumin induced an increase in LDH release that was inhibited by blockade of the TGFβR and by inhibition of smad activation. These findings show that albumin activates the canonical TGF receptor-smad signaling pathway. The albumin-induced increase in the pro-epileptogenic cytokine IL-1β involves the TGFβR, but is independent of smad activation. Taken together, the effects of albumin on both IL-1β and activation of the TGFβR pathway are further evidence for a role for albumin in neurotrauma-related epileptogenesis.Experimental Neurology 12/2010; 226(2):310-9. · 4.70 Impact Factor
