Intracellular and extracellular expression of the major inducible 70 kDa heat shock protein in experimental ischemia-reperfusion injury of the spinal cord
Department of Anesthesiology, College of Medicine and Public Health, The Ohio State University, USA. Experimental Neurology
(Impact Factor: 4.7).
05/2008; 212(2):275-84. DOI: 10.1016/j.expneurol.2008.03.024
Inflammatory responses exacerbate ischemia-reperfusion (IR) injury of spinal cord, although understanding of mediators is incomplete. The major inducible 70kDa heat shock protein (hsp70) is induced by ischemia and extracellular hsp70 (e-hsp70) can modulate inflammatory responses, but there is no published information regarding e-hsp70 levels in the cerebrospinal fluid (CSF) or serum as part of any neurological disease state save trauma. The present work addresses this deficiency by examining e-hsp70 in serum and CSF of dogs in an experimental model of spinal cord IR injury. IR injury of spinal cord caused hind limb paraplegia within 2-3 h that was correlated to lumbosacral poliomalacia with T cell infiltrates at 3 d post-ischemia. In this context, we showed a 5.2-fold elevation of e-hsp70 in CSF that was induced by ischemia and was sustained for the following 3 d observation interval. Plasma e-hsp70 levels were unaffected by IR injury, indicating e-hsp70 release from within the central nervous system. A putative source of this e-hsp70 was ependymal cells in the ischemic penumbra, based upon elevated i-hsp70 levels detected within these cells. Results warrant further investigation of e-hsp70's potential to modulate spinal cord IR injury.
Available from: PubMed Central
- "Release of hsp70 into cerebrospinal fluid (CSF) of the central nervous system (CNS) is an emerging field of research. Increased hsp70 levels in CSF have been reported in association with the inflammatory response to ischemia-reperfusion injury in spinal cords of humans and dogs [92,93]. Data from the ischemic-reperfusion injury model in dogs supports secretory release from within the CNS since hsp70 levels in serum was unaffected . "
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ABSTRACT: Virus infections induce heat shock proteins that in turn enhance virus gene expression, a phenomenon that is particularly well characterized for the major inducible 70 kDa heat shock protein (hsp70). However, hsp70 is also readily induced by fever, a phylogenetically conserved response to microbial infections, and when released from cells, hsp70 can stimulate innate immune responses through toll like receptors 2 and 4 (TLR2 and 4). This review examines how the virus-hsp70 relationship can lead to host protective innate antiviral immunity, and the importance of hsp70 dependent stimulation of virus gene expression in this host response. Beginning with the well-characterized measles virus-hsp70 relationship and the mouse model of neuronal infection in brain, we examine data indicating that the innate immune response is not driven by intracellular sensors of pathogen associated molecular patterns, but rather by extracellular ligands signaling through TLR2 and 4. Specifically, we address the relationship between virus gene expression, extracellular release of hsp70 (as a damage associated molecular pattern), and hsp70-mediated induction of antigen presentation and type 1 interferons in uninfected macrophages as a novel axis of antiviral immunity. New data are discussed that examines the more broad relevance of this protective mechanism using vesicular stomatitis virus, and a review of the literature is presented that supports the probable relevance to both RNA and DNA viruses and for infections both within and outside of the central nervous system.
Available from: Andrea Tipold
- "A lack of correlation between serum and CSF ehsp70 concentrations supports local production and release of ehsp70 and not simply leakage from serum. Results support segregation of CSF and serum pools of ehsp70, a phenomenon that has been previously observed in humans and in experimental canine models (Oglesbee et al., 1999; Steensberg et al., 2006; Awad et al., 2008). Heat shock protein 70 release can occur passively from necrotic cells or by active secretory release (Basu et al., 2000; Bausero et al., 2005). "
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ABSTRACT: The role of extracellular 70 kDa heat shock protein 70 (ehsp70) in central nervous system inflammation is vastly understudied, despite evidence supporting the ability to drive a pro-inflammatory state. We investigated the presence of ehsp70 in cerebrospinal fluid (CSF) and serum of dogs with Steroid Responsive Meningitis-Arteritis (SRMA), with the hypothesis that an ehsp70 response would occur, and might play a role in the pathogenesis of this disease. Samples from 30 dogs acutely affected with SRMA, and 30 dogs treated with corticosteroids and currently in clinical remission from SRMA were compared with normal dogs. Serum and CSF concentrations of ehsp70 were quantified using an enzyme-linked immunosorbent assay. An ehsp70 response occurred in the CSF of dogs with SRMA and this response was attenuated by corticosteroid treatment. There was no correlation between serum and CSF concentrations of ehsp70, supporting local production and release of ehsp70 and not simply leakage from serum. Dogs with SRMA thus represent a powerful spontaneous model by which to study the role of ehsp70 in CNS inflammation.
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ABSTRACT: We have performed neutron scattering experiments to investigate the static magnetic structure and the magnetic critical scattering in the three-dimensional percolating Heisenberg antiferromagnet, RbMn0.31Mg0.69F3, whose magnetic concentration is just at the percolation concentration for a cubic lattice, cP=0.312. Magnetic scattering was observed around the superlattice point, (12,12,12). We determined the Néel temperature of this system to be TN=4.0±0.5K, and found that the critical scattering above TN is similar to that observed in the homogeneous system. At T=1.6K well below TN, the scattering function is described by a sum of the critical scattering and elastic scattering components, and we demonstrated that the q-variation of the intensity of the elastic scattering component can be described using the fractal dimension.
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