Accumulating evidence indicates that activated microglia contribute to the neuropathology involved in many neurodegenerative diseases and after traumatic injury to the CNS. The cytokine transforming growth factor-beta 1 (TGF-b1), a potent deactivator of microglia, should have the potential to reduce microglial-mediated neurodegeneration. It is therefore perplexing that high levels of TGF-b1 are found in conditions where microglia are chronically activated. We hypothesized that TGF-b1 signaling is suppressed in activated microglia. We therefore activated primary rat microglia with lipopolysaccharide (LPS) and determined the expression of proteins important to TGF-b1 signaling. We found that LPS treatment decreased the expression of the TGF-b receptors, TbR1 and TbR2, and reduced protein levels of Smad2, a key mediator of TGF-b signaling. LPS treatment also antagonized the ability of TGF-b to suppress expression of pro-inflammatory cytokines and to induce microglial cell death. LPS treatment similarly inhibited the ability of the TGF-b related cytokine, Activin-A, to down-regulate expression of pro-inflammatory cytokines and to induce microglial cell death. Together, these data suggest that microglial activators may oppose the actions of TGF-b1, ensuring continued microglial activation and survival that eventually may contribute to the neurodegeneration prevalent in chronic neuroinflammatory conditions.
BackgroundBone morphogenetic protein-2 (BMP-2) is a pleiotropic, secreted molecule with diverse effects. The potent ability of BMP-2 to stimulate bone growth prompted its widespread clinical use for arthrodesis (spine fusion). However, elevated post-operative pain in patients treated with BMP-2 has been increasingly reported. Determining whether BMP-2 induces pain directly or whether it induces neuroinflammation, which could lower the threshold for pain, is important for developing therapeutic interventions. We therefore modeled the clinical use of BMP-2 for posterior lumbar fusion by implanting absorbable collagen sponges soaked with either recombinant human BMP-2 (rhBMP-2) or vehicle above the L4–L5 transverse processes of rat spine.ResultsUsing microarray analysis we found that implantation of rhBMP-2-soaked absorbable collagen sponges resulted in altered expression of numerous pro-inflammatory genes in the adjacent dorsal root ganglia (DRG) showing that implantation of rhBMP-2/absorbable collagen sponges triggers potent neuroinflammatory responses in the DRG-2. Interestingly, direct BMP-2 treatment of DRG explants resulted in changes in gene expression that were not specifically pro-inflammatory. Rats implanted with rhBMP-2 in absorbable collagen sponges also exhibited a transient change in thermal and mechanical sensitivity indicating that rhBMP-2 applied to the lumbar spine could increase pain sensitivity. Immunohistochemical analysis indicated macrophage infiltration in the DRG and spinal nerve in rats implanted with rhBMP-2/absorbable collagen sponges or absorbable collagen sponges alone, but not in rats that underwent surgery without implantation of the absorbable collagen sponges suggesting that the sponges contributed to the biological response. Indeed, analysis of DRGs taken from rats implanted with absorbable collagen sponges without rhBMP-2 showed a significant change in gene expression distinct from DRGs from rats undergoing surgery only.ConclusionsOur data indicate that implantation of rhBMP-2/absorbable collagen sponges on the lumbar spine triggers potent neuroinflammatory responses in the DRG. Importantly, however, these BMP-2 effects may be partially mediated through a response to the absorbable collagen sponges.
Immobilization is often needed for the treatment of wrist and hand injuries. The current best method of immobilization for several types of injuries has yet to be elucidated with little being reported on the functional differences of each type of immobilization. The purpose of this study is to compare the functional outcome between healthy young volunteers with a 24-hour short arm cast (SAC) versus thumb spica cast (TSC) immobilization. A total of 50 healthy volunteers completed a baseline typing assessment and a Patient-Reported Outcomes Measurement Information System (PROMIS) upper extremity functional scoring assessment. Participants in group 1 were randomly initially assigned to a TSC of their dominant hand followed by an SAC, whereas participants in group 2 were randomly initially assigned to a TSC of their nondominant hand followed by an SAC. The volunteers completed the typing assessment and PROMIS assessment at the end of the 24-hour casting period. A total of 50 participants were enrolled in the study with 25 in group 1 and 25 in group 2. There was a 24.3-point difference between the average PROMIS score for participants with SAC compared with participants with TSC (93 vs. 68.7; = 0.0001). There was a significant difference between the typing speed and accuracy of participants with SAC compared with participants with TSC ( = 0.0001). There is a significant difference in functionality of a TSC immobilization versus an SAC immobilization according to the PROMIS functional outcome score and typing speed in a 24-hour casting period. SAC immobilization should be considered to have a possible similar effect in pathologic conditions instead of TSC immobilization given these findings even though a 24-hour period is not enough to provide adequate long-term conclusions. I, prospective comparative study.
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