The role of primary blast in blast-induced traumatic brain injury (bTBI) is controversial in part due to the technical difficulties of generating free-field blast conditions in the laboratory. The use of traditional shock tubes often results in artifacts, particularly of dynamic pressure, whereas the forces affecting the head are dependent on where the animal is placed relative to the tube, whether the exposure is whole-body or head-only, and on how the head is actually exposed to the insult (restrained or not). An advanced blast simulator (ABS) has been developed that enables high-fidelity simulation of free-field blastwaves, including sharply defined static and dynamic overpressure rise times, underpressures, and secondary shockwaves. Rats were exposed in head-only fashion to single-pulse blastwaves of 15 to 30 psi static overpressure. Head restraints were configured so as to eliminate concussive and minimize whiplash forces exerted on the head, as shown by kinematic analysis. No overt signs of trauma were present in the animals post-exposure. However, significant changes in brain 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNPase) and neurofilament heavy chain levels were evident by 7 days. In contrast to most studies of primary blast-induced TBI (PbTBI), no elevation of glial fibrillary acidic protein (GFAP) levels was noted when head movement was minimized. The ABS described in this article enables the generation of shockwaves highly representative of free-field blast. The use of this technology, in concert with head-only exposure, minimized head movement, and the kinematic analysis of the forces exerted on the head provide convincing evidence that primary blast directly causes changes in brain function and that GFAP may not be an appropriate biomarker of PbTBI.
1. The effects of racemic (rac) ibuprofen and its S(+)‐ and R(−)− enantiomers on functions of human polymorphonuclear cells (PMN) and platelets were studied in vitro. 2. Rac‐ibuprofen inhibited PMN functions (O2‐ generation, beta‐glucuronidase release, LTB4 formation). Similar IC50 values (40‐100 microM) were obtained for the S(+)‐ and R(‐ )‐enantiomers. 3. All forms of ibuprofen inhibited cyclooxygenase‐ related platelet functions (aggregation, thromboxane formation). The S(+)‐enantiomer was about twice as active as the racemate while the R(‐ )‐enantiomer was at least 10‐fold less active. This demonstrates that the S(+) is the only cyclooxygenase inhibitory component of the racemate. 4. The concentrations of rac‐ibuprofen in PMN and platelets were similar to those in the incubation medium and represented equal concentrations of the enantiomers. This indicates that neither interconversion nor tissue accumulation of the compounds occurred. 5. These data indicate that antineutrophil effects of ibuprofen on human PMN are independent of cyclooxygenase inhibition. Therefore, R(−)− ibuprofen may be superior to the S(+)‐isomer for the treatment of PMN‐ dependent inflammatory diseases. However, effective free drug concentrations may not be obtained in vivo.
Previous work in this laboratory used underwater explosive exposures to isolate the effects of shock-induced principle stress without shear on rat brain aggregate cultures. The current study has utilized simulated air blast to expose aggregates in suspension and enclosed within a spherical shell, enabling the examination of a much more complex biomechanical insult. Culture medium-filled spheres were exposed to single pulse overpressures of 15-30 psi (∼6-7 msec duration) and measurements within the sphere at defined sites showed complex and spatially dependent pressure changes. When brain aggregates were exposed to similar conditions, no cell death was observed and no changes in several commonly used biomarkers of traumatic brain injury (TBI) were noted. However, similarly to underwater blast, immediate and transient increases in the protein kinase B signaling pathway were observed at early time-points (3 days). In contrast, the oligodendrocyte marker 2',3'-cyclic nucleotide 3'-phosphodiesterase, as well as vascular endothelial growth factor, both displayed markedly delayed (14-28 days) and pressure-dependent responses. The imposition of a spherical shell between the single pulse shock wave and the target brain tissue introduces greatly increased complexity to the insult. This work shows that brain tissue can not only discriminate the nature of the pressure changes it experiences, but that a portion of its response is significantly delayed. These results have mechanistic implications for the study of primary blast-induced TBI and also highlight the importance of rigorously characterizing the actual pressure variations experienced by target tissue in primary blast studies.
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