Shock : molecular, cellular, and systemic pathobiological aspects and therapeutic approaches : the official journal the Shock Society, the European Shock Society, the Brazilian Shock Society, the International Federation of Shock Societies
-
Hypertonic saline solutions improve cerebral blood flow (CBF) when used for acute resuscitation from hemorrhagic hypotension accompanying some models of traumatic brain injury (TBI); however, the duration of increased CBF is brief. Because the nitric oxide synthase substrate l-arginine provides prolonged improvement in CBF after TBI, we investigated whether a hypertonic resuscitation fluid containing l-arginine would improve CBF in comparison to hypertonic saline without l-arginine in a model of moderate, paramedian, fluid-percussion TBI followed immediately by hemorrhagic hypotension (mean arterial pressure [MAP] = 60 mm Hg for 45 min). Sprague-Dawley rats were anesthetized with 4.0% isoflurane, intubated and ventilated with 1.5%-2.0% isoflurane in oxygen/air (50:50). ⋯ CBF increased similarly in all groups during infusion and then decreased similarly in all groups. At 120 min after infusion, CBF was highest in the group infused with hypertonic saline, but the difference was not significant. We conclude that the improvement of MAP, ICP, and CBF produced by hypertonic saline alone after TBI and hemorrhagic hypotension is not significantly enhanced by the addition of L-arginine at these doses.
-
The objective of this study was to evaluate the negative regulatory role of heat shock protein 70 (HSP70) on endotoxin-induced activation of inflammatory cytokine signaling pathways in a macrophage cell line. Our studies show that elevation of HSP70 either by activation of the heat shock response (HSR) or through forced expression of the hsp70.1 gene downregulates cytokine expression. Our experiments showed that activation of the HSR and HSP70 overexpression could inhibit LPS-mediated expression of the proinflammatory cytokines TNF-alpha and IL-1 at the mRNA and protein levels. ⋯ Overexpression of HSP70 inhibited the nuclear translocation of p65, the transcriptionally active component of the NF-kappaB complex, and prevented the degradation of IkappaBalpha, the regulator of NF-kappaB activity. However, HSP70 elevation did not markedly inhibit signaling through the MAPK arm of the LPS-induced pathway, suggesting that the effects of HSP70 are mediated primarily through the NF-kappaB cascade. Our experiments therefore suggested that elevated levels of HSP70 inhibit LPS-induced production of inflammatory cytokines by a mechanisms involving inactivation of NF-kappaB but cast doubt on significant role for the MAPK pathway in these effects.