Noradrenergic Inhibition of TNF Upregulation in Hemorrhagic Shock

Abstract

The early stress responses to hemorrhagic shock, trauma and endotoxicosis are associated with an early proinflammatory response characterized by increased gene expression of proinflammatory cytokines, PMN influx and accumulation in the lung and apoptosis. The central role of the neuroendocrine system in modulating these proinflammatory responses has been strongly suggested by recent studies. Objectives: To examine the role of noradrenergic innervation in modulating the early increase in lung and spleen content of TNF-α in response to fixed-pressure (40 mm Hg) hemorrhage in vivo. Methods: Conscious unrestrained nonheparinized male Sprague-Dawley rats (n = 42) were randomized to receive intraperitoneally either 6-hydroxy-dopamine (6-OHDA; chemical sympathectomy, SNSx) or saline (0.3 ml) prior to undergoing hemorrhage followed by fluid resuscitation with lactated Ringer’s solution. Animals were sacrificed at completion of the resuscitation period and tissue samples (lung and spleen) excised for determination of TNF-α content, myeloperoxidase activity and apoptosis. Results: Hemorrhage resulted in an immediate marked elevation in circulating epinephrine and norepinephrine levels (10- and 2-fold, respectively), increasing their plasma ratio to 6:1. SNSx depleted tissue stores of norepinephrine (80%), did not alter basal plasma levels of epi- or norepinephrine or the hemorrhage-induced rise in epinephrine, but completely prevented the rise in circulating norepinephrine. Hemorrhage increased lung and spleen contents of TNF-α (55 and 72%, respectively). SNSx significantly enhanced the hemorrhage-induced rise in lung TNF in response to hemorrhage. Conclusions: These results show a suppressive role for noradrenergic innervation on the hemorrhage-induced increase in tissue TNF-α content in vivo. We speculate that the effects of norepinephrine are protective from tissue injury but are likely to contribute to the generalized immunosuppression following trauma.