Early Organ-Specific Hemorrhage-Induced Increases in Tissue Cytokine Content: Associated Neurohormonal and Opioid Alterations

Abstract

Hemorrhage is associated with an impairment in the immune response and with increased concentrations of circulating inflammatory cytokines. The present study determined the time course and localization of alterations in circulating and tissue pro-inflammatory cytokines (TNF-α, IL-1-α and -β) in response to fixed-pressure (40 mm Hg) hemorrhage as well as the associated hanges in circulating neurohormonal and opioid mediators. Conscious unrestrained non-heparinized male Sprague-Dawley rats (n = 24) underwent hemorrhage followed by standard resuscitation with lactated Ringer''s solution. Animals were sacrificed at three time points; immediately after the hemorrhage period, at completion of resuscitation and 1.5 h after the resuscitation period. Hemorrhage resulted in marked elevations in circulating levels of TNF-α, which averaged 860 ± 201 pg/ml. The levels were similarly elevated following fluid resuscitation (877 ±196 pg/ml) and had decreased towards baseline 1.5 h after completion of resuscitation (281 ±134 pg/ml). TNF-α was not detectable in plasma of time-matched controls. Hemorrhage elevated TNF-α content in spleen (25%), lung (55%) and heart (20%), and tissue content remained elevated despite resuscitation. No significant changes in tissue content of TNF-α were detected in the liver, kidney or brain. Circulating levels of IL1-α and -β were not detectable in either the time-matched controls or hemorrhaged animals. However, statistically significant elevations in tissue content of IL-1α were observed in heart, spleen, lung, gut and whole brain (15–30%). Tissue content of IL-1β did not change in response to hemorrhage and/or fluid resuscitation. Activation of sympathetic outflow, as evidenced by a 3- to 4-fold elevation in circulating epinephrine and norepinephrine levels, was observed immediately after hemorrhage, and was associated with a 5-fold rise in circulating β-endorphin. These results demonstrate an early increase in tissue cytokine content following hemorrhagic shock, which is associated with elevations in circulating catecholamines and endogenous opioids, consistent with their potential modulatory role in this response.

Noradrenergic Inhibition of TNF Upregulation in Hemorrhagic Shock

“…It is important to take into consideration that within the hypotensive period, and thus the hypoperfusion state of hemorrhagic shock, the hemorrhage-induced rise in norepinephrine levels was abolished. In addition, our previous studies indicate that tissue proinflammatory cytokine upregulation is evident at completion of the blood loss period, prior to initiation of the fluid resuscitation period [6]. Furthermore, perhaps more important is that when the tissues were obtained at the end of the resuscitation period, a time point at which both tissue catecholamines and cytokines were measured, the tissue content of norepinephrine in the sympathectomized animals was significantly reduced.…”

“…Hemorrhagic shock results in an early proinflammatory response characterized by enhanced tissue expression of TNF, PMN migration to the lung and increased apoptosis in the lung [6], followed by a delayed immunosuppressive state [22]. Hemorrhagic shock is a potent activator of the sympathetic nervous system, resulting in a massive release of catecholamines into the circulation and tissues.…”

“…One hypothesis is that this tissue cytokine response may be under modulation by neural pathways, which are activated to mediate the hemodynamic homeostatic counterregulatory responses to blood loss [5]. This modulation of the cytokine response could be either directly mediated through activation of the sympathetic nervous system or indirectly through opiate and hormonal mechanisms [6]. Furthermore, the effects could be elicited either by direct actions on immune cells following receptor stimulation by specific neurotransmitters or indirectly by affecting responsiveness of the cell to the specific insult.…”

The physiological changes of cumulative hemorrhagic shock in conscious rats

“…In addition, an early increase in tissue cytokine content was initiated by hemorrhagic shock, which is associated with elevations in circulating epinephrine and norepinephrine [33]. Norepinephrine is a more potent inhibitor of TNF-a.…”

Insulin resistance and glucose-induced thermogenesis in critical illness

“…More importantly, local expression of TNF mRNA in skeletal muscle has been shown to correlate with the severity of insulin resistance in cancer (Noguchi et al 1998). This finding is important, since it places a cytokine (or at least its mRNA) in increased quantities in a target tissue for insulin resistance, and there is increasing evidence that injury can lead to induction of pro-inflammatory cytokines such as TNFα, and interleukins 1 and 6 in uninjured tissues, distant to the site of injury (Molina et al 1997;Catania et al 1999). At the present time, however, TNFα and other pro-inflammatory cytokines have not been shown to be capable of inducing insulin resistance in intact muscle (Furnsinn et al 1997).…”