Anemia in intensive care unit patients resembles the anemia of chronic disease, being characterized by diminished erythropoietin production relative to decreased hematocrit, altered iron metabolism, and impaired proliferation and differentiation of erythroid progenitors in the bone marrow. Inflammatory mediators play a major role in the development of insufficient erythropoiesis and altered iron metabolism. Furthermore, a proinflammatory milieu promotes structural and functional alterations of erythrocytes, impairing their deformability and possibly impairing microvascular perfusion. Collectively, these changes in red blood cell physiology can impair oxygen transport to tissues and, thereby, might contribute to the development of multiple organ failure in critical illness.

We suggest that DARC predominantly exerts its effects by controlling spatial chemokine distribution, which in turn regulates neutrophil recruitment and subsequent acute renal failure.

Cellular adaptation to hypoxia depends, in part, on the transcription factor hypoxia-inducible factor-1 (HIF-1). Normoxic cells exposed to an inflammatory milieu often manifest phenotypic changes, such as increased glycolysis, that are reminiscent of those observed in hypoxic cells. Accordingly, we investigated the effects of cytomix, a mixture containing IFN-gamma, TNF, and IL-1beta on the expression of HIF-1-dependent proteins under normoxic and hypoxic conditions. Incubation of intestine-derived epithelial cells (IEC-6) under 1% O(2) increased HIF-1 DNA binding and expression of aldolase A, enolase-1, and VEGF mRNA. Incubation of normoxic cells with cytomix for 48 h also markedly increased HIF-1 DNA binding and expression of mRNAs for these proteins. Incubation of hypoxic cells with cytomix did not inhibit HIF-1 DNA binding or upregulation of HIF-1-dependent genes in response to hypoxia. Neither cytomix nor hypoxia increased steady-state levels of HIF-1alpha mRNA. Incubation of IEC-6 cells with cytomix induced nitric oxide (NO.) biosynthesis, which was blocked if the cultures contained l-N(G)-(1-iminoethyl)lysine hydrochloride (l-NIL). Treatment with l-NIL, however, failed to significantly alter aldolase A, enolase-1, and VEGF mRNA levels in normoxic cytomix-treated cells. Proinflammatory cytokines activate the HIF-1 pathway and increase expression of glycolytic genes in nontransformed rat intestinal epithelial cells, largely through an NO.-independent mechanism.

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Terlipressin reversed the hemodynamic changes in ovine endotoxemia. However, its pulmonary vasopressive effect might limit its therapeutic use in septic shock.

Besides providing effective analgesia, thoracic epidural anesthesia (TEA) has been shown to decrease perioperative morbidity and mortality. Because of its vasodilatory properties in association with the sympathetic blockade, however, TEA may potentially aggravate cardiovascular dysfunctions resulting from sepsis and systemic inflammatory response syndrome. The objective of the present study was to assess the effects of TEA on hemodynamics, global oxygen transport, and renal function in ovine endotoxemia. After a baseline measurement in healthy sheep (n = 18), Salmonella typhosa endotoxin was centrally infused at incremental doses to induce and maintain a hypotensive-hypodynamic circulation using an established protocol. The animals were then randomly assigned to one of two groups. In the treatment group, continuous TEA was initiated with 0.1 mL.kg of 0.125% bupivacaine at the onset of endotoxemia and maintained with 0.1 mL.kg.h. In the control group, the same amount of isotonic sodium chloride solution was injected through the epidural catheter. In the animals surviving the entire experiment (n = 7 per group), cardiac index and mean arterial pressure decreased in a dose-dependent manner during endotoxin infusion. In the TEA group, neither systemic hemodynamics nor global oxygen transport were impaired beyond the changes caused by endotoxemia itself. Urinary output was increased in the TEA group as compared with the control group (P < 0.05). In this model of endotoxic shock, TEA improved renal perfusion without affecting cardiopulmonary hemodynamics and global oxygen transport.

Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that mediates the adaptive response to hypoxia. Increasing evidence suggests a crucial role for HIF-1 in immune reactions. Here we investigated the effect of the Th2 type cytokines IL-4 and IL-10 on HIF-1a mediated response in normoxia (21% O 2 ) and hypoxia (1% O 2 ). Incubation of human transformed intestinal cells (HT-29) with IL-4 significantly increased HIF1a protein levels during hypoxia but not during normoxia. Mechanisms involved are IL-4 induced up-regulation of HIF-1a gene transcription and the PI3K signaling pathway. The increase in hypoxia-induced accumulation of HIF-1a protein after IL-4 treatment did not result in up-regulation of HIF-1 DNA-binding activity or HIF-1 dependent gene expression. IL-10 did not affect HIF-1a protein levels.

No abstract