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Background: Peroxisome Proliferator-Activated Receptor ! (PPAR! ) is a nuclear receptor that regulates the transcription of genes associated with lipid and glucose metabolism. Recently, it has been shown that PPAR! modulates the activity of T cells, resulting in inhibition of T cell proliferation and IL-2 release. In this study we investigated whether the PPAR! ligand rosiglitazone (R) enhances in vitro the immunosuppressive effects of cyclosporine A (CsA). Methods: CD4 + T cells isolated from peripheral blood mononuclear cells of healthy donors were activated either with mitogens or by one-way mixed lymphocyte reaction. The activated T cells were treated with (1) CsA at low and high concentration (50, 150 ng/ml); (2) R (20 " M); (3) R (20 " M) in combination with CsA at low concentration (50 ng/ml). We studied the effects of the various treatments on cell proliferation (incorporation of [ 3 H] thymidine), the cell-cycle phases (FACS analysis), IL-2 release (ELISA), and IL-2 receptor (CD25) expression (FACS analysis). Results: R used alone reduced T cell proliferation and CD25 expression. Low-dose CsA combined with R was significantly more powerful than either high-dose CsA alone or R alone in suppressing IL-2 release, arresting the T cell cycle, and blocking the growth of activated T cells. Conclusion: PPAR! ligand R potentiates in vitro the inhibitory action of CsA on activated T helper cells. The combined use of PPAR! ligands and low-dose CsA represents a rationale therapeutic approach aimed to prevent CsA nephrotoxicity while maintaining adequate immunosuppression. © 2007 Elsevier B.V. All rights reserved.

Hemofiltration reduces the serum priming activity on neutrophil chemiluminescence in septic patients. Background Priming of the polymorphonuclear neutrophil (PMN) response has been implicated in the activation of oxidative burst and tissue injury in patients with septic shock and acute renal failure (ARF). This study evaluated whether hemofiltration (HF) removes substances able to enhance the oxidative burst of PMNs. Methods Chemiluminescence (CL) priming activity induced by sera and ultrafiltrates of seven patients with septic shock, multiorgan dysfunction syndrome, and ARF (ARF/HF group) and of 10 uremic stable patients (Control/HF group) was evaluated on normal human PMNs stimulated with bacterial formyl-methionyl-leucyl-phenylalanine (FMLP). Patients submitted to HF were studied by determining blood and ultrafiltrate interleukin-8 (IL-8), platelet-activating factor (PAF), and CL priming activity at the beginning (T 0 ), and after four hours (T 4 ) of treatment. Results Preincubation of normal human PMNs with sera and ultrafiltrates from septic patients induced a potent priming of CL activity in subsequent FMLP stimulation. In the ARF/HF group, the prefilter blood concentrations of IL-8 and CL PMN-priming activity significantly decreased during the four hours of HF treatment, with a loss of IL-8 in the ultrafiltrate of 6930 (median, range 4292 to 9282) ng per four hours. PAF detected in the ultrafiltrate and associated with the membrane (7.3 ng, range 1.45 to 9.89) was minimal. In the ARF/HF group, a significantly positive correlation between CL PMN-priming activity and IL-8 concentrations was observed. The CL priming activity in blood and ultrafiltrates was reduced to 55 and 46% by preabsorption with monoclonal antibody (mAb) anti-IL-8. In contrast, the PAF receptor antagonist WEB 2170 did not affect CL priming activity. In the control/HF group, the CL PMN-priming activity was significantly lower than in the ARF/HF group and was independent of IL-8. Conclusions Sera from septic patients demonstrate an enhanced CL priming activity on PMNs. This activity is reduced by ultrafiltration and is due, at least in part, to ultrafiltered IL-8.

meters related to the severity of ARF and sepsis suggests that PAF may contribute to the development Background. Studies in experimental animals have suggested that platelet-activating factor (PAF ) is a of renal injury in septic patients. mediator of sepsis-associated acute renal failure Key words: acute renal failure; cytokines; humans; (ARF ). In the present study we have evaluated whether platelet activating factor; septic shock an increased concentration of PAF within circulation or urine of septic patients correlated with the worsening of renal function. Methods. The concentration of PAF and selected Introduction cytokines (TNF, IL-1, IL-6, IL-8) was evaluated in blood and urine of 12 patients with septic shock and Platelet activating factor (PAF ), a phospholipid mediARF for 4 consecutive days. ator of inflammation with a wide range of biological Results. The data obtained indicate that blood and activities, has been implicated in the pathogenesis of urinary concentrations of PAF and of IL-1, IL-6 and septic shock [1]. Blockade of PAF receptors in experiIL-8 were significantly higher in septic patients than in mental animals inhibits and reverses endotoxin-induced controls subjects and in patients with chronic renal hypotension and renal insuYciency, and significantly failure. The concentration of TNF was significantly improves survival [1,2]. The synthesis of PAF during increased only in urine. A significantly positive correla- Gram-negative sepsis may be initiated either by the tion was found among blood concentration of PAF direct stimulatory eVect of endotoxin or by the release and heart rate (r=0.4193, P