Hans-Juergen Dieterich

Inducible Expression of Inflammatory Chemokines in Respiratory Syncytial Virus-Infected Mice: Role of MIP-1α in Lung Pathology

ABSTRACT Lower respiratory tract disease caused by respiratory syncytial virus (RSV) is characterized by profound airway mucosa inflammation, both in infants with naturally acquired infection and in experimentally inoculated animal models. Chemokines are central regulatory molecules in inflammatory, immune, and infectious processes of the lung. In this study, we demonstrate that intranasal infection of BALB/c mice with RSV A results in inducible expression of lung chemokines belonging to the CXC (MIP-2 and IP-10), CC (RANTES, eotaxin, MIP-1β, MIP-1α, MCP-1, TCA-3) and C (lymphotactin) families. Chemokine mRNA expression occurred as early as 24 h following inoculation and persisted for at least 5 days in mice inoculated with the highest dose of virus (107 PFU). In general, levels of chemokine mRNA and protein were dependent on the dose of RSV inoculum and paralleled the intensity of lung cellular inflammation. Immunohisthochemical studies indicated that RSV-induced expression of MIP-1α, one of the most abundantly expressed chemokines, was primarily localized in epithelial cells of the alveoli and bronchioles, as well as in adjoining capillary endothelium. Genetically altered mice with a selective deletion of the MIP-1α gene (−/− mice) demonstrated a significant reduction in lung inflammation following RSV infection, compared to control littermates (+/+ mice). Despite the paucity of infiltrating cells, the peak RSV titer in the lung of −/− mice was not significantly different from that observed in +/+ mice. These results provide the first direct evidence that RSV infection may induce lung inflammation via the early production of inflammatory chemokines.

Correlation of meropenem plasma levels with pharmacodynamic requirements in critically ill patients receiving continuous veno-venous hemofiltration.

Background: In patients with acute renal failure, the pharmacokinetics of meropenem depend on the operational characteristics of the renal replacement therapy. Dosage recommendations are based on the correlation of plasma levels with pharmacodynamic requirements. Methods: Eight critically ill patients with acute renal failure were treated by continuous veno-venous hemofiltration with a filtrate flow of 1,600 ml/h and received 500 mg of meropenem every 12 h. Plasma and hemofiltrate concentrations of meropenem at steady state were determined by HPLC. Results: Peak levels in plasma amounted to 39.5 ± 10.5 mg/l (mean ± SD) and trough levels were 2.4 ± 1.5 mg/l. The minimal inhibitory concentration (MIC) for susceptible bacteria (4 mg/l) was covered for 40% of the dosing interval or longer in all patients. The MIC for intermediately susceptible organisms (8 mg/l) was covered for 33% in 6 of the 8 patients. The elimination half-life was prolonged to 3.63 ± 0.77 h. The sieving coefficient of meropenem was 0.91 ± 0.10 and the recovery in hemofiltrate amounted to 30.9 ± 11.5% of the dose. Conclusions: A dosage of 500 mg twice daily provides appropriate serum levels for the treatment of infections caused by susceptible bacteria. A higher dosage is adequate for infections by intermediately susceptible bacteria or for renal replacement therapies with markedly higher filtrate flow rates.

Synthetic colloids attenuate leukocyte-endothelial interactions by inhibition of integrin function

Background: It has been suspected that synthetic colloids may interfere with leukocyte adhesion by down-regulation of endothelial cell adhesion molecules. Although inhibition of endothelial inflammation might reduce leukocyte-related tissue injury, the same mechanism may be detrimental for host defense during severe infection. Regarding the widespread use of colloids, the authors performed a laboratory investigation to determine the mechanisms by which synthetic colloids interfere with leukocyte-endothelial interactions. Methods: Adhesion molecule expression on native and cytokine-activated endothelium from umbilical veins was measured after pretreatment with gelatin and various preparations of dextran or hydroxyethyl starch. Inhibition of neutrophil adhesion to activated endothelium was examined in a flow chamber by perfusion of untreated and colloid-treated neutrophils over colloid-pretreated endothelium at 2 dyn/cm2. Comparisons were made between untreated controls, colloid-pretreated endothelium, and colloid-cotreated neutrophils. Results: Intercellular adhesion molecule 1, vascular cell adhesion molecule 1, E-selectin, and P-selectin were not attenuated by any colloid. Accordingly, colloid pretreatment of endothelium alone did not reduce neutrophil adhesion. In contrast, when neutrophils were cotreated by addition of colloids to the perfusate immediately before perfusion, adhesion decreased by 31–51% (P < 0.05) regardless of the colloid type. As indicated by the twofold increased rolling fractions, this reduction was due to an inhibition of neutrophil integrins. Conclusions: This study shows that synthetic colloids inhibit neutrophil adhesion by a neutrophil-dependent mechanism rather than interfering with endothelial cell activation. This suggests that inhibition of leukocyte sequestration by volume support is a common and transient phenomenon depending on the colloid concentration in plasma.

A fish oil emulsion used for parenteral nutrition attenuates monocyte-endothelial interactions under flow

Monocyte adhesion contributes to perfusion abnormalities, tissue damage, and activation of the coagulation system seen during trauma, shock, or overwhelming inflammation. This study was performed to determine whether an intravenous fish oil emulsion used for parenteral nutrition attenuates monocyte-endothelial interactions under flow and reduces procoagulant activity, measured as tissue factor (TF) expression on adherent monocytes in vitro. Endothelial cell monolayers were incubated with either an intravenous fish oil emulsion or a conventional ω-6 lipid emulsion at 0.05 to 1 mg/ml for 24 h. Six hours following activation with TNF&agr; (25 ng/ml), expression of endothelial cell adhesion molecules was measured by flow cytometry. Adhesion of isolated monocytes to pretreated endothelium was examined in a parallel plate flow chamber at a shear stress of 1.5 dynes/cm2. Following perfusion, the cells were cocultured for an additional 4 h and TF expression on monocytes was determined by flow cytometry. In contrast to ω-6 lipids, fish oil down-regulated E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 in a dose-dependent manner. P-selectin, however, remained unchanged. In addition, firm adhesion was reduced to 54%, whereas rolling interactions remained unchanged. Fish oil exhibited no effect on the TF expression on cocultured monocytes. We conclude that intravenous fish oil emulsions reduce both endothelial cell adhesion molecule expression and monocyte adhesion. However, under postcapillary flow conditions, rolling interactions via P-selectin remain unaltered. The functional importance of this effect is illustrated by the corresponding upregulation of TF in response to residual monocyte-endothelial interactions.

A different view on human albumin

With great interest we have read the article by Zhang and Frei on the anti-inflammatory effects of human albumin in the September issue of this journal [1]. They report a downregulation of vascular cell adhesion molecule-1 (VCAM-1) on albumin-treated human aortic endothelial cells which supports our previous results of a reduced VCAM-1 expression on TNFα-activated venous endothelial cells (HUVEC) [2]. Nevertheless, their paper warrants further comments since the authors exclusively discuss the beneficial effects of albumin and do not take into account possible risks of albumin supplementation. Fast infusion of human albumin is well known to cause severe hypotension and flushing. Such …