Achim Jörres

IL-17 Stimulates Intraperitoneal Neutrophil Infiltration Through the Release of GROα Chemokine from Mesothelial Cells

IL-17 is a newly discovered cytokine implicated in the regulation of hemopoiesis and inflammation. Because IL-17 production is restricted to activated T lymphocytes, the effects exerted by IL-17 may help one to understand the contribution of T cells to the inflammatory response. We investigated the role of IL-17 in leukocyte recruitment into the peritoneal cavity. Leukocyte infiltration in vivo was assessed in BALB/Cj mice. Effects of IL-17 on chemokine generation in vitro were examined in human peritoneal mesothelial cells (HPMC). Administration of IL-17 i.p. resulted in a selective recruitment of neutrophils into the peritoneum and increased levels of KC chemokine (murine homologue of human growth-related oncogene α (GROα). Pretreatment with anti-KC Ab significantly reduced the IL-17-driven neutrophil accumulation. Primary cultures of HPMC expressed IL-17 receptor mRNA. Exposure of HPMC to IL-17 led to a dose- and time-dependent induction of GROα mRNA and protein. Combination of IL-17 together with TNF-α resulted in an increased stability of GROα mRNA and synergistic release of GROα protein. Anti-IL-17 Ab blocked the effects of IL-17 in vitro and in vivo. IL-17 is capable of selectively recruiting neutrophils into the peritoneal cavity via the release of neutrophil-specific chemokines from the peritoneal mesothelium.

Haemodialysis-membrane biocompatibility and mortality of patients with dialysis-dependent acute renal failure : A prospective randomised multicentre trial

BACKGROUND There is controversy as to whether haemodialysis-membrane biocompatibility (ie, the potential to activate complement and neutrophils) influences mortality of patients with acute renal failure. We did a prospective randomised multicentre trial in patients with dialysis-dependent acute renal failure treated with two different types of low-flux membrane. METHODS 180 patients with acute renal failure were randomly assigned bioincompatible Cuprophan (n=90) or polymethyl-methacrylate (n=90) membranes. The main outcome was survival 14 days after the end of therapy (treatment success). Odds ratios for survival were calculated and the two groups were compared by Fishers exact test. Analyses were based on patients treated according to protocol (76 Cuprophan, 84 polymethyl methacrylate). FINDINGS At the start of dialysis, the groups did not differ significantly in age, sex, severity of illness (as calculated by APACHE II scores), prevalence of oliguria, or biochemical measures of acute renal failure. 44 patients (58% [95% CI 46-69]) assigned Cuprophan membranes and 50 patients (60% [48-70]) assigned polymethyl-methacrylate membranes survived. The odds ratio for treatment failure on Cuprophan compared with polymethyl-methacrylate membranes was 1.07 (0.54-2.11; p=0.87). No difference between Cuprophan and polymethyl-methacrylate membranes was detected when the analysis was adjusted for age and APACHE II score. 18 patients in the Cuprophan group and 20 in the polymethyl-methacrylate group had clinical complications of therapy (mainly hypotension). INTERPRETATION There were no differences in outcome for patients with dialysis-dependent acute renal failure between those treated with Cuprophan membranes and those treated with polymethyl-methacrylate membranes.

Synthesis of C-X-C and C-C Chemokines by Human Peritoneal Fibroblasts: Induction by Macrophage-Derived Cytokines

Leukocyte accumulation during peritonitis is believed to be controlled by chemotactic factors released by resident peritoneal macrophages or mesothelial cells. Recent data indicate, however, that in many tissues fibroblasts play a key role in mediating leukocyte recruitment. We have therefore examined human peritoneal fibroblasts (HPFBs) for the expression and regulation of C-X-C and C-C chemokines. Quiescent HPFBs secreted monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-8 constitutively. This release could be dose-dependently augmented with the pro-inflammatory cytokines IL-1beta and tumor necrosis factor-alpha. Stimulated IL-8 production reached a plateau within 48 hours while MCP-1 continued to accumulate throughout 96 hours. Induction of IL-8 and MCP-1 synthesis by HPFBs was also triggered by peritoneal macrophage-conditioned medium. This effect was partly related to the presence of IL-1beta as demonstrated by IL-1 receptor antagonist inhibition. Pretreatment of HPFBs with actinomycin D or puromycin dose-dependently reduced cytokine-stimulated IL-8 and MCP-1 secretion, which suggested de novo chemokine synthesis. Indeed, exposure of HPFBs to IL-1beta and tumor necrosis factor-alpha produced a significant up-regulation of IL-8 and MCP-1 mRNA. This effect was associated with the rapid induction of nuclear factor-kappaB binding activity mediated through p65 and p50 subunits, and with a transient increase in the mRNA expression for RelB and inhibitory protein kappaB-alpha proteins. These data indicate that peritoneal fibroblasts are capable of generating large quantities of chemokines under a tight control of nuclear factor-kappaB/Rel transcription factors. Thus, peritoneal fibroblast-derived chemokines may contribute to the intraperitoneal recruitment of leukocytes during peritonitis.

Administration of prostacyclin after liver transplantation: a placebo controlled randomized trial

The shortage of suitable organs for liver grafts is responsible for the use of marginal donors for liver transplantation (OLT). If these liver grafts function poorly initially after OLT, a supportive therapy is necessary. The purpose of this study was to evaluate the effects of prostacyclin (PGI2) on postoperative liver graft function after OLT.A total of 30 adult recipients of primary OLT were randomized to either receive PGI2 (4 ng/kg per min body weight, n=15) or a placebo for 6 d. To evaluate regional splanchnic oxygenation a fiberoptic pulmonary‐artery catheter was inserted into a hepatic vein and the difference between mixed venous oxygen content and hepatic venous oxygen content was determined (ΔO2). Measurements were performed directly after transplantation and at 6, 12, 24 and 48 h postoperatively.A significant correlation between ΔO2 and the level of transaminases (ALT/AST) was observed 24 and 48 h after transplantation (p<0.05). PGI2 treatment induced a significant decrease in ΔO2 after 24 and 48 h after reperfusion (p<0.05). Peak AST levels tended to be lower in the PGI2 treatment group (418±99 vs. 638±156 U/L, p<0.1).These results suggest that administration of PGI2 after OLT improves hepatic‐splanchnic oxygenation and may thereby reduce reperfusion injury after OLT.

Continuous Flow Peritoneal Dialysis: Solution Formulation and Biocompatibility

When peritoneal dialysis was introduced several years ago an important alternative dialysis therapy to hemodialysis was made available for the treatment of end‐stage chronic disease. However, a continuous search for new developments and technologies is necessary to find the optimal peritoneal dialysis fluid (PDF) to preserve peritoneal membrane function as long as possible. Conventional PDFs are known to compromise the functional integrity of the peritoneal membrane as a consequence of their acidic pH in combination with their high lactate content, as well as the high concentrations of glucose and glucose degradation products (GDPs) present in currently used conventional solutions. Novel solutions such as bicarbonate‐buffered PDF (at neutral pH) display improved in vitro biocompatibility as compared to conventional, acidic lactate‐buffered PDF. Since these novel solutions are manufactured in dual‐chambered bags they also contain fewer GDPs, thus further reducing their potential toxicity and protein glycation. Clinically the novel solutions reduce inflow pain and improve peritoneal membrane transport characteristics, ultrafiltration capacity, and effluent markers of peritoneal membrane integrity. The concept of continuous flow peritoneal dialysis (CFPD) is another approach to optimize PDF. The technique of CFPD not only enables the individualization of acid‐base correction by variable concentrations of HCO3− but may also help to restore peritoneal cell functions by neutral pH, reduced glucose load, diminished GDP content, and reduced advanced glycation end product (AGE) formation, thereby potentially contributing to the improved preservation of peritoneal membrane function.

Glucose degradation products in peritoneal dialysis: From bench to bedside

In continuous ambulatory peritoneal dialysis patients, treatment success is inextricably linked to the functional and morphological integrity of the peritoneal membrane. This membrane, however, is repeatedly exposed to peritoneal dialysis fluids (PDFs) with unphysiological composition (e.g., acidic pH, high glucose content, hyperosmolarity). More recently, attention of researchers and clinicians has been focused on the presence of glucose degradation products (GDPs) that are generated during heat sterilization of PDF. These GDPs were found to adversely affect peritoneal cell function both acutely and chronically. Recently, a new family of multi-chambered PDFs has been introduced into clinical practice. By keeping the glucose in a separate compartment at very low pH, the generation of GDPs during heat sterilization is markedly reduced. Initial clinical studies indicate that treatment with these novel PDFs may lead to improved clinical outcomes. The current article reviews recent experimental and clinical experience with both conventional and multi-chambered PDFs.

Systemic liberation of interleukin- 1β and interleukin-1 receptor antagonist in the perioperative phase of liver transplantation

We measured systemic serum levels of interleukin-1 receptor antagonist (IL-1ra), interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), and interleukin-6 (IL-6) during the preoperative, anhepatic, and postreperfusional phases up to the 7th postoperative day in 60 patients undergoing orthotopic liver transplantation (LTx). In contrast to IL-1β, IL-1ra, TNF-α, and IL-6 showed a significant elevation in relation to the early phase after reperfusion, while TNF-α displayed a high grade of scatter. In addition, IL-1ra levels were significantly elevated during the anhepatic phase. Maximum serum levels were found at 15 min after reperfusion, 120 min after reperfusion, and on the 1st postoperative day, respectively. Serum levels decreased considerably at 24 h and 7 days after reperfusion. The comparative monitoring of systemic cytokine and cytokine antagonist levels, in particular the liberation of IL-1ra and IL-6 may provide useful parameters for the development of new liver preservation theories for LTx.