Katharina Cziupka

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) improves the innate immune response and enhances survival in murine polymicrobial sepsis.

Objective:To investigate the role of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) in postoperative polymicrobial abdominal sepsis.Sepsis is the leading cause of death among critically ill surgical patients. TRAIL is commonly known as an apoptosis-inducing agent in cancer cells. It also plays an important role in the regulation of inflammatory reactions. The role of TRAIL in polymicrobial sepsis is still unclear. Design:Experimental animal model. Setting:University laboratory. Subjects:C57BL/6 mice. Interventions:Colon ascendens stent peritonitis (CASP) was induced in female mice. One hour, 24 hrs, and 48 hrs after induction of CASP, murine recombinant TRAIL was given intravenously. Measurements and Main Results:This study demonstrates a protective effect of TRAIL in CASP, an experimental model of murine polymicrobial sepsis. Intravenous administration of recombinant TRAIL to mice after CASP induction led to highly significantly prolonged survival. The migration of effector cells into the peritoneal cavity was strongly enhanced. Consequently, TRAIL-treated mice eliminated bacteria significantly better from the peritoneal cavity, the source of infection. Systemic spread of gut bacteria was also reduced by several orders of magnitude. As a result of the reduced systemic spread of bacteria, the accumulation of neutrophils within the spleen and mesenteric lymph nodes was strongly decreased. Conclusion:TRAIL-treated mice are highly protected from abdominal sepsis. Because diagnosis and therapy are frequently delayed in human sepsis, it is remarkable that TRAIL is effective when given via a therapeutic approach. Therefore, this study suggests a therapeutic potential for TRAIL in human sepsis. This should be addressed in future trials.

Surgical Trauma and Postoperative Immune Dysfunction

Background: In postoperative sepsis, mortality is increased due to the surgically induced immune dysfunction. Further causes of this traumatic effect on the immune system include burn injuries and polytrauma, as well as endogenous traumata like stroke. Several animal models have been defined to analyse the characteristics of trauma-induced immune suppression. This article will correlate our results from animal studies and clinical observations with the recent literature on postoperative immune suppression. Methods: The previously described model of surgically induced immune dysfunction (SID) was performed in mice by laparotomy and manipulation of the small intestine in the antegrade direction. Blood samples were collected 6 and 72 h following SID to analyse the white blood cell count and corticosterone levels. To assess the postoperative immune status in humans, we analysed expression of HLA-DR on monocytes of 118 patients by flow cytometry prior to and 24, 48 and 72 h after surgery. Results: The postoperative immune suppression in our SID model is characterised by lymphocytopenia and significantly increased corticosterone levels in mice dependent on the degree of surgical trauma. This is comparable to the postoperative situation in humans: major and especially long-lasting surgery results in a significantly reduced expression of HLA-DR on circulating monocytes. Previous studies describe a similar situation following burn injury and endogenous trauma, i.e. stroke. Conclusions: We suggest the completion of our previously published sepsis classification due to the immune status at the onset of sepsis: type A as the spontaneously acquired sepsis and type B as sepsis in trauma-induced pre-existing immune suppression.

Colon Ascendens Stent Peritonitis (CASP) - a Standardized Model for Polymicrobial Abdominal Sepsis

Sepsis remains a persistent problem on intensive care units all over the world. Understanding the complex mechanisms of sepsis is the precondition for establishing new therapeutic approaches in this field. Therefore, animal models are required that are able to closely mimic the human disease and also sufficiently deal with scientific questions. The Colon Ascendens Stent Peritonitis (CASP) is a highly standardized model for polymicrobial abdominal sepsis in rodents. In this model, a small stent is surgically inserted into the ascending colon of mice or rats leading to a continuous leakage of intestinal bacteria into the peritoneal cavity. The procedure results in peritonitis, systemic bacteraemia, organ infection by gut bacteria, and systemic but also local release of several pro- and anti-inflammatory cytokines. The lethality of CASP can be controlled by the diameter of the inserted stent. A variant of this model, the so-called CASP with intervention (CASPI), raises opportunity to remove the septic focus by a second operation according to common procedures in clinical practice. CASP is an easily learnable and highly reproducible model that closely mimics the clinical course of abdominal sepsis. It leads way to study on questions in several scientific fields e.g. immunology, infectiology, or surgery.

Detrimental Role of CC Chemokine Receptor 4 in Murine Polymicrobial Sepsis

ABSTRACT CC chemokine receptor 4 (CCR4) and its two ligands, CCL17 and CCL22, are critically involved in different immune processes. In models of lipopolysaccharide-induced shock, CCR4-deficient (CCR4−/−) mice showed improved survival rates associated with attenuated proinflammatory cytokine release. Using CCR4−/− mice with a C57BL/6 background, this study describes for the first time the role of CCR4 in a murine model of polymicrobial abdominal sepsis, the colon ascendens stent peritonitis (CASP). CASP-induced sepsis led to a massive downregulation of CCR4 in lymphoid and nonlymphoid tissues, whereas the expression of CCL17 and CCL22 was independent of the presence of CCR4. After CASP, CCR4−/− animals showed a strongly enhanced bacterial clearance in several organs but not in the peritoneal lavage fluid and the blood. In addition, significantly reduced levels of proinflammatory cytokines/chemokines were measured in organ supernatants as well as in the sera of CCR4−/− mice. CCR4 deficiency consequently resulted in an attenuated severity of systemic sepsis and a strongly improved survival rate after CASP or CASP with intervention. Thus, our data provide clear evidence that CCR4 plays a strictly detrimental role in the course of polymicrobial sepsis.

Selective depletion of alveolar macrophages in polymicrobial sepsis increases lung injury, bacterial load and mortality but does not affect cytokine release.

Background: Resident tissue macrophages exert important functions during severe systemic infection and contribute to changes in local as well as systemic immune responses. Alveolar macrophages (AM) play a crucial role in airway diseases and in the defense against microorganisms invading the body via the bronchopulmonary tract. It has been postulated that AM are involved in the development of acute local disorders as a consequence of extrapulmonary stimuli like pancreatitis, peritonitis, or trauma. Objective: The aim of this study was to analyze the local and systemic role of AM during sepsis using selective AM depletion in the murine colon ascendens stent peritonitis (CASP) model of polymicrobial sepsis. Methods: 48 h prior to CASP surgery, AM of female C57BL/6 mice were selectively depleted by intratracheal application of clodronate liposomes (Lipo-clod). For control purposes, phosphate-buffered saline (PBS) liposomes (Lipo-PBS) were used. Results: CASP led to significantly elevated levels of local and systemic cytokines independent of the presence of AM. In contrast, levels of gut-derived bacteria in bronchoalveolar lavage and lung of septic mice were significantly higher in Lipo-clod-treated animals compared to Lipo-PBS-treated animals. After CASP-induced sepsis, local barrier dysfunction in the lung was detected; AM depletion resulted in severely enhanced development of acute lung injury. Consequently, Lipo-clod-treated animals showed strongly reduced survival rates after CASP. Conclusions: Contrarily to other macrophage populations, AM do not significantly contribute to local and systemic cytokine release during polymicrobial abdominal sepsis. AM have important protective functions for local clearance of gut-derived bacteria and attenuation of lung injury.

Outcomes and prognostic factors in gallbladder cancer: a single-centre experience

IntroductionGallbladder cancer is the most common malignant tumour of the biliary system with an extraordinarily poor prognosis. In this study, we retrospectively evaluated forty-two patients with histologically proven gallbladder cancer.Patients and methodsEstimated survival rates were calculated by the Kaplan–Meier method, and differences were assessed using the logrank test. The GKR (combined registry of cancer) and demographic data were used to gain information on community cancer statistics.ResultsIn this study, patients with metastases showed poorer survival rates. Furthermore, the survival was significantly better in patients with R0 resections, smaller tumour sizes and without lymph node infiltration. T stage, M stage and R stage were independent prognostic parameters. Sex and age had no significant effect on survival. Also, we found that patients with incidental gallbladder cancer and those with cholecystolithiasis showed significantly better survival rates. Demographic analyses of the study group confirmed a high coverage of our institution for incident cases in our catchment area and no significant regional deviations from the expected incidence of gallbladder cancer.ConclusionDespite differences in the incidence in different geographical areas, gallbladder cancer appears to be fairly normally distributed in Western Pomerania, a predominantly rural area of Northeastern Germany. Coverage of incident cases in our catchment area was high. T stage, M stage and R stage were independent prognostic factors in our study. We conclude that, whenever possible, an R0 resection should be the surgical goal in all patients staged resectable before surgery, but heroic resections in patients with highly advanced cancer disease or severe accompanying non-tumour diseases are not warranted.

The role of the vagus nerve: modulation of the inflammatory reaction in murine polymicrobial sepsis.

The particular importance of the vagus nerve for the pathophysiology of peritonitis becomes more and more apparent. In this work we provide evidence for the vagal modulation of inflammation in the murine model of colon ascendens stent peritonitis (CASP). Vagotomy significantly increases mortality in polymicrobial sepsis. This effect is not accounted for by the dilatation of gastric volume following vagotomy. As the stimulation of cholinergic receptors by nicotine has no therapeutic effect, the lack of nicotine is also not the reason for the reduced survival rate. In fact, increased septic mortality is a consequence of the absent modulating influence of the vagus nerve on the immune system: we detected significantly elevated serum corticosterone levels in vagotomised mice 24 h following CASP and a decreased ex vivo TNF-alpha secretion of Kupffer cells upon stimulation with LPS. In conclusion, the vagus nerve has a modulating influence in polymicrobial sepsis by attenuating the immune dysregulation.

Single-Port-Access-Cholezystektomie als sichere Alternative zum 4-Port-Vorgehen: Ein retrospektiver Vergleich

PURPOSE As laparoscopic surgery develops, one current goal is the reduction of scarring and operative trauma to a minimum. Single-port access surgery (SPA) uses a single small incision hidden in the umbilicus. This report describes our experiences with 69 SPA cholecystectomies compared to the conventional laparoscopic approach. METHODS Within two years 69 SPA cholecystectomies were performed. Data including demographic distribution, incision to closure time, duration of the postoperative hospital stay, rates of intraoperative and postoperative complications, and conversion rates were collected retrospectively. Data for a matched control group treated by standard laparoscopic cholecystectomy were gathered within the same time frame and then compared. RESULTS There were no significant differences in the rates of intraoperative or postoperative complications in the SPA group when compared to the standard laparoscopy group. The incision-to-closure time strongly depended on the surgeon but did not depend on the method. The duration of postoperative hospital stay was slightly decreased in the SPA group. However, this effect was statistically not significant. CONCLUSIONS For selected patient groups, SPA cholecystectomy is on par with the conventional laparoscopic method. The cosmetic advantage that it offers does not come at the cost of any loss of safety.

Contents Vol. 48, 2012

I. Alwayn, Halifax D.K. Bartsch, Marburg C. Bassi, Verona W.O. Bechstein, Frankfurt am Main J.A. Bradley, Cambridge M. Cikirikcioglu, Geneva P.-A. Clavien, Zurich C. Eipel, Rostock R.W.F. de Bruin, Rotterdam H. Friess, Munich S. Fichtner-Feigl, Regensburg G. Galata, London D.J. Gouma, Amsterdam J.K. Habermann, Lübeck M. Heberer, Basel W.R. Jarnagin, New York, NY J.C. Kalff , Bonn M.W. Laschke, Homburg/Saar H.-A. Lehr, Lausanne C.M. Malata, Cambridge T. Minor, Bonn M. Morino, Torino J. Pirenne, Leuven R. Schramm, Munich L. Steinstraesser, Bochum T.M. van Gulik, Amsterdam M.A. Venermo, Helsinki D.C. Winter, Dublin Y. Yamamoto, Akita Clinical and Experimental Surgery