Colon Ascendens Stent Peritonitis Surgery Research Articles

Gemfibrozil Improves Microcirculatory Oxygenation of Colon and Liver without Affecting Mitochondrial Function in a Model of Abdominal Sepsis in Rats.

Recent studies observed, despite an anti-hyperlipidaemic effect, a positive impact of fibrates on septic conditions. This study evaluates the effects of gemfibrozil on microcirculatory variables, mitochondrial function, and lipid peroxidation levels with regard to its potential role as an indicator for oxidative stress in the colon and liver under control and septic conditions and dependencies on PPARα-mediated mechanisms of action. With the approval of the local ethics committee, 120 Wistar rats were randomly divided into 12 groups. Sham and septic animals were treated with a vehicle, gemfibrozil (30 and 100 mg/kg BW), GW 6471 (1 mg/kg BW, PPARα inhibitor), or a combination of both drugs. Sepsis was induced via the colon ascendens stent peritonitis (CASP) model. Then, 24 h post sham or CASP surgery, a re-laparotomy was performed. Measures of vital parameters (heart rate (HR), mean arterial pressure (MAP), and microcirculation (µHbO2)) were recorded for 90 min. Mitochondrial respirometry and assessment of lipid peroxidation via a malondialdehyde (MDA) assay were performed on colon and liver tissues. In the untreated sham animals, microcirculation remained stable, while pre-treatment with gemfibrozil showed significant decreases in the microcirculatory oxygenation of the colon. In the CASP animals, µHbO2 levels in the colon and the liver were significantly decreased 90 min after laparotomy. Pre-treatment with gemfibrozil prevented the microcirculatory aberrations in both organs. Gemfibrozil did not affect mitochondrial function and lipid peroxidation levels in the sham or CASP animals. Gemfibrozil treatment influences microcirculation depending on the underlying condition. Gemfibrozil prevents sepsis-induced microcirculatory aberrances in the colon and liver PPARα-independently. In non-septic animals, gemfibrozil impairs the microcirculatory variables in the colon without affecting those in the liver.

Colon Ascendens Stent Peritonitis (CASP ).

Colon ascendens stent peritonitis (CASP) is one of the well-established models of experimental abdominal sepsis. In CASP surgery, an open link between the gut lumen and the abdominal cavity is created by placing a stent into the colon ascendens. This mimics well the insufficient intestinal anastomosis. It causes a continuous leakage of the gut contents into the peritoneum and leads therefore to peritonitis and sepsis. The abdominal cavity is opened under general anesthesia and a plastic stent is located through and sutured to the colonic wall. The septic severity in CASP models can be titrated by altering the size of the stent catheter. Therefore, CASP models with small stents sizes are suitable for long-term studies and studies with mild/moderate sepsis severity. Within 24h, animals develop clinical signs of sepsis. Monitoring of the clinical state, sufficient analgesia, appropriate antibiotics and fluid resuscitation should be performed postoperatively.

The novel iron chelator, DIBI, attenuates inflammation and improves outcome in colon ascendens stent peritonitis-induced experimental sepsis.

Sepsis is the result of a dysregulated host immune response to an infection. An ideal therapy would target both the underlying infection and the dysregulated immune response. DIBI, a novel iron-binding polymer, was specifically developed as an antimicrobial agent and has also demonstrated in vivo anti-inflammatory properties. This study aimed to further investigate the effects of DIBI with and without the antibiotic imipenem (IMI) in colon ascendens stent peritonitis (CASP)-induced experimental sepsis. Vehicle, DIBI and/or IMI were administered in C57BL/6 mice after CASP surgery. Intestinal leukocyte activation and capillary perfusion was evaluated by intravital microscopy. Moreover, bacterial load in peritoneal lavage fluid and blood, and plasma cytokine levels were assessed. In a second series of experiments, surgery to repair the colon was performed at 5 hr and these mice were followed for long-term survival over 7 days. DIBI reduced leukocyte adhesion, improved capillary blood flow, and decreased key plasma cytokines levels. DIBI also improved survival of infected mice and greatly improved IMI efficacy. Survivors treated with IMI and DIBI were found to be free of systemic infection. DIBI has promising potential for sepsis treatment including its use as a sole or an adjunct therapeutic with antibiotics.

Effect of Pravastatin Pretreatment and Hypercapnia on Intestinal Microvascular Oxygenation and Blood Flow During Sepsis.

In septic patients, adequate microvascular oxygenation (μHBO2) of the intestine is vital for their outcome. Recent studies suggest that statins can ameliorate septic microcirculation in a variety of tissues. However, the effect on intestinal microvascular oxygenation and blood flow is largely unknown. Furthermore, there are indications that statin therapy might not be beneficial in the presence of hypercapnia, as observed in septic acute respiratory distress syndrome (ARDS) patients. Therefore, the present study explores the effect of pravastatin with and without additional moderate acute hypercapnia on intestinal microvascular oxygenation and blood flow in experimental sepsis. Forty male Wistar rats were randomized into four groups. Half of the animals received 0.2 mg • kg pravastatin s.c., the other half received the same volume as vehicle (NaCl 0.9%). After 18 h, colon ascendens stent peritonitis surgery was conducted in all animals to induce sepsis. Twenty-four hours after surgery, baseline was established and the animals were subjected to either 120 min of normocapnic (pCO2 40 ± 6 mm Hg) or moderate hypercapnic (pCO2 72 ± 10 mm Hg) ventilation. Microcirculatory oxygenation (μHBO2) and perfusion (μflow) of the colon were continuously recorded using tissue reflectance spectrophotometry and laser Doppler, respectively. In normocapnic septic animals μHBO2 decreased over time (-8.4 ± 8.7%; P < 0.05 vs. baseline), whereas after pravastatin pretreatment μHBO2 remained constant (-1.9 ± 5.7% vs. baseline). However, in hypercapnic septic animals pretreated with pravastatin μHBO2 declined significantly over time (-8.9 ± 11.8%; P < 0.05 vs. baseline) and was significantly lower compared with normocapnic pravastatin-pretreated animals. μflow did not change over time in any group. Pravastatin pretreatment ameliorates the intestinal microvascular oxygenation in sepsis and thus seems to prevent intestinal hypoxia. Furthermore, we demonstrated that additional hypercapnia abolishes this effect, indicating why septic ARDS patients might not benefit from pravastatin therapy.

Production of IFNβ by Conventional Dendritic Cells after Stimulation with Viral Compounds and IFNβ-Independent IFNAR1-Signaling Pathways are Associated with Aggravation of Polymicrobial Sepsis.

Viral infections are associated with increased incidence of severe sepsis. Particularly during the early stages, type I interferons (IFNs) are known mediators of detrimental effects. However, the functional role of early interferon β (IFNβ) and its cellular source during sepsis in the context of preexisting viral infections has not been defined. Using the colon ascendens stent peritonitis (CASP) model, we demonstrate that IFNβ−/− and type I IFN receptor (IFNAR1)−/− mice were less susceptible to sepsis after pre-stimulation with the viral mimetic poly(I:C). Wild type (WT) mice treated with poly(I:C) exhibited altered expression patterns of TNF and IL-12p40 during CASP which were dependent on IFNβ or IFNAR1, suggesting a mechanism for the increased sepsis susceptibility of WT mice. Using a double cytokine reporter mouse model, we present novel data on the simultaneous expression of IFNβ and IL-12p40 on a single cell level during polymicrobial sepsis in vivo. Conventional dendritic cells (cDCs) were identified as primary source of IFNβ and the protective cytokine IL-12p40 after CASP surgery irrespective of poly(I:C) pre-stimulation. These data demonstrated that if polymicrobial sepsis is preceded by a viral infection, IFNβ and IL-12p40 are expressed by polyfunctional cDCs suggesting that these cells can play both detrimental and beneficial roles during sepsis development.

Colon Ascendens Stent Peritonitis (CASP) Induces Excessive Inflammation and Systemic Metabolic Dysfunction in a Septic Rat Model.

The colon ascendens stent peritonitis (CASP) surgery induces a leakage of gut contents, causing polymicrobial sepsis related to post-operative multiple organ failure and death in surgical patient. To evaluate the effects of CASP on multiple organs, we analyzed the systemic metabolic consequences in liver, kidney, lung, and heart of rats after CASP by employing a combination of metabolomics, clinical chemistry, and biological assays. We found that CASP surgery after 18 h resulted in striking elevations of lipid, amino acids, acetate, choline, PC, and GPC in rat liver together with significant depletion of glucose and glycogen. Marked elevations of organic acids including lactate, acetate, and creatine and amino acids accompanied by decline of glucose, betaine, TMAO, choline metabolites (PC and GPC) nucleotides, and a range of organic osmolytes such as myo-inositol are observed in the kidney of 18 h post-operative rat. Furthermore, 18 h post-operative rats exhibited accumulations of lipid, amino acids, and depletions of taurine, myo-inositol, choline, PC, and GPC and some nucleotides including uridine, inosine, and adenosine in the lung. In addition, significant elevations of some amino acids, uracil, betaine, and choline metabolites, together with depletion of inosine-5'-monophosphate, were only observed in the heart of 18 h post-operative rats. These results provide new insights into pathological consequences of CASP surgery, which are important for timely prognosis of sepsis.

Calcium/Calmodulin Protein Kinase II-Dependent Ryanodine Receptor Phosphorylation Mediates Cardiac Contractile Dysfunction Associated With Sepsis.

Sepsis is associated with cardiac contractile dysfunction attributed to alterations in Ca handling. We examined the subcellular mechanisms involved in sarcoplasmic reticulum Ca loss that mediate altered Ca handling and contractile dysfunction associated with sepsis. Randomized controlled trial. Research laboratorySUBJECTS:: Male wild type and transgenic miceINTERVENTIONS:: We induced sepsis in mice using the colon ascendens stent peritonitis model. Twenty-four hours after colon ascendens stent peritonitis surgery, we observed that wild type mice had significantly elevated proinflammatory cytokine levels, reduced ejection fraction, and fractional shortening (ejection fraction %, 54.76 ± 0.67; fractional shortening %, 27.53 ± 0.50) compared with sham controls (ejection fraction %, 73.57 ± 0.20; fractional shortening %, 46.75 ± 0.38). At the cardiac myocyte level, colon ascendens stent peritonitis cells showed reduced cell shortening, Ca transient amplitude and sarcoplasmic reticulum Ca content compared with sham cardiomyocytes. Colon ascendens stent peritonitis hearts showed a significant increase in oxidation-dependent calcium and calmodulin-dependent protein kinase II activity, which could be prevented by pretreating animals with the antioxidant tempol. Pharmacologic inhibition of calcium and calmodulin-dependent protein kinase II with 2.5 µM of KN93 prevented the decrease in cell shortening, Ca transient amplitude, and sarcoplasmic reticulum Ca content in colon ascendens stent peritonitis myocytes. Contractile function was also preserved in colon ascendens stent peritonitis myocytes isolated from transgenic mice expressing a calcium and calmodulin-dependent protein kinase II inhibitory peptide (AC3-I) and in colon ascendens stent peritonitis myocytes isolated from mutant mice that have the ryanodine receptor 2 calcium and calmodulin-dependent protein kinase II-dependent phosphorylation site (serine 2814) mutated to alanine (S2814A). Furthermore, colon ascendens stent peritonitis S2814A mice showed preserved ejection fraction and fractional shortening (ejection fraction %, 73.06 ± 6.31; fractional shortening %, 42.33 ± 5.70) compared with sham S2814A mice (ejection fraction %, 71.60 ± 4.02; fractional shortening %, 39.63 ± 3.23). Results indicate that oxidation and subsequent activation of calcium and calmodulin-dependent protein kinase II has a causal role in the contractile dysfunction associated with sepsis. Calcium and calmodulin-dependent protein kinase II, through phosphorylation of the ryanodine receptor would lead to Ca leak from the sarcoplasmic reticulum, reducing sarcoplasmic reticulum Ca content, Ca transient amplitude and contractility. Development of organ-specific calcium and calmodulin-dependent protein kinase II inhibitors may result in a beneficial therapeutic strategy to ameliorate contractile dysfunction associated with sepsis.

Acute, short-term hypercapnia improves microvascular oxygenation of the colon in an animal model of sepsis

IntroductionThe deterioration of microcirculatory oxygenation of the gut plays a vital role in the development of sepsis. Acute hypercapnia enhances the microcirculatory oxygenation of the splanchnic region under physiological conditions, while the effect of hypercapnia under sepsis is unknown. The aim of this study was to investigate the effects of acute hypercapnia and hypercapnic acidosis on the colonic microcirculation and early cytokine response in polymicrobial sepsis. MethodsExperiments were performed on 103 male Wistar rats. Colon ascendens stent peritonitis (CASP) surgery with varying stent diameters was conducted to establish a moderate polymicrobial sepsis model. In a second series, 24h of sepsis development induced by CASP surgery was followed by 120min of volume-controlled and pressure-limited ventilation with either normocapnic (pCO2 45±5mmHg) or moderate hypercapnic ventilation targets (pCO2 75±5mmHg) via exogenous carbon dioxide application. The effect of acidosis was investigated by metabolically buffering the hypercapnic acidosis with tromethamine. Microcirculatory oxygenation of the colon wall (tissue reflectance spectrophotometry) and hemodynamic variables were recorded continuously and arterial blood gas and cytokine (TNF-α, IL-6, IL-10) levels were analyzed intermittently. ResultsIn septic animals the microcirculatory oxygenation of the colon deteriorated under normocapnia (−7.0±7.6% at 90min) but was maintained under hypercapnic acidosis (+3.6±7.6%) and buffered hypercapnia (+1.5±4.4%). Cytokine levels were significantly higher in septic animals as opposed to sham animals but did not differ between normocapnic and hypercapnic groups. ConclusionsAcute hypercapnic acidosis and buffered hypercapnia both improve splanchnic microcirculatory oxygenation in a septic animal model, thereby counteracting the adverse effect induced by sepsis. The circulating pro- and anti-inflammatory cytokine levels are not modulated after 120min of hypercapnia.

RapidlyIn SituForming Platelet-Rich Plasma Gel Enhances Angiogenic Responses and Augments Early Wound Healing after Open Abdomen

Objective. The purposes of our present study were to evaluate the potential of platelet-rich plasma gel to enhance granulation tissue formation after open abdomen and to examine whether the effect was attributable to stimulating rapid neovascularization. Methods. Twenty-four rats underwent colon ascendens stent peritonitis surgery to induce sepsis, followed by intraperitoneal injection of nitrogen to create intra-abdominal hypertension. Four hours later, laparotomies were performed. The rats were randomized into three groups (n = 8 for each group): control, platelet-poor plasma (PPP), and platelet-rich plasma (PRP) groups. One week after the treatment, granulation tissue formation and angiogenesis were evaluated by histological and laser Doppler analysis. Results. The resultant platelet count in platelet-rich plasma was higher than that of PPP. The concentrations of platelet-derived growth factor BB, transforming growth factor β-1, and vascular endothelial growth factor in PRP were significantly higher when compared with that of PPP. Myofibroblast count, granulation tissue thickness, vessel numbers, and blood perfusion were increased in PRP group, followed by PPP group, with control being the least. Conclusion. Rapidly in situ forming platelet-rich plasma gel promoted remarkable neovascularization and early wound healing after open abdomen and may lead to novel and effective treatments for open abdominal wounds.

Evaluation of the effects of gender and estradiol treatment on the intestinal microcirculation during experimental sepsis

Intestinal barrier dysfunction plays an important role in sepsis. Females may tolerate sepsis better than males, which could be due to the relative resistance of the female intestine to gut injury and inflammation when subjected to sepsis.In this study the intestinal microcirculation was investigated in 50 female and 40 male rats divided in to 9 groups of 10 animals. Male and female rats were subjected to sham CASP (colon ascendens stent peritonitis). We induced experimental sepsis (CASP) in another two groups of male and female rats. The role of the estradiol treatment was evaluated both in male and ovariectomized female rats. Female rats were subjected to sham ovariectomy 3weeks before sham CASP. Male and ovariectomized female rats were treated with estradiol (10mg/kg estradiol in rizinus oil immediately and 12h following CASP). Another two groups of male and ovariectomized female rats received placebo oil treatment. To evaluate the effects of gender and estradiol treatment on the microvascular perfusion during sepsis, intravital microscopy was performed twenty-four hours after sham CASP or CASP surgery, which permits the in vivo determination of leukocyte–endothelial cell interaction (rolling leukocytes and adherent leukocytes) and the measurement of functional capillary density (FCD), which served as the measure of quality of microvascular perfusion.We found that there was gender difference mainly in the leukocyte endothelial interaction rather than the functional capillary density (FCD), in which male showed significant increases (P<0.05) both in the leukocyte adhesion and rolling leukocytes in submucosal venules (V1 and V3) in comparison to female rats. (Leukocyte adhesion: V1 107.1±49.2n/mm2; V3 112.3±68.1n/mm2) (Rolling leukocytes:V1 16.2±10.3n/min; V3 8.4±8.2n/min). In addition estradiol replacement in ovariectomized female and male rats induced significant decreases (P<0.05) in the leukocyte adhesion and rolling (V1 and V3) with a significant increase in the muscular FCD in comparison to the corresponding placebo treated groups. (Leukocyte adhesion: V1 60±31n/mm2; V3 78.11±37.6n/mm2) (Rolling leukocytes: V1 13.4±8.9n/min; V3 5.8±7.4n/min) (Longitudinal muscular FCD (cm/cm2): in ovariectomized female rats 107.1±12.2; in male rats 106.2±15.3) (Circular muscular FCD (cm/cm2): in ovariectomized female rats: 84.8±14.2; in male rats: 86.1±15.3).We conclude that gender difference in the leukocyte endothelial interaction could explain the resistance of female intestine to injury, and that estradiol treatment could improve the intestinal microcirculation through its effects on the leukocyte endothelial interaction and the FCD both in male and ovariectomized female rats.

Kupffer cell depletion reduces hepatic inflammation and apoptosis but decreases survival in abdominal sepsis

During abdominal sepsis, the activation of hepatic Kupffer cells (KC) and its consequences are of central interest. This study evaluates the impact of selective KC depletion on hepatic microcirculation, cytokine release, and systemic alterations in the colon ascendens stent peritonitis (CASP), a model of polymicrobial abdominal sepsis. For KC depletion clodronate liposomes were injected 24 h before CASP surgery in female C57BL/6N mice. Three and 12 h after CASP, in-vivo fluorescence microscopy of the liver was performed. Analysis of hepatocellular apoptosis was conducted by immunohistochemistry. In addition, levels of tumor necrosis factor (TNF), IL-6, and IL-10 in the liver, lungs, spleen, and plasma were determined, and bacteriology and survival analysis were performed. CASP led to significant sinusoidal perfusion failure, increased leukocyte recruitment, hepatocellular apoptosis and increased levels of TNF, IL-6, and IL-10 in the liver and plasma. KC depletion before CASP significantly reduced leukocyte recruitment to the liver and hepatocellular apoptosis. IL-10 secretion decreased dramatically in the liver and plasma of KC-depleted septic mice. In contrast, TNF levels were clearly elevated after clodronate treatment. In the lung and spleen, a compensatory upregulation of IL-10 could be detected after KC depletion. Clodronate treatment resulted in a significant reduction in survival. The results indicate that KC depletion is locally protective in polymicrobial abdominal sepsis, as it reduces hepatic inflammation and apoptosis. These effects could be observed in the presence of clearly elevated TNF levels. However, the lack of IL-10 in KC-depleted mice resulted in a detrimental systemic proinflammation.

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.

COLON ASCENDENS STENT PERITONITIS-A MODEL OF SEPSIS ADOPTED TO THE RAT

The colon ascendens stent peritonitis (CASP) procedure creates an intestinal leakage of feces, resulting in diffuse peritonitis and polymicrobial sepsis. Mouse models of CASP have been used to study sepsis experimentally. The aim of the present study was to establish CASP sepsis in rats and to provide basic functional characteristics of this model. In analogy to the mouse model, 3 degrees of severity of CASP sepsis, 2 sublethal and 1 lethal, were established depending on the stent diameter. Radio-telemetric recordings in a sublethal model showed that the nonsurvivors remained hemodynamically stable until approximately 1 h before death, when heart rate and blood pressure fell rapidly. Intestinal microcirculatory changes were analyzed 3, 6, 12, and 18 h after CASP surgery using intravital microscopy in a sublethal model. After 18 h, the numbers of the leukocytes firmly adhering to the endothelium and of the ones temporarily interacting were significantly increased. The levels of IL-6 and IL-1beta increased continuously during the CASP experiments while remaining unchanged in the sham group. TNF-alpha and IL-10 levels of CASP animals reached a maximum after 12 h. In conclusion, a rat model of CASP sepsis has been established and characterized with regard to alterations in cardiovascular and microcirculatory function as well as plasma cytokine levels. In experimental settings where genetically engineered animals are not required, it will facilitate detailed examination of dynamic changes in integrated organ function during the course of sepsis and the investigation of treatment strategies.

Mechanisms of acute inflammatory lung injury induced by abdominal sepsis.

Sequestration of neutrophils and release of histotoxic mediators are considered important for the development of pathologic alterations of the lung defined as adult respiratory distress syndrome. Mechanisms of inflammatory lung injury caused by abdominal sepsis were investigated using the colon ascendens stent peritonitis (CASP) model that closely mimics the human disease. In the CASP model, a continuous leakage of intraluminal bacteria into the peritoneal cavity is induced by implantation of a stent in the ascending colon, generating a septic focus. In contrast to the cecal ligation and puncture model of peritonitis, survival of mice following CASP surgery is dependent on IFN-gamma, but independent of tumor necrosis factor (TNF). Here we show that the systemic inflammation induced by CASP surgery results in a rapid and profound increase of lung vascular permeability that was associated with the activation and recruitment of neutrophils to the lung. Activation of circulating granulocytes was characterized by increased production of serine proteinases and reactive oxygen metabolites, as well as elevated expression of cell surface Mac-1. Expression of MIP-2, KC, MIP-1alpha and E-selectin mRNA in lung was strongly increased within 3 h following CASP surgery, whereas up-regulation of IP-10, MCP-1 and P-selectin was delayed. In contrast, induction of RANTES, LIX, ICAM-1 and VCAM-1 mRNA was weak or not detectable after CASP surgery. Importantly, recruitment of leukocytes to the lung was normal in lipopolysaccharide-resistant mice, and was not affected by antibody neutralization of TNF or the chemokines MIP-2 and KC.

Essential role of gamma interferon in survival of colon ascendens stent peritonitis, a novel murine model of abdominal sepsis.

Despite considerable progress, peritonitis and sepsis remain life-threatening conditions. To improve the understanding of the pathophysiology encountered in sepsis, a new standardized and highly reproducible murine model of abdominal sepsis termed colon ascendens stent peritonitis (CASP) was developed. In CASP, a stent is inserted into the ascending colon, which generates a septic focus. CASP employing a stent of 14-gauge diameter (14G stent) results in a mortality of 100% within 18 to 48 h after surgery. By inserting stents of small diameters, mortality can be exactly controlled. Thus, CASP surgery with insertion of a 22G or 18G stent (22G or 18G CASP surgery) results in 38 or 68% mortality, respectively. 14G CASP surgery leads to a rapid invasion of bacteria into the peritoneum and the blood. As a consequence, endotoxemia occurs, inflammatory cells are recruited, and a systemic inflammatory response syndrome develops. Interestingly, the most pronounced upregulation of inflammatory cytokines (gamma interferon [IFN-gamma], tumor necrosis factor alpha [TNF-alpha] and interleukin-12) is observed in spleen and lungs. CASP surgery followed by stent removal at specific time intervals revealed that all animals survived if intervention was performed after 3 h, whereas removal of the septic focus after 9 h did not prevent death, suggesting induction of autonomous mechanisms of a lethal inflammatory response syndrome. 18G CASP surgery in IFN-gamma receptor-deficient (IFNgammaR-/-) mice revealed an essential role of IFN-gamma in survival of sepsis, whereas TNF receptor p55-deficient (TNFRp55-/-) mice did not show altered survival rates. In summary, this study describes a novel animal model that closely mimics human sepsis and appears to be highly suitable for the study of the pathophysiology of abdominal sepsis. Importantly, this model demonstrates a protective role of IFN-gamma in survival of bacterial sepsis.