Peritoneal Cytokine Concentrations Research Articles

Antagonism of the Neurokinin-1 Receptor Improves Survival in a Mouse Model of Sepsis by Decreasing Inflammation and Increasing Early Cardiovascular Function.

Sepsis remains a serious clinical problem despite intensive research efforts and numerous attempts to improve outcome by modifying the inflammatory response. Substance P, the principal ligand for the neurokinin-1 receptor, is a potent proinflammatory mediator that exacerbates inflammatory responses and cardiovascular variables in sepsis. The current study examined whether inhibition of the neurokinin-1 receptor with a specific antagonist (CJ-12,255) would improve survival in the cecal ligation and puncture model of sepsis in adult female outbred mice. University basic science research laboratory. Neurokinin-1 receptor treatment at the initiation of sepsis improved survival in cecal ligation and puncture sepsis (neurokinin-1 receptor antagonist survival = 79% vs vehicle = 54%). Delaying therapy for as little as 8 hours postcecal ligation and puncture failed to provide a survival benefit. Neurokinin-1 receptor antagonist treatment did not prevent the sepsis-induced decrease in circulating WBCs, augment the early (6 hr postcecal ligation and puncture) recruitment of inflammatory cells to the peritoneum, or improve phagocytic cell killing of pathogens. However, the neurokinin-1 receptor antagonist significantly reduced both circulating and peritoneal cytokine concentrations. In addition, the cardiovascular variable, pulse distension (a surrogate for stroke volume) was improved in the neurokinin-1 receptor antagonist group during the first 6 hours of sepsis, and there was a significant reduction in loss of fluid into the intestine. These data show that early activation of the neurokinin-1 receptor by substance P decreases sepsis survival through multiple mechanisms including depressing stroke volume, increasing fluid loss into the intestine, and increasing inflammatory cytokine production.

Peritoneal Cytokine Levels Can Predict Anastomotic Leak on the First Postoperative Day.

Accumulating evidence suggests that peritoneal cytokine concentrations may predict anastomotic leak after colorectal surgery, but previous studies have been underpowered. We aimed to test this hypothesis by using a larger prospectively collected data set. This study is an analysis of prospectively collected data. This study was conducted at 3 public hospitals in Auckland, New Zealand. Patients undergoing colorectal surgery recruited as part of 3 previous randomized controlled trials were included. Data on peritoneal and plasma levels of interleukin-6, interleukin-8, interleukin-10, and tumor necrosis factor-α on day 1 after colorectal surgery were reanalyzed to evaluate their predictive value for clinically important anastomotic leak. Area under receiver operating characteristic curve analysis was performed. A total of 206 patients with complete cytokine data were included. The overall anastomotic leak rate was 8.3%. Concentration levels of peritoneal interleukin-6 and interleukin-10 on day 1 after colorectal surgery were predictive of anastomotic leak (area under receiver operating characteristic curve, 0.72 and 0.74; p = 0.006 and 0.004). Plasma cytokine levels of interleukin-6 were higher on day 1 after colorectal surgery in patients who had an anastomotic leak, but this was a poor predictor of anastomotic leak. Levels of other peritoneal and plasma cytokines were not predictive. The study was not powered a priori for anastomotic leak prediction. Although the current data do suggest that peritoneal levels of interleukin-6 and interleukin-10 are predictive of leak, the discriminative value in clinical practice remains unclear. Peritoneal levels of interleukin-6 and interleukin-10 on day 1 after colorectal surgery can predict clinically important anastomotic leak.

Impact of microbial tolerance in persistent secondary Klebsiella pneumoniae peritonitis

Purpose and methodsMicrobial tolerance represents a diminished pro-inflammatory response following repeated stimulation by a host of pathogen-associated molecular patterns (PAMPs) of varying origins. Toll-like receptors (TLRs) have been centrally implicated in the development of tolerance. The purpose of this study was to investigate the impact of tolerance in a previously described murine model.C57BL/6 mice were pretreated intraperitoneally with phosphate buffered saline (PBS), heat-killed Klebsiella 2×108 CFU (hkKlebsiella), LPS 10mg/kg (LPS 10), or BLP 10mg/kg (BLP 10). Following pretreatment, peritonitis was induced 24h later using 103 intraperitoneal Klebsiella CFU. Peritoneal concentrations of TNF-α, IL-10 and nitric oxide (NO), as well as characteristic cell patterns, were determined. Long-term consequences of microbial tolerance were assessed by measuring survival and weight-loss. ResultsFollowing in vitro stimulation with Klebsiella 105 and 103 CFU, TNF-α and IL-10 secretion were diminished in macrophages harvested from mice pretreated with hkKlebsiella, LPS 10 and BLP 10. Pretreated animals had significantly lower bacterial counts. Conversely, local NO levels were elevated. Survival was not different between the groups. ConclusionPretreatment with TLR ligands induced microbial tolerance, with reduced peritoneal cytokine concentrations and enhanced early bacterial clearance. However, this did not translate into improved survival.

Microbial tolerance in secondary peritonitis is dose dependent

Local microbial tolerance was investigated in a murine model of peritonitis. Peritoneal bacterial burden and inflammatory cytokine concentrations were determined at different times, within 48 h after infection. Peritoneal macrophages were harvested from naïve mice or from mice 48 h after infection and underwent ex vivo stimulation with different concentrations of Klebsiella. Cytokine secretion was determined in the supernatants. Peritoneal bacteria concentrations, remained relatively steady between 24 h (median: 5.04 log CFU) and 48 h (median: 5.19 log CFU) after infection. Peritoneal cytokine concentrations peaked early but were already diminished at 48 h after infection, despite persistent high bacteria levels. Macrophages, harvested from naïve mice responded vigorously to ex vivo stimulation with 10 5 CFU and 2 × 10 8 CFU Klebsiella. Cells harvested from animals 48 h after infection, were unresponsive to an ex vivo stimulation with 10 5 CFU Klebsiella, but fully responded to 10 8 CFU. Persistent intraabdominal bacterial infection induced dose dependent microbial tolerance in peritoneal macrophages.

Clinical effects of laparotomy with perioperative continuous peritoneal lavage and postoperative hemofiltration in patients with severe acute pancreatitis

BackgroundThe elevated serum and peritoneal cytokine concentrations responsible for the systemic response syndrome (SIRS) and multiorgan failure in patients with severe acute pancreatitis lead to high morbidity and mortality rates. Prompted by reports underlining the importance of reducing circulating inflammatory mediators in severe acute pancreatitis, we designed this study to evaluate the efficiency of laparotomy followed by continuous perioperative peritoneal lavage combined with postoperative continuous venovenous diahemofiltration (CVVDH) in managing critically ill patients refractory to intensive care therapy. As the major clinical outcome variables we measured morbidity, mortality and changes in the Acute Physiology and Chronic Health Evaluation (APACHE II) score and cytokine concentrations in serum and peritoneal lavage fluid over time.MethodsFrom a consecutive group of 23 patients hospitalized for acute pancreatitis, we studied 6 patients all with Apache II scores ≥19, who underwent emergency surgery for acute complications (5 for an abdominal compartment syndrome and 1 for septic shock) followed by continuous perioperative peritoneal lavage and postoperative CVVDH. CVVDH was started within 12 hours after surgery and maintained for at least 72 hours, until the multiorgan dysfunction syndrome improved. Samples were collected from serum, peritoneal lavage fluid and CVVDH dialysate for cytokine assay. Apache II scores were measured daily and their association with cytokine levels was assessed.ResultsAll six patients tolerated CVVDH well, and the procedure lasted a mean 6 days (range, 3-12). Five patients survived and one died of Acinetobacter infection after surgery (mortality rate 16.6%). The mean APACHE II score was ≥ 19 (range 19-22) before laparotomy and decreased significantly during peritoneal lavage and postoperative CVVDH (P = 0.013 by matched-pairs Students t-test). The decrease in cytokine concentrations in serum and lavage fluid was associated with the decrease in APACHE II scores and high interleukin 6 (IL-6) and tumor necrosis factor (TNF) concentrations in the hemofiltrate.ConclusionIn critically ill patients with abdominal compartment syndrome, septic shock or high APACHE II scores related to severe acute pancreatitis, combining emergency laparotomy with continuous perioperative peritoneal lavage followed by postoperative CVVHD effectively reduces the local and systemic cytokines responsible for multiorgan dysfunction syndrome thus improving patients' outcome.

Interleukin-18 concentration in the peritoneal fluid correlates with the severity of peritonitis

Background Interleukin (IL)-18 is a novel cytokine that has recently been characterized as an inducer of interferon-gamma (IFN-γ). The aim of this study was to investigate the clinical significance of peritoneal IL-18 concentrations in patients with peritonitis. Methods We measured IL-18, IFN-γ, and IL-10 concentrations in the peritoneal fluid of 28 patients undergoing laparotomy for peritonitis. Correlations between the peritoneal cytokine concentrations and the severity of illness determined by systemic inflammatory response syndrome (SIRS) criteria, Acute Physiological and Chronic Health Evaluation II (APACHE II) score, peritoneal fluid bacterial culture results, subsequent development of organ failure, and length of hospital stay were assessed. Results Interleukin-18 concentration was significantly increased in patients who developed SIRS, in those with culture-positive peritonitis, and in those who developed organ failure, as compared with the other patients. Interleukin-10 concentration, which was also significantly increased in patients with culture-positive peritonitis, showed a close correlation with IL-18 concentration. Although a weak correlation was observed between IL-18 and IFN-γ concentrations, IFN-γ concentrations did not show any association with patients’ clinical parameters. However, the IFN-γ/IL-18 ratio was significantly lower in patients with an APACHE II ≥10, and in those with culture-positive peritonitis, as compared with the other patients. Conclusions Peritoneal IL-18 concentration increased in response to intraperitoneal bacterial infection and seemed to reflect the severity of peritonitis. However, the capacity of IL-18 to produce IFN-γ may be altered depending on the severity of peritonitis.

Proliferative and cytokine responses in CTLA4-Ig-treated diabetic NOD mice transplanted with microencapsulated neonatal porcine ICCs.

Our goal is to develop effective islet xenografts for treating human diabetes. We have studied microencapsulated neonatal porcine islet cell clusters (ICCs) transplanted intraperitoneally in spontaneously diabetic NOD mice, where they function to maintain normoglycemia in the autoimmune host. Nonencapsulated neonatal porcine ICCs functioned for 4.5 +/- 0.5 days before being rejected; encapsulation prolonged graft function to 17 +/- 2 days. CTLA4-Ig treatment did not enhance the survival of nonencapsulated ICCs. However, CTLA4-Ig treatment significantly extended the function of encapsulated ICCs to 73 +/- 5 days. Histological analyses demonstrated a profuse pericapsular cellular reaction associated with rejection of encapsulated islet xenografts in untreated mice, while this reaction was significantly reduced in CTLA4-Ig-treated mice. To study mechanisms of xenograft rejection in this model, we analyzed proliferative responses to neonatal porcine ICCs and cytokines present in the peritoneal cavities of transplanted mice. Spleen cells from both CTLA4-Ig-treated and untreated rejecting NODs exhibited vigorous proliferation in the absence of antigenic stimulation, suggesting prior activation in vivo, while splenocytes from CTLA4-Ig-treated NODs with functioning grafts had low proliferative levels, equal to controls. Islet-specific proliferation was not detected in islet-rejecting mice, perhaps due to their high background levels. With the exception of elevated IL-6 levels, empty capsules did not provoke a significant peritoneal cytokine response compared with sham surgery or untransplanted control mice. However, IL-5, IL-12, TGF-beta, and IL-1beta were significantly elevated in NODs receiving encapsulated neonatal porcine ICCs compared with untransplanted controls. There were no significant differences between peritoneal cytokine concentrations in CTLA4-Ig-treated mice with long-term functioning grafts compared to mice that rejected grafts at earlier time points. We conclude that the combination of donor islet microencapsulation and brief treatment of the recipient with co-stimulatory blockade delays sensitization of the host, possibly by altering mechanism(s) for recruitment and/or activation of host effector cells.

Limits of peritoneal cytokine measurements during abdominal lavage treatment for intraabdominal sepsis

Background: Monitoring of peritoneal cytokine concentrations of tumor necrosis factor (TNF)-α was recommended for early detection of severe postoperative complications. In the present study the clinical application of cytokine monitoring was examined in the treatment course of severe peritonitis. Methods: Nineteen patients with secondary peritonitis were followed up during 75 abdominal lavages. Serum and peritoneal interleukin (IL)-6, IL-8, and IL-10 and TNF-α were measured before the surgical intervention, after 1 hour, 3 hours, 6 hours, and 24 hours. Additionally, cardiorespiratory parameters, osmolarity, C-reactive protein, and total leucocyte count were recorded. Results: Serum and peritoneal cytokine concentrations did not correlate to each other as well as to the observed cardiorespiratory parameters. Peritoneal cytokine concentrations were 10- to 1000-fold higher to serum concentrations and showed an intermittent wash out. There were no differences in determined cytokine concentrations between survivors and nonsurvivors Conclusions: Once elevated, peritoneal cytokine measurements offer no new diagnostic or prognostic tool in abdominal lavage peritonitis treatment.

Peritoneal cytokine concentrations and survival outcome in an experimental bacterial infusion model of peritonitis.

To correlate the dynamics of peritoneal cytokines with systemic concentrations and survival outcome. Randomized, controlled study using a recently developed rat model of peritonitis. Government research facility. Male Sprague-Dawley rats. Infected animals (INF) received an intraperitoneal infusion of 6.5 x 10(8) colony-forming units of Escherichia coli over 12 hrs, whereas control rats (CON) received a sterile inoculum. Peritoneal fluid and plasma samples were obtained from all rats at the end of the 12-hr infusion period as well as from all animals that survived the 7-day study (SURV). Interleukin (IL)-1beta concentration in the peritoneal fluid at 12 hrs tended to be higher in nonsurvivors (NONSURV) than in SURV. Tumor necrosis factor-alpha and IL-6 peritoneal concentrations at 12 hrs were significantly greater in NONSURV than in SURV. There were no significant differences in IL-2 and IL-4 peritoneal concentrations at 12 hrs between SURV and NONSURV. Although the concentrations of IL-1beta and tumor necrosis factor-alpha in the peritoneal fluid of INF decreased gradually during the study, these concentrations remained significantly higher than those of CON at 7 days. In contrast, peritoneal IL-2 concentrations remained lower in INF than in CON for most of the experiment. Peritoneal IL-6 concentrations in INF were transiently elevated above those of CON for 12 hrs. Cytokine concentrations in the peritoneal fluid of INF were always higher than those in plasma, which remained relatively unchanged throughout the study. For most of the variables as. sessed, CON showed no significant changes compared with INF. This model of peritonitis is associated with a significant and prolonged peritoneal inflammatory response that is adversely correlated with survival outcome. Our data would suggest that to be effective, novel immunotherapies should target mainly the peritoneal compartment.