Current management of small-bowel obstruction.

The most significant advances in the management of small-bowel obstruction are developments in imaging modalities available to assist in the diagnosis itself, as well as to possibly assist in the early identification of those cases requiring urgent operative decompression. The most marked of these have been in the use and interpretation of contrast-enhanced CT. This has decreased the use of barium studies and has largely supplanted ultrasound and magnetic resonance imaging in the management of these patients. Diagnostic and therapeutic laparoscopic techniques are also growing in both capability and popularity. Laparoscopic adhesiolysis and the adjuvant of bioresorbable membranes each hold promise but have yet to become established as standard treatment. Further progress is needed in the detection of early, reversible strangulation. As a consequence, the fundamentals of the surgical management of small-bowel obstruction have evolved little over the past 15 years. With our persistent inability to detect reversible ischemia, a substantial risk of progression to irreversible ischemia remains when surgery is delayed, particularly in the setting of suspected complete obstruction.

Reactive oxygen species are essential mediators in antigen presentation by Kupffer cells.

Kupffer cells (KC) act as APC in the liver and play a major role in the clearance of gut-derived antigens and pathogens entering the liver with portal venous blood. Antigen presentation by KC has been implicated in regulation of the local and systemic immune responses. In this study, modulation of KC antigen presentation by antioxidants and the role of reactive oxygen species (ROS) as essential mediators of antigen presentation in KC were investigated. Co-culture of KC with ovalbumin (OVA) antigens resulted in upstream intracellular endogenous ROS generation and increased expression of MHC class II and costimulator molecules, and consequent OVA-specific CD4(+) T-cell proliferation in response to antigen presentation by KC. Scavenging of KC ROS by antioxidants, or blocking of KC ROS generation by specific inhibitors of NADPH oxidase and/or xanthine oxidase, or by specific inhibitors of the mitochondrial electron transport chain, significantly decreased OVA-specific T-cell proliferation in response to antigen presentation by KC. Increased expression of MHC class II and costimulatory molecules in KC pulsed with OVA antigens was blocked by inhibiting ROS generation enzymatically. Intracellular endogenous ROS generation during antigen processing may therefore provide essential secondary signalling for KC antigen presentation.

Lipopolysaccharides induced increases in Fas ligand expression by Kupffer cells via mechanisms dependent on reactive oxygen species.

Fas-Fas ligand (FasL)-dependent pathways exert a suppressive effect on inflammatory responses in immune-privileged organs. FasL expression in hepatic Kupffer cells (KC) has been implicated in hepatic immunoregulation. In this study, modulation of FasL expression of KC by endogenous gut-derived bacterial LPS and the role of reactive oxygen species (ROS) as potential mediators of FasL expression in KC were investigated. LPS stimulation of KC resulted in upstream ROS generation and, subsequently, increased FasL expression and consequent Jurkat cell (Fas-positive) apoptosis. The NADPH oxidase and xanthine oxidase enzymatic pathways appear to be major sources of this upstream ROS generation. Increased FasL expression was blocked by antioxidants and by enzymatic blocking of ROS generation. Exogenous administration of H2O2 stimulated KC FasL expression and subsequent Jurkat cell apoptosis. Intracellular endogenous ROS generation may therefore represent an important signal transduction pathway for FasL expression in KC.

Hepatic reticuloendothelial system dysfunction after ischemia-reperfusion: role of P-selectin-mediated neutrophil accumulation.

The relationship between hepatic ischemia-reperfusion (I-R) and subsequent injury through neutrophil accumulation is well described. Although alterations in reticuloendothelial system (RES) function (specifically Kupffer cell function) after I-R have been delineated, the degree to which discrete components of RES function (phagocytosis and killing) are independently modulated under these conditions has not been quantified. A hepatic segmental I-R model was established in mice, in which blood supply to the left lateral lobe of the liver was occluded for 45 minutes, the liver was reperfused, and the laparotomy incision was closed. Experimental animals were pretreated with either vinblastin (1.5 mg/kg) to induce neutropenia or anti-P-selectin monoclonal antibody (mAb; 50 microg/mice) 4 days and 5 minutes before ischemia, respectively. We previously reported that after intravenous injection of chromium 51 ((51)Cr) and iodine 125 ((125)I) double-labeled Escherichia coli, hepatic (51)Cr levels could be used to reliably quantify hepatic phagocytic clearance (HPC) of bacteria from blood, whereas the subsequent release of (125)I from the liver accurately paralleled hepatic bacterial killing efficiency (HKE). Using this double-label bacteria clearance assay, HPC and HKE were depressed after I-R, in association with hepatic neutrophil accumulation. Segmental I-R resulted in decreased HPC and HKE activity in both ischemic and nonischemic hepatic lobes. Depressions in HPC and HKE were attenuated by either vinblastin-induced neutropenia or blocking neutrophil adhesion to the hepatic endothelium with anti-P-selectin mAb. These findings support the hypothesis that I-R induces hepatic RES dysfunction, at least in part, through P-selectin-mediated neutrophil accumulation.

Biliary obstruction reduces hepatic killing and phagocytic clearance of circulating microorganisms in rats.

Septic complications are common in patients with biliary obstruction. This is thought to be related, in part, to dysfunction of the hepatic reticuloendothelial system (RES). It has been reported that nearly 80% of circulating microorganisms are phagocytosed and killed within the liver and that clearance of circulating pathogens is significantly impaired in patients with jaundice. However, the effect of biliary obstruction specifically on phagocytic killing within the liver is less well described. Therefore this study was designed to quantify the effect of biliary obstruction, simultaneously and discriminately, on two important components of hepatic RES function (phagocytosis and phagocytic killing). Rats were divided into three experimental groups: control, sham, and jaundiced (common bile duct ligation). At 7, 10, 14, and 21 days after operation, E. coli labeled with both 125I and 51Cr were injected intravenously. Using the previously validated double-labeled in vivo E. coli technique, hepatic phagocytic clearance (HPC), hepatic killing efficiency (HKE), and net hepatic killing (NHK) were measured. Common bile duct ligation resulted in a significant decrease in the HPC of E. coli 10, 14, and 21 days postoperatively. Similarly, HKE was significantly decreased in jaundiced animals by postoperative day 10, but returned to baseline values by day 14. The net effect of these changes in HPC and HKE values were reflected in a significant reduction in NHK in jaundiced animals. Results of the present study suggest that obstructive jaundice impairs both phagocytosis and phagocytic killing within the liver. These findings may help to explain the susceptibility of patients with biliary tract obstruction to the morbidity and mortality of septic complications.

Mesenteric hemodynamic response to circulatory shock.

PURPOSE OF REVIEW: The mesenteric hemodynamic response to circulatory shock is substantial and asymmetrical; the vasoconstrictive response disproportionately affects the mesenteric organs. The cardiac output is sustained partially, at no cost in nutrient flow to the mesenteric organs, by vasoconstriction of the mesenteric veins, resulting in the "autotransfusion" of up to 30% of the circulating blood volume into the systemic circulation. RECENT FINDINGS: Hemorrhagic or cardiogenic shock also results in decreased perfusion pressure, prompting selective vasoconstriction of the mesenteric arterioles to maintain perfusion pressure of the vital organs, here at the selective expense of the mesenteric organs. Septic shock may be associated with increased or decreased mesenteric blood flow but is characterized by increased oxygen consumption, exceeding the capability of mesenteric oxygen delivery. SUMMARY: The response to any of these conditions can, variably and unpredictably, cause hemorrhagic gastric stress erosions, nonocclusive mesenteric ischemia of the small bowel, ischemic colitis, ischemic hepatitis, acalculous cholecystitis, and/or ischemic pancreatitis. Injury to the mesenteric organs can also initiate the systemic inflammatory response syndrome and, consequently, multiple organ failure.

Hepatic killing but not clearance of systemically circulating bacteria is dependent upon peripheral leukocytes via Mac-1 (CD11b/CD18).

The hepatic reticuloendothelial system (RES) is the primary mechanism for removing circulating bacteria from the systemic circulation. While Kupffer cells are important for this process, leukocytes appear to play a significant role as well. Hepatic leukocyte accumulation following ischemia/reperfusion or cytokine stimulation is well documented, but its contribution to phagocytic killing by the hepatic RES is not fully understood. We evaluated the role of leukocytes in general, and leukocyte-endothelial adhesion in particular, in hepatic RES function. This was done by inducing confirmed leukopenia with cyclophosphamide or by blocking leukocyte-endothelial adhesion molecules with specific blocking antibodies. Hepatic phagocytic clearance (HPC) and hepatic phagocytic killing (HKE) of systemically intravenously injected E. coli were assayed and quantitated by a validated dual isotope label technique. HPC among the various experimental groups and respective controls varied only slightly, with no statistically significant differences observed. Leukopenia or CD11b blockade each significantly decreased the HKE relative to the controls. Antibody blockade of certain other adhesion molecules had no significant effect on HKE (or HPC). The role of leukocytes in killing systemically circulating bacteria is an integral component of hepatic RES function. This capability of the leukocyte appears to be dependent, in part, on the adhesion molecule, Mac-1.

Rapid upregulation of endothelial P-selectin expression via reactive oxygen species generation.

Endothelial cell ICAM-1 upregulation in response to TNF-alpha is mediated in part by reactive oxygen species (ROS) generated by the endothelial membrane-associated NADPH oxidase and occurs maximally after 4 h as the synthesis of new protein is required. However, thrombin-stimulated P-selectin upregulation is bimodal, the first peak occurring within minutes. We hypothesize that this early peak, which results from the release of preformed P-selectin from within Weibel-Palade bodies, is mediated in part by ROS generated from the endothelial membrane-associated xanthine oxidase. We found that this rapid expression of P-selectin on the surface of endothelial cells was accompanied by qualitatively parallel increases in ROS generation. Both P-selectin expression and ROS generation were inhibited, dose dependently, by the exogenous administration of disparate cell-permeable antioxidants and also by the inhibition of either of the known membrane-associated ROS-generating enzymes NADPH oxidase or xanthine oxidase. This rapid, posttranslational cell signaling response, mediated by ROS generated not only by the classical NADPH oxidase but also by xanthine oxidase, may well represent an important physiological trigger of the microvascular inflammatory response.

The physiology of endothelial xanthine oxidase: from urate catabolism to reperfusion injury to inflammatory signal transduction.

Xanthine oxidoreductase (XOR) is a ubiquitous metalloflavoprotein that appears in two interconvertible yet functionally distinct forms: xanthine dehydrogenase (XD), which is constitutively expressed in vivo; and xanthine oxidase (XO), which is generated by the posttranslational modification of XD, either through the reversible, incremental thiol oxidation of sulfhydryl residues on XD or the irreversible proteolytic cleavage of a segment of XD, which occurs at low oxygen tension and in the presence of several proinflammatory mediators. Functionally, both XD and XO catalyze the oxidation of purines to urate. However, whereas XD requires NAD+ as an electron acceptor for these redox reactions, thereby generating the stable product NADH, XO is unable to use NAD+ as an electron acceptor, requiring instead the reduction of molecular oxygen for this purine oxidation and generating the highly reactive superoxide free radical. Nearly 100 years of study has documented the physiologic role of XD in urate catabolism. However, the rapid, posttranslational conversion of XD to the oxidant-generating form XO provides a possible physiologic mechanism for rapid, posttranslational, oxidant-mediated signaling. XO-generated reactive oxygen species (ROS) have been implicated in various clinicopathologic entities, including ischemia/reperfusion injury and multisystem organ failure. More recently, the concept of physiologic signal transduction mediated by ROS has been proposed, and the possibility of XD to XO conversion, with subsequent ROS generation, serving as the trigger of the microvascular inflammatory response in vivo has been hypothesized. This review presents the evidence and basis for this hypothesis.