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

Abstract

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 g/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-Pselectin mAb. These findings support the hypothesis that I-R induces hepatic RES dysfunction, at least in part, through P-selectin-mediated neutrophil accumulation. The liver is the principle anatomic site of RES activity and is responsible for approximately 80% of total-body RES function. 2 During the past three decades, liver transplantation has evolved from an experimental attempt to salvage desperately ill patients dying of liver failure to preferred definitive therapy for a defined population of patients with acute or chronic liver disease. Despite advancements in preoperative, intraoperative, and postoperative patient management and refinements in immunosuppressive protocols that have resulted in improved patient survival, postoperative sepsis has been documented in the majority of liver recipients. 3 Infection remains the predominant cause of posttransplantation morbidity and mortality. [4][5][6] The risk for infectious complications after liver transplantation has been reported to be between 50% and 83%. 4-7 Proportionally, the incidence of septic events seems to be greater than in recipients of other types of transplanted organs (i.e., kidney or heart) who undergo similar or often more intensive regimens of systemic immunosuppression.We previously reported that hepatic RES function, quantified by the liver's capacity to phagocytose and kill circulating bacteria or fungi, is altered after liver transplantation in the rat. 7...

In vitro characterization of leukocyte mimetic for targeting therapeutics to the endothelium using two receptors

“…Furthermore, expression of endothelial selectin and other endothelial expressed leukocyte adhesion molecules (ELAMs) have been known to play a role in the progression of other human diseases, including metastasis in cancers [5,8], atherosclerosis [9,10], hepatic [11,12] and renal diseases [13,14], and graft rejection [15,16]. As a result, the selectins and other ELAMs have become attractive targets for site-specific delivery of therapeutic agents in these human diseases.…”

Warm Ischemia-induced Alterations in Oxidative and Inflammatory Proteins in Hepatic Kupffer Cells in Rats

“…There is substantial evidence that indicates that Kupffer cells play a central role in the pathogenesis of liver parenchymal cell damage as seen during ischemia/reperfusion injury (1). The activation of Kupffer cells that occurs during ischemia results in the production of oxygen radicals and the modulation of proinflammatory and anti-inflammatory cytokines (2).…”

“…Isotope ratio mass spectrometry with isobaric tags for relative and absolute quantitation (iTRAQ) 1 allows for the quantification and identification of the protein content of up to four samples in one experiment by labeling all peptides in a given sample (14). Peptides of the samples are modified by incorporating the four different reagents.…”

Repercussões pulmonares após isquemia hepática parcial e reperfusão: modelo experimental

“…Most experimental models in animals maintained spontaneous breathing during the operation [15][16][17][18] . The pathophysiology of the effects of variations of the partial pressures of gases and pH are well established 19 .…”