Role of P-selectin in the recruitment of leukocytes in mouse liver exposed to ischemia and reperfusion (original) (raw)
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The American journal of physiology, 1998
Leukocytes recruited during ischemia-reperfusion to the liver are important mediators of injury. However, the mechanisms of leukocyte adhesion and the role of adhesion receptors in hepatic vasculature remain elusive. L-selectin may critically contribute to injury, priming adhesion for later action of intercellular adhesion molecule-1 (ICAM-1). Paired experiments were performed using mutant mice (L-selectin -/-, ICAM-1 -/-, and L-selectin/ICAM-1 -/-) and wild-type mice (C57BL/6) to investigate leukocyte adhesion in the ischemic liver. Leukocyte adhesion and infiltration were assessed histologically. Aspartate aminotransferase levels were significantly reduced (2- to 3-fold) in mutant vs. wild-type mice in most groups but most significantly after 90 min of partial hepatic ischemia. Leukocyte adhesion was significantly reduced in all mutant mice. Areas of microcirculatory failure, visualized by intravital microscopy, were prevalent in wild-type but virtually absent in L-selectin-defici...
Hepatology, 1999
Hepatic damage following ischemia-reperfusion injury involves polymorphonuclear leukocytes (PMN) and platelet sequestration, however the mechanisms of adhesion remain elusive. In this study, using gene-targeted deficient mice, we evaluated P-selectin and its contribution to PMN and platelet adhesion in hepatic damage. In an in vivo warm ischemia model, hepatic injury was assessed by serum transaminase levels, survival, PMN adhesion by histological analysis, and platelet sequestration by immunostaining. Serum transaminase levels were strikingly reduced (by up to threefold) in the P-selectin deficient mice, particularly at 90 minutes of ischemia, when compared with wild-type controls. PMN adhesion and platelet sequestration was also significantly decreased in P-selectin deficient mice following 90 minutes of partial ischemia. Animal survival was significantly improved after 75 minutes of total hepatic ischemia in P-selectin deficient mice when compared with wild-type mice. Survival was also achieved after 90 minutes of ischemia in the mutant mice whereas none of the wild-type animals survived. These data show that P-selectin plays a critical role in PMN and platelet adhesion following ischemia-reperfusion injury to the liver. (HEPATOLOGY 1999; 29:1494-1502.)
Reduction of Hepatic Ischemia/Reperfusion Injury by a Soluble P-Selectin Glycoprotein Ligand-1
Annals of Surgery, 1998
The authors' goal was to determine the effects of specific binding and blockade of P-and E-selectins by a soluble Pselectin glycoprotein ligand-1 (PSGL-1) in rat models of hepatic in vivo warm ischemia and ex vivo cold ischemia. The authors also sought to determine the effect of selectin blockade on isograft survival in a syngeneic rat orthotopic liver transplant model.
American Journal Of Pathology
Journal of leukocyte biology, 1998
We studied the role of P-selectin, an adhesion molecule known to be important for neutrophil localization to sites of inflammation, in a model of inflammatory liver injury. Male C3Heb/FeJ (ET-sensitive) mice treated with 700 mg/kg galactosamine and 100 microg/kg Salmonella abortus equi endotoxin (Gal/ET), murine tumor necrosis factor alpha (TNF-alpha, 15 microg/kg), or interleukin-1 (IL-1, 13-23 microg/kg), showed increased P-selectin mRNA levels in the liver. In contrast, C3H/HeJ (ET-resistant) mice responded only to cytokines with P-selectin mRNA formation. Whereas no P-selectin expression was detectable in control livers, there was temporary staining of endothelium in large blood vessels but not in sinusoids between 3 and 5 h after ET, TNF-alpha, or IL-1 treatment. Severe liver injury induced by Gal/ET at 7 h was not inhibited by an anti-P-selectin antibody in C3Heb/FeJ mice or in P-selectin-deficient animals. Sequestration of neutrophils in sinusoids, i.e. those neutrophils that...
Anti-P-selectin antibody protects against hepatic ichemia–reperfusion injury
Transplantation Proceedings, 1998
E ARLY restitution of blood flow to ischcmic tissue is essential to halt thc progression of ccllular injury associated with decreased oxygen and nutrient dclivery. In rcccnt literature, investigators have shown that repcrfusion of ischcmic tissues initiates a complex series of rcactions that paradoxically injures tissues. Although several mechanisms have been proposed to explain the pathobiology of ischemic-rcperfusion (IfR) injury, most attention has focused on the role of reactive oxygen metabolites and inflammatory leukocytes. A simple mechanism for I B injury proposcd by most researchcs is presented in The initial insult of 1/R produces rcnctive oxygen metiibolites which induces the production of cytokines. Cytokines not only activate NFKP, a nuclear transcription protein, but aho nonspecifically attract leukocytes to the injured tissue. NFKP then binds to the complimentruy DNA promotor site and propagates the transcription of adhesion molecule messenger RNA. As the lcukocytes enter the injured organ, the adhesion molecules now are resvonsiblc for the rollina, -.
British Journal of Surgery, 2004
Background Activated neutrophils may be important mediators in liver ischaemia–reperfusion injury (I/R). Adhesion of leucocytes to the endothelial cell surface is a result of activation of cell adhesion molecules. The aim of this study was to investigate the effect of I/R on the hepatic microcirculation (HM) and intercellular adhesion molecule (ICAM) 1 expression. Methods Four groups of six Sprague–Dawley rats underwent laparotomy for liver exposure. Group 1 acted as controls, and groups 2–4 underwent partial liver ischaemia for 30, 45 and 60 min respectively followed by reperfusion for 60 min. Flow in the HM was measured by laser Doppler flowmetry. Liver biopsies were taken at the end of the reperfusion period. ICAM-1 expression was assessed by immunohistochemistry (graded 0–3). Results Mean flow in the HM was significantly reduced with I/R (mean(s.e.m.) red cell flux 140(21), 52(3) and 43(2) with 30, 45 and 60 min ischaemia compared with control 230(17); all P < 0·001). ICAM-1 ...