Reduction of Hepatic Ischemia/Reperfusion Injury by a Soluble P-Selectin Glycoprotein Ligand-1

Dulkanchainun, T S; Goss, John A.; Imagawa, David K.; Shaw, Gray D.; Anselmo, Dean M.; Kaldas, Fady M.; Wang, Tao; Zhao, Delai; Busuttil, Ashley; Kato, Hirohisa; Murray, Natalie; Kupiec‐Weglinski, Jerzy W.; Busuttil, Ronald W.

doi:10.1097/00000658-199806000-00006

Cited by 107 publications

(71 citation statements)

References 38 publications

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“…Although MPO assay also may detect macrophages, 26 our findings are consistent with recent study in a rat model of hepatic cold ischemia followed by isotransplantation, in which cytoprotection rendered by CD62 P-selectin blockade was accompanied by decreased macrophage and diminished MPO content. 25 This report is the first to document the importance of Stat4 signaling in the mechanism of T cell-mediated I/R hepatic injury. Indeed, disruption of Stat4 transcription virtually prevented hepatic I/R insult, as analyzed by sALT/MPO activities and confirmed by Suzuki's criteria.…”

Section: Discussionmentioning

confidence: 85%

Stat4 and Stat6 signaling in hepatic ischemia/reperfusion injury in mice: HO-1 dependence of Stat4 disruption-mediated cytoprotection

Shen

2003

Hepatology

103

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Section: Discussionmentioning

confidence: 85%

Stat4 and Stat6 signaling in hepatic ischemia/reperfusion injury in mice: HO-1 dependence of Stat4 disruption-mediated cytoprotection

Shen

2003

Hepatology

103

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“…We have shown that the blockade of PSGL-1-mediated interactions with a soluble recombinant form of PSGL-1 (sPSGL-1) inhibits recruitment of polymorphonuclear leukocytes (PMN) and mononuclear cells (MNC) in rat models of kidney (Takada et al, 1997) and liver ischemia/reperfusion (I/R) injury (Dulkanchainun et al, 1998), resulting in significantly less organ dysfunction. There is evidence that functional selectin ligands are predominantly expressed on Th1 rather than Th2 cells (Lim et al, 1999).…”

mentioning

confidence: 99%

Selectin-Mediated Interactions Regulate Cytokine Networks and Macrophage Heme Oxygenase-1 Induction in Cardiac Allograft Recipients

Coito¹,

Shaw

Li³

et al. 2002

Laboratory Investigation

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SUMMARY:Host sensitization to major histocompatibility complex (MHC) antigens is among the most critical of problems facing heart transplantation. Selectins are postulated to mediate the early adhesive events in the recruitment of leukocytes at the allograft site. We investigated the significance of selectin-P-selectin glycoprotein ligand-1 (PSGL-1)-mediated in vivo interactions in the immune cascade leading to rejection of cardiac allografts in skin presensitized rats. Infusion of a soluble recombinant form of PSGL-1 (rPSGL-Ig) during skin graft-mediated sensitization prevented Day 1.0 Ϯ 0.1 "accelerated" rejection in sensitized rat recipients, and prolonged cardiac allograft survival to Day 3.8 Ϯ 1.0 (p Ͻ 0.001). This therapy significantly depressed serum IgM levels and decreased intragraft expression of Th1 type cytokines (IL-2 and IFN-␥) as well as of IL-1␤ and MCP-1, as compared with controls, without affecting the initial number of infiltrating mononuclear cells (MNC). A profound decrease in graft-infiltrating MNC was recorded at 24 hours in rPSGL-Ig-treated rats. The expression of heme oxygenase-1 (HO-1), an inducible heat shock protein 32 that protects against oxidative cell/tissue injury, was found in approximately 14-fold higher levels in the rPSGL-Igtreated recipients as compared with controls. The HO-1 overexpression in rPSGL-Ig-treated hosts, primarily by infiltrating macrophages, was accompanied by virtual absence of myocardial infarcts and decreased frequency of TUNEL ϩ cells at the graft site. Moreover, down-regulation of HO-1 expression by zinc protoporphyrin, an HO-1 antagonist, decreased expression of antiapoptotic Bag-1 molecule in recipients conditioned with rPSGL-Ig. Thus, the blockade of selectin-PSGL-1 interactions depresses intracardiac allograft expression of Th1 type cytokines, and might inhibit the differentiation of Th1 type cells. In addition, it up-regulates HO-1 expression and protects against myocardial infarction and apoptosis. Hence, this study reports on a previously unrecognized role of selectin-PSGL-1-mediated interactions after in vivo alloantigenic challenge. (Lab Invest 2002, 82:61-70).

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“…A Mab against P-selectin attenuated PMN accumulation and necrosis in a rat model of hepatic I/Rp injury, 28 and the administration of a soluble PSGL-1 ligand to block P-selectin receptors improved animal survival in a rat transplant model. 29 While important in providing new strategies to protect the ischemic liver from reperfusion injury, studies using blocking agents may not provide a full insight into the mechanisms of injury because of the inherent possibility of concomitantly inhibiting or stimulating other receptors. For instance, PSGL-1 has been shown to serve as a Abbreviations: PMN, polymorphonuclear leukocytes; I/Rp, ischemia-reperfusion; PSGL-1, P-selectin glycoprotein ligand-1; AST, aspartate transaminase; ALT, alanine transaminase; P-selectin Ϫ/Ϫ , P-selectin deficient.…”

mentioning

confidence: 99%

P-selectin mediates reperfusion injury through neutrophil and platelet sequestration in the warm ischemic mouse liver

Yadav¹,

et al. 1999

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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.)The pathogenesis of cell damage following reperfusion of ischemic tissue is an incompletely understood series of events. 1,2 Various mechanisms have been proposed including enhanced production of inflammatory mediators, 3-5 recruitment of polymorphonuclear leukocytes (PMN), 6,7 and blockage of blood flow. 7-9 The leukocyte-endothelial interaction that occurs following ischemia/reperfusion (I/Rp) injury has been shown to be important for microvascular dysfunction and release of cytotoxic mediators such as reactive oxygen intermediates and a variety of proteases. 10-12 We 13 and others 5,6,9,14,15 have shown leukocyte accumulation to be a critical determinant of hepatic I/Rp injury. Other blood elements including platelets adhere to the hepatic sinusoids in conditions of ischemia, 16,17 but little is known about their contribution to the injury.The adhesion of PMN and platelets to the vascular endothelium involves a variety of adhesion receptors. [18][19][20][21] The selectin family (P-, E-, and L-selectin) are the first to be engaged in the process, 19 with P-selectin acting at the earliest stage of interaction between PMN and the endothelium. P-selectin is found in the ␣ granules of resting platelets and Weibel-Palade bodies of endothelial cells, 18 and expression of P-selectin on the cell surface can occur within minutes under stimulation by mediators of inflammation such as thrombin, histamine, complement, and peroxide. 22 P-selectin is able to tether leukocytes to the endothelial surface through its ligand P-selectin glycoprotein ligand-1 (PSGL-1), which leads to their activation. 23 Once leukocytes attach, they can interact with flowing PMN and platelets through the action of P-and L-selectin, 23 which may lead to further adhesion of PMN and platelets as we...

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Reduction of Hepatic Ischemia/Reperfusion Injury by a Soluble P-Selectin Glycoprotein Ligand-1

Cited by 107 publications

References 38 publications

Stat4 and Stat6 signaling in hepatic ischemia/reperfusion injury in mice: HO-1 dependence of Stat4 disruption-mediated cytoprotection

Stat4 and Stat6 signaling in hepatic ischemia/reperfusion injury in mice: HO-1 dependence of Stat4 disruption-mediated cytoprotection

Selectin-Mediated Interactions Regulate Cytokine Networks and Macrophage Heme Oxygenase-1 Induction in Cardiac Allograft Recipients

P-selectin mediates reperfusion injury through neutrophil and platelet sequestration in the warm ischemic mouse liver

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