P-Selectin Contributes to the Initial Recruitment of Rolling and Adherent Leukocytes in Hepatic Venules After Ischemia/Reperfusion

De, Sawaya; Gb, Zibari; Minardi, A; Bilton, Bradley; Burney, Donna; Granger, D. N.; Jc, McDonald; Brown, Mark F.

doi:10.1097/00024382-199909000-00010

Cited by 62 publications

(45 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The accumulation of leukocytes to sites of tissue injury is mediated by three groups of cell adhesion molecules, i.e., the selectin family (P-, E-, and L-selectin), the ␤ 2 -integrin family (CD11/CD18), and the Ig superfamily (ICAM-1, PE-CAM-1) (2, 3). P-selectin, which is stored in the Weibel-Palade bodies of endothelial cell and ␣ granules of the platelets (33), is expressed rapidly in early phase of reperfusion (14,34). Indeed, P-selectin initiates the adhesion, rolling of leukocytes, and then recruits them to the injured site.…”

Section: Discussionmentioning

confidence: 99%

Molecular Characterization of Rat Leukocyte P-Selectin Glycoprotein Ligand-1 and Effect of Its Blockade: Protection from Ischemia-Reperfusion Injury in Liver Transplantation

Tsuchihashi

Fondevila

Shaw³

et al. 2006

The Journal of Immunology

View full text Add to dashboard Cite

P-selectin glycoprotein ligand-1 (PSGL-1) mediates the initial tethering of leukocytes to activated platelets and endothelium. We report molecular cloning and characterization of the rat PSGL-1 gene. A neutralizing Ab was generated, and its binding epitope was mapped to the N-terminal binding region of rat PSGL-1. We examined the effects of early PSGL-1 blockade in rat liver models of cold ischemia, followed by ex vivo reperfusion or transplantation (orthotopic liver transplantation (OLT)) using an anti-PSGL-1 Ab with diminished Fc-mediated effector function. In the ex vivo hepatic cold ischemia and reperfusion model, pretreatment with anti-PSGL-1 Ab improved portal venous flow, increased bile production, and decreased hepatocellular damage. Rat pretreatment with anti-PSGL-1 Ab prevented hepatic insult in a model of cold ischemia, followed by OLT, as assessed by 1) decreased hepatocellular damage (serum glutamic oxaloacetic transaminase/glutamic-pyruvic transaminase levels), and ameliorated histological features of ischemia/reperfusion injury, consistent with extended OLT survival; 2) reduced intrahepatic leukocyte infiltration, as evidenced by decreased expression of P-selectin, ED-1, CD3, and OX-62 cells; 3) inhibited expression of proinflammatory cytokine genes (TNF-α, IL-1β, IL-6, IFN-γ, and IL-2); and 4) prevented hepatic apoptosis accompanied by up-regulation of antiapoptotic Bcl-2/Bcl-xL protective genes. Thus, targeting PSGL-1 with a blocking Ab that has diminished Fc-mediated effector function is a simple and effective strategy that provides the rationale for novel therapeutic approaches to maximize the organ donor pool through the safer use of liver transplants despite prolonged periods of cold ischemia.

show abstract

Section: Discussionmentioning

confidence: 99%

Molecular Characterization of Rat Leukocyte P-Selectin Glycoprotein Ligand-1 and Effect of Its Blockade: Protection from Ischemia-Reperfusion Injury in Liver Transplantation

Tsuchihashi

Fondevila

Shaw³

et al. 2006

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Initial leukocyte tethering in sinusoidal EC requires expression of CD62 selectins. In sinusoidal EC, P-selectin and ICAM-1 become up-regulated by I/R through ROS/RNS (5,(32)(33)(34). NO, a free radical or RNS can activate this inflammatory cascade and thus promote the development of IRI.…”

Section: Fk330 In Liver Ischemia and Reperfusion Injurymentioning

confidence: 99%

FK330, a Novel Inducible Nitric Oxide Synthase Inhibitor, Prevents Ischemia and Reperfusion Injury in Rat Liver Transplantation

Tsuchihashi

Kaldas

Chida

et al. 2006

American Journal of Transplantation

View full text Add to dashboard Cite

Nitric oxide (NO), produced via inducible NO synthase (iNOS), is implicated in the pathophysiology of liver ischemia/reperfusion injury (IRI).We examined the effects of a novel iNOS inhibitor, FK330 (FR260330), in well-defined rat liver IRI models. In a model of liver cold ischemia followed by ex vivo reperfusion, treatment with FK330 improved portal venous flow, increased bile production and decreased hepatocellular damage. FK330 prevented IRI in rat model of 40-h cold ischemia followed by syngeneic orthotopic liver transplantation (OLT), as evidenced by: (1) increased OLT survival (from 20% to 80%); (2) decreased hepatocellular damage (serum glutamic oxaloacetic transaminase/glutamic pyruvic transaminase levels); (3) improved histological features of IRI; (4) reduced intrahepatic leukocyte infiltration, as evidenced by decreased expression of P-selectin/intracellular adhesion molecule 1, ED-1/CD3 cells and neutrophils; (5) depressed lymphocyte activation, as evidenced by expression of pro-inflammatory cytokine (TNF-a , IL-1b , IL-6) and chemokine (IP-10, MCP-1, MIP-2) programs; (6) prevented hepatic apoptosis and down-regulated Bax/Bcl-2 ratio. Thus, by modulating leukocyte trafficking and cell activation patterns, treatment of rats with FK330, a specific iNOS inhibitor, prevented liver IRI. These results provide the rationale for novel therapeutic approaches to maximize organ donor pool through the safer use of liver grafts despite prolonged periods of cold ischemia.

show abstract

“…A study on rat liver microvasculature could not demonstrate an involvement of endothelial selectins in the recruitment of leucocytes [31]. However, a clear dependency of leucocyte±endothelial interaction on functioning P-selectin molecules has been proven in murine hepatic [32,33] and splanchnic [34] I/R models. Similarly, in a murine renal I/R model, P-selectin deficiency as well as blocking P-selectin by antibodies resulted in less neutrophil infiltration and in better organ function [35].…”

Section: Discussionmentioning

confidence: 95%

N-acetylcysteine induces shedding of selectins from liver and intestine during orthotopic liver transplantation

Taut¹,

Schmidt²,

Zapletal

et al. 2001

Clinical and Experimental Immunology

View full text Add to dashboard Cite

SUMMARYIn orthotopic liver transplantation (OLT), N-acetylcysteine (NAC) reduces ischaemia/reperfusion (I/R) injury, improves liver synthesis function and prevents primary nonfunction of the graft. To further elucidate the mechanisms of these beneficial effects of NAC, we investigated influence of high-dose NAC therapy on the pattern of adhesion molecule release from liver and intestine during OLT. Nine patients receiving allograft OLT were treated with 150 mg NAC/kg during the first hour after reperfusion; 10 patients received the carrier only. One hour after reperfusion, samples of arterial, portal venous and hepatic venous plasma were taken and blood flow in the hepatic artery and the portal vein was measured. Absolute concentrations of sICAM-1, sVCAM-1, sP-selectin and sE-selectin were not markedly different. However, balance calculations showed release of selectins from NAC-treated livers as opposed to net uptake in controls (P # 0´02 for sP-selectin). This shedding of selectins might be a contributing factor to the decrease in leucocyte adherence and improved haemodynamics found experimentally with NAC-treatment.

show abstract

P-Selectin Contributes to the Initial Recruitment of Rolling and Adherent Leukocytes in Hepatic Venules After Ischemia/Reperfusion

Cited by 62 publications

References 0 publications

Molecular Characterization of Rat Leukocyte P-Selectin Glycoprotein Ligand-1 and Effect of Its Blockade: Protection from Ischemia-Reperfusion Injury in Liver Transplantation

Molecular Characterization of Rat Leukocyte P-Selectin Glycoprotein Ligand-1 and Effect of Its Blockade: Protection from Ischemia-Reperfusion Injury in Liver Transplantation

FK330, a Novel Inducible Nitric Oxide Synthase Inhibitor, Prevents Ischemia and Reperfusion Injury in Rat Liver Transplantation

N-acetylcysteine induces shedding of selectins from liver and intestine during orthotopic liver transplantation

Contact Info

Product

Resources

About