Platelets modulate ischemia/reperfusion-induced leukocyte recruitment in the mesenteric circulation.
P-selectin-dependent leukocyte-endothelial cell adhesion has been implicated in the pathogenesis of ischemia/reperfusion (I/R) injury in several vascular beds, including the gut. Because platelet-endothelial (P/E) cell adhesion also occurs in postischemic venules, the possibility exists that the expression of P-selectin on the surface of platelets that are adherent to venular endothelial cells may mediate the leukocyte recruitment elicited by I/R. P-selectin expression [dual radiolabeled monoclonal antibody (MAb) technique] and neutrophil accumulation [myeloperoxidase (MPO) activity] were measured in the postischemic small intestine of untreated rats and rats treated with either antiplatelet serum (APS) or MAbs directed against either P-selectin, GPIIb/IIIa, or fibrinogen. The increases in P-selectin expression and tissue MPO normally elicited by I/R were significantly attenuated in the different treatment groups, suggesting that I/R-induced neutrophil recruitment is a platelet-dependent, P-selectin-mediated process. Intravital microscopy was then employed to examine this process relative to leukocyte-endothelial cell adhesion in postischemic rat mesenteric venules. The recruitment of adherent and emigrated leukocytes after I/R was attenuated by pretreatment with a MAb against, either P-selectin, GPIIb/IIIa, or fibrinogen, as well as an Arg-Gly-Asp peptide. Whereas thrombocytopenia greatly blunted leukocyte emigration, it did not alter the leukocyte adherence response to I/R. These findings suggest that platelet-associated P-selectin contributes to the accumulation of leukocytes in postischemic tissue via a mechanism that alters transendothelial leukocyte migration.
Salter
J W
JW
Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130, USA.
Krieglstein
C F
CF
Issekutz
A C
AC
Granger
D N
DN
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001792:Blood Platelets / Q000276:immunology / Q000502:physiology*; D002448:Cell Adhesion; D002634:Chemotaxis, Leukocyte; D005340:Fibrinogen / Q000276:immunology / Q000502:physiology; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D007962:Leukocytes / Q000473:pathology / Q000502:physiology*; D008297:Male; D008638:Mesenteric Arteries / Q000503:physiopathology; D008641:Mesenteric Vascular Occlusion / Q000473:pathology / Q000503:physiopathology; D008642:Mesenteric Veins / Q000473:pathology / Q000503:physiopathology; D009842:Oligopeptides / Q000494:pharmacology; D019007:P-Selectin / Q000276:immunology / Q000502:physiology; D009195:Peroxidase / Q000378:metabolism; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000276:immunology / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology; D013152:Splanchnic Circulation
D000906:Antibodies; D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D009842:Oligopeptides; D019007:P-Selectin; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C047981:arginyl-glycyl-aspartic acid; D005340:Fibrinogen; D009195:Peroxidase