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Analysis of Physiologic E-Selectin-Mediated Leukocyte Rolling on Microvascular Endothelium
Published on: February 11, 2009
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Inflammatory roles of P-selectin
D E Lorant1, M K Topham, R E Whatley
1Department of Pediatrics, University of Utah School of Medicine, Salt Lake City 84112.
The Journal of Clinical Investigation
|August 1, 1993
Summary
P-selectin rapidly binds polymorphonuclear leukocytes (PMNs) to endothelial cells, initiating an adhesion cascade. Platelet-activating factor (PAF) then primes these PMNs for enhanced responses, highlighting distinct roles in leukocyte adhesion and activation.
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- Polymorphonuclear leukocytes (PMNs) interact with endothelial cells during inflammation.
- P-selectin is a key adhesion molecule mediating leukocyte-endothelial cell interactions.
- The precise signaling mechanisms initiated by P-selectin on PMNs are not fully understood.
Purpose of the Study:
- To elucidate the distinct roles of P-selectin and platelet-activating factor (PAF) in PMN adhesion and activation.
- To investigate whether P-selectin directly activates PMNs or facilitates activation by other signals.
- To understand the cascade of events leading to PMN priming.
Main Methods:
- Utilized purified P-selectin and P-selectin incorporated into model membranes.
- Employed blocking monoclonal antibodies to inhibit P-selectin function.
- Investigated the role of platelet-activating factor (PAF) and its receptor in PMN priming.
- Observed PMN intracellular Ca2+ transients, beta-2-integrin upregulation, and shape changes.
Main Results:
- P-selectin mediates rapid, reversible PMN binding to endothelial cells but does not directly activate them.
- PMNs adherent via P-selectin show Ca2+ transients, beta-2-integrin upregulation, and shape changes.
- Tethering by P-selectin is essential for efficient PMN priming.
- Platelet-activating factor (PAF) directly mediates the priming event, inhibited by PAF receptor blockade.
Conclusions:
- P-selectin acts as a tethering molecule, capturing PMNs, while PAF mediates juxtacrine activation.
- P-selectin and PAF function sequentially in an adhesion and activation cascade.
- In vivo, selectins likely facilitate interactions with membrane-bound signaling molecules beyond leukocyte rolling.
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