Reperfusion Injury After Hemorrhage: A Collective Review

G D. Rushing, MD; L D. Britt, MD, MPH


Annals of Surgery. 2008;247(6):929-937. 

In This Article

Leukocytes and Their Adhesion Molecules

Leukocytes use binding proteins to attach themselves to endothelium and facilitate extravasation. A review of selectins, integrins, and other adhesion molecules is beyond the scope of this review, however, several are relevant to reperfusion injury (Figure 1). All 3 selectins (endothelial-E, platelet-P, and leukocyte-L) are involved in various aspects of reperfusion injury. Intercellular adhesion molecule-1 (ICAM-1) is expressed by endothelial cells after damage and increased by tumor necrosis factor (TNF)-α and interleukin (IL)-1. This protein binds to a beta integrin dimer that is present on neutrophils. This dimer is made of the 2 monomers CD18 and CD11. CD11 has 3 subtypes including CD11a, CD11b, and CD11c. One of these 3 monomers is expressed together with CD18 to create a binding complex with ICAM-1. This CD11/CD18 complex is integral to 5 activities that promote neutrophil damage during reperfusion. Initially, CD11/CD18 allows neutrophil adhesion to endothelium by the binding of ICAM-1 as described above[50,51,52,53] and is required for transendothelial migration.[52] This dimer is also necessary for H2O2 production by neutrophils that are adherent.[54] CD18 itself is the mediator of neutrophil-neutrophil adherence and clumping.[55] Finally, CD11/CD18 is the receptor complex for the complement fragment C3bi, which mediates neutrophil and macrophage phagocytosis of C3bi bound particles.[56] CD18 blockade by monoclonal antibodies has proven effective at decreasing neutrophil extravasation in animal models. CD18 is the one constant monomer that comprises the dimer CD11/CD18 complex and, as such, is the theoretical optimal target for therapy. However, blockade of this target has shown no mortality benefit in several clinical trials.[57,58]

Leukocyte and endothelial cell adhesion molecules. The leukocyte adhesion molecule is a dimmer composed of 2 entities, CD-11a/CD-11b and CD-18. CD-18 is the constant member of this association. LFA-1 or MAC-1 bind to the endothelial receptor ICAM-1 causing activation and extravasation of the leukocyte. ICAM-1 indicates intercellular adhesion molecule-1; LFA-1, lymphocyte function antigen-1; Mac-1 macrophage antigen-1.


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