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(Circulation Research. 2002;90:1143.)
© 2002 American Heart Association, Inc.

Editorials

Leukocyte-Induced Microvascular Permeability

How Contractile Tweaks Lead to Leaks

Randal O. Dull, Joe G.N. Garcia

From the Division of Pulmonary and Critical Care Medicine, Johns Hopkins Asthma & Allergy Center, Baltimore, Md.

Correspondence to Joe G.N. Garcia, MD, Office of the Director, Division of Pulmonary and Critical Care Medicine, Johns Hopkins Asthma & Allergy Center, 4B.77, Bayview Medical Center, 5501 Hopkins Bayview Cir, Baltimore, MD 21224-6801. E-mail drgarcia@jhmi.edu

Key Words: leukocytes • endothelium • permeability • microvascular • myosin light chain kinase

Neutrophil infiltration into tissues, a hallmark of acute inflammation, is a complex process requiring an intricate orchestration of signals between microvascular endothelial cells and both circulating and adherent neutrophils. Cytokines and inflammatory mediators elaborated during injury or infection activate both endothelial cells and circulating neutrophils (primary paracrine mechanism), causing neutrophil rolling to slow, formation of endothelial-neutrophil tethering, and ultimately, firm neutrophil adhesion.¹ Neutrophil adhesion to the endothelial surface, via E- and P-selectins and vascular cell adhesion molecule-1 (VCAM-1), contributes to further activation of both cell types (adhesion-dependent activation).² This adhesion-dependent activation of the neutrophil through ligation of the CD11/18 complex promotes the release of neutrophil granules³ that propagate the inflammatory process (secondary paracrine).^3,4

One important consequence of this inflammatory process is an increase in endothelial permeability, which leads to excessive tissue edema with attendant changes in microvascular hemodynamics, tissue oxygenation, and organ failure. Although the molecular determinants that regulate the intimate cell-cell interaction between the adherent leukocyte and the vascular endothelium have been extensively evaluated, relatively little information exists on the mechanisms by which polymorphonuclear leukocytes (PMNs) alter paracellular junctional integrity to allow PMNs to traverse the endothelium and increase leakage of circulating proteins and fluid. Historically, the concepts of leukocyte-mediated vascular dysfunction viewed the endothelial cell as a passive target for PMN-derived reactive oxygen species and granule products with endothelial toxicity the valued endpoint for these studies. The notion that endothelium can be an active participant in leukocyte-mediated vascular dysregulation began to emerge when a rise in endothelial cell . . . [Full Text of this Article]

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