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1978 Part XII: Hemostasis and Thrombosis Chapter 115: Vascular Function In Hemostasis 1979

between leukocytes and endothelial cells regulate transendothelial receptors similar to sialylated Lewis X antigen. Endothelial cell P-se-
278
migration for the vast majority of neutrophils, monocytes, and nat- lectin stimulated by thrombin or histamine is transient, but can be
ural killer (NK) cells. Transendothelial migration and the nomencla- prolonged to hours or days by IL-3, IL-4, or oncostatin M stimulation
ture of the junctional adhesion molecule (JAM) family are reviewed of human endothelium, and by TNF-α stimulation of murine, but not
elsewhere. 17,259,260 PECAM/CD31 on the leukocyte contacts the same human endothelium. 279–282
molecule concentrated at the endothelial junctions in a homophilic In general, expression of the immunoglobulin superfamily mem-
manner. 261–263 Although the relevant signal(s) transduced by this inter- bers ICAM-1 and VCAM-1 is induced by the same stimuli that induce
action remain unclear, a transient rise in endothelial cell intracellular E-selectin. Some specializations exist, at least in vitro. For example, IL-4
264
calcium is required for transmigration. Blocking the function of induces VCAM-1 but not E-selectin or ICAM-1 in microvascular endo-
either leukocyte PECAM or endothelial cell PECAM arrests the leu- thelial cells. 283,284 These molecules serve as counter-receptors for the leu-
kocyte poised over the junction, 263,265,266 a phenotype very similar to kocyte integrins in the tight adhesion step.
that seen when the rise in intracellular calcium is blocked by the chela-
tor, bis(2-amino-5-methylphenoxy)ethane-N,N,N’,N’-tetraacetic acid
tetraacetoxymethyl ester (MAPTAM). 264 CHRONIC CHANGES
Because anti-PECAM reagents never block diapedesis completely, Stimulation of endothelial cells over several days with IFN-γ leads to
PECAM-independent pathways of transendothelial migration must surface expression of MHC class II molecules (human leukocyte anti-
exist. The leukocyte integrins α β (very-late antigen [VLA]-4) and gen [HLA]-DR and -DQ). In human tissues such as skin and gut, class
4 1
α β /α β (lymphocyte function-associated antigen [LFA]-1/macro- II is commonly seen even in the absence of overt inflammation, and is
L 2
M 2
phage [Mac]-1) and their endothelial counter-receptors VCAM-1 and thought to be a result of chronic exposure of these sites to subclinical
ICAM-1, have been implicated in transmigration. Interaction of leu- inflammation and antigenic stimulation. When costimulatory mole-
254
kocyte LFA-1 with JAM-A on endothelial cells has also been implicated cules such as CD40, ICAM-1, or LFA-3 are induced by inflammatory
267
in leukocyte recruitment. Antibodies directed against JAM-C also stimuli, the endothelial cell becomes capable (at least in vitro) of act-
blocked migration of lymphocytes across endothelial cell monolay- ing as an antigen presenting cell that can stimulate CD4+ memory T
ers, implicating its role in lymphocyte migration. In addition, under cells. This mechanism may stimulate graft rejection by the host when
268
certain specialized conditions, there appear to be pathways across the the endothelium belongs to an organ graft with foreign MHC class
endothelial cell that bypass the intercellular junction. 269,270 II. 285–287
CD99 is a GP expressed on leukocytes, platelets, and erythrocytes, In contrast, the expression of the adhesion molecule ICAM-2 does
and concentrated at the endothelial cell borders. CD99 controls a step not change in response to inflammatory mediators. PECAM-1 shows
in diapedesis distal to the step controlled by PECAM both in vitro and a unique expression pattern in response to IFN-γ in vitro and in
288
289
in vivo, 271–273 by interfering with homophilic interaction between leuko- vivo, as its distribution becomes diffuse over the surface of the cell,
cyte CD99 and endothelial cell CD99-arrested monocytes. Their lead- rather than being concentrated at intercellular borders. In vitro chronic
ing edges were below the endothelial cell monolayer, while their trailing exposure of human umbilical vein endothelial cells to a combination
uropods remained on the apical surface of the endothelial cell. of IFN-γ and TNF-α at relatively high doses leads to a decrease in total
At the onset of most acute inflammatory responses, vascular PECAM-1 expression. Such a response has not been described to date
290
permeability transiently increases as a result of histamine release. The in vivo.
endothelial junctions are soon re-established, and the junctions are
closed to the leukocytes that arrive at the scene over the next hour. Stud- ADHESION MOLECULES IN A
ies performed both in vivo and in vitro indicate that, during subsequent
diapedesis, leukocytes penetrate the vessel wall without further com- THROMBOTIC MILIEU
promising the vascular permeability barrier. 264,274 Cortactin-deficient Activation of the hemostatic system exposes leukocytes to ligands that
mice, for example, have constitutively leaky vascular junctions in the promote their adhesion and recruitment to the vessel wall. For exam-
postcapillary venule circulation, and an exaggerated response to his- ple, in vitro thrombin induces E-selectin expression and IL-8 secretion
tamine, yet leukocyte recruitment is diminished because of inefficient by human umbilical vein endothelial cells. These changes are clas-
291
275
clustering of ICAM-1, which prevents exposure of subendothelial col- sically induced by inflammatory cytokines such as IL-1 and TNF-α.
lagen and VWF deposits to circulating platelets. Although PECAM-1 Table 115–5 lists some mediators that could have dual roles in inflam-
has no known role in binding platelets to endothelial cells, it has been mation and hemostasis/thrombosis.
hypothesized to maintain the tight apposition of endothelial cells and
leukocytes during diapedesis. 263
LEUKOCYTE–PLATELET AND ENDOTHELIAL
CELL–PLATELET INTERACTIONS
ACUTE CHANGES Activated platelets bind to circulating lymphocytes in a P-selectin–
In addition to stimulating endothelial cell immediate responses, cytok- dependent manner. This interaction can facilitate leukocyte rolling on
ines and inflammatory mediators released at the site of inflammation the endothelium and also allows homing of lymphocytes to periph-
292
activate new endothelial cell genetic programs. Within several hours of eral lymph nodes in the absence of L-selectin, because P-selectin on
exposure to mediator, de novo synthesis of mRNA and protein estab- the adherent platelets will interact with the peripheral lymph node
lishes an inflammatory endothelial cell phenotype that is both procoag- addressin. In vitro, neutrophils are capable of rolling on immobi-
293
ulant and proadhesive. lized platelets via PSGL-1 on the leukocyte interacting with degranu-
Inflammatory cytokines such as TNF-α and IL-1 induce endo- lated P-selectin on the platelet membranes. Moreover, α β (CD11b/
294
M 2
thelial cell surface expression of several important CAMs. Expression CD18)-dependent arrest and tight adhesion of neutrophils to bound
of E-selectin peaks at 4 to 6 hours in vitro, but may be maintained by platelets following P-selectin–dependent rolling has been described. 294,295
interferon (IFN)-γ for several days in vivo. 276,277 E-selectin mediates the The endothelial ligand for this is not known. ICAM-2 has been found
slow rolling of leukocytes bearing sialylated, fucosylated carbohydrate on the surface of activated platelets, but it is not a ligand for α β . In
M 2

Kaushansky_chapter 115_p1967-1984.indd 1978 9/18/15 10:09 AM