Page 2084 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 123 The Blood Vessel Wall 1853

concentration, the opening of calcium-activated potassium chan- forces acting on the leukocyte and adhesive interactions between
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nels, and the hyperpolarization of endothelial cells, resulting in an selectin receptors and their glycoconjugate counterstructures. It is
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endothelium-dependent hyperpolarization of smooth muscle cells. initiated primarily by activation of the endothelium by extravascular
Smooth muscle cell hyperpolarization may occur through direct myo- stimuli such as bacterial-derived products or by endogenous media-
endothelial electrical coupling or through accumulation of potassium tors produced by the endothelium or cells in tissue. Early on, rolling
ions in the intercellular space. Findings suggest that EDHF represents is mediated by endothelial P-selectin, which is rapidly translocated
cytochrome P450-linked arachidonate metabolites in some blood from Weibel-Palade bodies to the luminal surface, and L-selectin on
vessels but also lipoxygenase derivatives and hydrogen peroxide. 238 leukocyte microvilli. E-selectin is involved only at later time points
ET-1 is a 21-amino acid peptide, released preferentially at the because it is not constitutively expressed by endothelium but rather
abluminal surface of endothelial cells, that exhibits potent vasocon- is induced over hours by de novo synthesis.
strictor activity. 239,240 Of the three known ETs, only ET-1 is produced For leukocytes to circulate freely, their integrin receptors must be
by endothelial cells. At least two receptors (ET-A and ET-B) bind to minimally adhesive, but they also must be able to increase binding
all three ETs. Whereas ET-A is abundantly expressed on smooth rapidly at sites of inflammation. After being tethered to endothelium
muscle cells, ET-B is predominantly expressed on endothelial cells. by selectin interactions, leukocyte integrin receptors are activated by
The vasoconstrictor activity of ET-1 is preferentially mediated by endothelial membrane-expressed platelet-activating factor, endothe-
ET-A receptors on smooth muscle cells. Engagement of ET-B on lial membrane-bound chemokines, or locally secreted chemoattrac-
endothelial cells by ET-3 may paradoxically cause a transient vasodila- tants. Activation of leukocyte integrins involves changes in receptor
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tion. Little evidence indicates that ET-1 plays a role in essential affinity or affinity-independent receptor clustering, which promotes
hypertension, but it might contribute to pregnancy-induced hyper- firm adhesion to endothelial ligands, which are members of the
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tension and may play a role in reperfusion injury after ischemia. immunoglobulin gene superfamily (IgSF). These IgSF ligands are
ET-1 does appear to play a role in pulmonary arterial hypertension, constitutively expressed (ICAM-1, ICAM-2), further upregulated
and the dual ET receptor antagonist bosentan and ET-A antagonist (ICAM-1), or induced (VCAM-1) by inflammatory mediators (Table
ambrisentan have been approved for treatment of this disease. 241,242 123.1). Although these activation-dependent increases in leukocyte
Another seemingly important regulator of vascular tone is the integrin binding to endothelial IgSF ligands are necessary for shear-
superoxide anion. 231,243 The source of this free radical may be the resistant firm adhesion, subsequent leukocyte migration over the
endothelium itself or inflammatory cells that have been recruited to endothelium requires reversible adhesion caused by cyclic modulation
sites of injury or inflammation. Interaction of superoxide radicals and of receptor avidity. 249
NO produces peroxynitrite and reduces the concentration of NO. There are several caveats regarding the current multistep model of
Peroxynitrite can oxidize low-density lipoprotein (LDL) and deleteri- initial selectin-mediated rolling and subsequent integrin-mediated
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ously modify other proteins, thereby causing endothelial dysfunction. firm adhesion. First, selectin-mediated rolling is not a prerequisite
Increased production of superoxide inhibits synthesis of PGI 2 but not for emigration under conditions of reduced flow, as might occur at
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that of TXA 2 . 243 sites of inflammation. Second, the model was developed from
The endothelium expresses angiotensin-converting enzyme at its observations in the systemic microcirculation, where leukocyte emi-
surface; this enzyme converts angiotensin I to angiotensin II, a potent gration occurs in postcapillary venules under relatively low shear
vasoconstrictor. The interaction among ET, angiotensin II, and forces. However, selectins do not appear to play a major role in
α-adrenergic agonists in the pathogenesis of hypertension is neutrophil emigration in the pulmonary microcirculation, where
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complex. An altered balance of the vasoactive substances described emigration occurs predominantly in capillaries, or in the liver
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in this section has been proposed to cause endothelial dysfunction microvasculature, where leukocytes emigrate primarily in sinusoids.
and the attendant vascular pathology observed in atherosclerosis, Third, under some conditions leukocytes are able to tether and roll
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hypertension, and diabetes mellitus. Alteration of vascular function via receptors other than selectins and α4 integrins (e.g., CD44 or
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in these diseases then may perpetuate endothelial dysfunction and, VAP-1 ). Finally, several other adhesion pathways have been impli-
consequently, worsen disease. cated in leukocyte adhesion to endothelium in vitro, and their roles
in the adhesion cascade in vivo remain to be defined. 250
When adherent, leukocytes migrate upon the endothelial luminal
Interaction of Blood Cells With the Vessel Wall surface. Upon encountering an intercellular junction, some leuko-
cytes diapedese between endothelial cells (paracellular pathway),
Leukocytes enter extravascular tissue, and then migrate to the site of inflamma-
tory or immune reaction. 256,257 This process of transendothelial
In the absence of any inflammatory stimulus, neutrophils circulate migration uses leukocyte integrin interactions with endothelial IgSF
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freely and do not interact significantly with the endothelium. This ligands and several junctional proteins, including PECAM-1
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contrasts with continuous, low-level physiologic traffic of monocytes (CD31), JAM-1, CD99, CD99L2, ESAM, PVR, and
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and lymphocytes across the vessel wall. Monocytes emigrate from the CD47. Diapedesis involves signaling by the leukocyte to the
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bloodstream to develop into tissue macrophages that may exhibit endothelial cell that triggers opening of endothelial cell junctions.
tissue- or organ-specific functions. To maintain immune surveillance Although leukocyte migration is primarily paracellular (i.e., through
of tissue, lymphocytes recirculate between blood and lymphatics, endothelial cell–cell junctions), under certain circumstances, leuko-
gaining entrance to the latter at the high endothelial venule of cytes may emigrate directly through the body of an endothelial cell
postcapillary venules in lymphoid tissue. (transcellular pathway). 267
Intravital microscopic studies have established a sequence of Leukocyte recruitment is terminated by several mechanisms.
events involved in leukocyte emigration at extravascular sites of Whereas E-selectin and P-selectin are removed from the endothelial
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inflammation. Under conditions of flow, leukocytes first tether to and cell surface by endocytosis, L-selectin is cleaved from leukocytes by
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then roll along the endothelium of postcapillary venules adjacent to a membrane protease. Decay of cytokine, chemokine, or chemoat-
the site of inflammation. Some of the rolling leukocytes are activated tractant generation leads to gradual resolution of endothelial adhesion
and adhere firmly. The adherent leukocytes migrate along the endo- molecule expression and integrin activation. Locally expressed media-
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thelial surface and diapedese between endothelial junctions to enter tors, such as NO, TGFβ, and Fas ligand, also inhibit further
the extravascular tissue. These steps in emigration tethering, rolling, leukocyte adhesion to endothelium.
activation, firm adhesion, and diapedesis also are involved in lym- The adhesion molecules involved in leukocyte trafficking from
phocyte emigration at high endothelial venules. They result from the bloodstream to tissue have emerged as important therapeutic targets.
interaction of distinct leukocyte and endothelial receptors in an Extensive preclinical studies showed that blockade of leukocyte or
adhesion cascade (Fig. 123.3; see Chapter 16). 245,246 Rolling is endothelial adhesion molecules was efficacious in diverse disease
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observed only under flow conditions and is the consequence of shear models, prompting the development of adhesion antagonists for