Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

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Chapter | 11 Neutrophil Function
Estimates from in vitro studies of leukocyte extravasation
show the process to be rapid, with transmigration being
completed in 2 minutes ( Beesley et al. , 1978 ; Burns
et al. , 1997 ). Neutrophil transendothelial migration can
occur through distinct routes, either paracellular (between
endothelial cells) or transcellular (through endothelial
cells) ( Feng et al. , 1998 ; Yang et al. , 2005 ). Some of the
first observations of leukocyte interactions with the vascular
wall come from Albrecht von Haller (1756) , Rudolf
Virchow (1871) , and Rudolf Wagner (1839). Early mechanistic
insights into leukocyte transmigration came from
Julius Conheim (1877, 1889) and Elle Metchnikoff (1893) ,
who attributed leukocyte emigration to activities primarily
by endothelial cells or leukocytes, respectively. Research
since the 1980s has greatly enhanced our understanding of
the molecular basis for the regulation of leukocyte interactions
with the vascular endothelium at sites of inflammation.
The following is a general overview of the various
physiological parameters, adhesion molecules, and chemoattractants
that play a critical role in neutrophil capture/
rolling, activation, and arrest/locomotion.
2 . Physiological Factors Contributing to
Neutrophil Adherence
Neutrophil accumulation predominantly occurs along
the vascular endothelium of venules as a result of several
physiological factors. Neutrophil capture by the endothelium
is enhanced by red blood cells, those lined up behind
neutrophils as they leave the capillaries as well as by red
blood cells occupying the center of the bloodstream, which
force neutrophils toward the venular endothelium ( Nobis
et al. , 1985 ; Schmid-Schonbein et al. , 1980 ). Endothelial
cells lining postcapillary venules in secondary lymphoid
organs of humans and mice (high endothelial cell venules)
bulge into the luminal space, thus increasing their collision
with lymphocytes ( Von Andrian, 1996 ). Though endothelial
cells lining venules in nonlymphoid tissues tend to be
flat, attached neutrophils at sites of inflammation appear to
provide temporary extensions into the blood vessel lumen,
causing collisions and capture of free-flowing neutrophils.
This process is referred to as indirect or secondary capture
(tethering) and was observed as early as 1955 when
Allison and colleagues reported that “ leukocytes were
frequently seen to stick to one another, indicating that the
increased adhesiveness characteristic of the inflammatory
response is not limited to the endothelium ” ( Allison
et al. , 1955 ). Indeed, neutrophils individually and as a
monolayer facilitate indirect capture, and this appears to
accelerate and sustain their accumulation ( Bargatze et al. ,
1994 ; Eriksson et al. , 2001 ; Sperandio et al. , 2003 ; St. Hill
et al. , 2003 ; Walcheck et al. , 1996 ). In addition, because
leukocyte accumulation on activated endothelium at sites
of inflammation shows spatial variability ( Kunkel et al. ,
Direct capture
1998 ), indirect capture may be a mechanism for compacting
(pavementing) leukocytes within discrete sites of activated
endothelium, as illustrated in Figure 11-1 .
Neutrophils from the flowing blood that adhere to the
vascular endothelium incur forces (wall shear stresses)
that are affected by several factors, including blood flow
velocity, vessel diameter, red blood cell concentration, and
plasma viscosity. Shear stresses on adhered neutrophils
in venules in vivo range between 1 and 35 dynes/cm
2
,
assuming a cell-free, plasma viscosity of 1.1 centipoise
( Damiano et al. , 1996 ). In general, leukocyte adhesion
and rolling are reduced with increasing wall shear stress
( Damiano et al. , 1996 ). The wall shear stress is generally
lower in venules than in arterioles of equal size. These
forces are balanced by the interaction of adhesion molecules
on the leukocyte with those on the endothelium,
which is discussed in more detail later.
3 . Selectins
Single cellmediated
Compaction
Monolayermediated
Indirect capture
FIGURE 11-1 Indirect (2 ° ) neutrophil capture increases their accumulation
rate and density on the vascular endothelium. Direct neutrophil
binding to the endothelium (e.g., via P-selectin) occurs randomly (open
circles). Next, neutrophil-neutrophil interactions mediate two means of
indirect capture. Individual attached neutrophils capture free-flowing
neutrophils (gray circles) during initial neutrophil accumulation. In
addition, a monolayer of attached neutrophils will capture free-flowing
neutrophils, which roll across the neutrophil monolayer (black circles
containing arrows) resulting in pavementing by the neutrophils and their
compaction in discrete locations.
Selectins mediate the initial interactions between neutrophils
and the endothelium resulting in their attachment and rolling
at velocities considerably below that of cells in the flowing
blood. The nature of cell adhesion mediated by selectins
differs from that mediated by most other classes of adhesion
molecules. Rapid on and off bonding events between
selectins and their ligands cause leukocytes attached to the
endothelium to roll under blood flow conditions ( Fig. 11-2 ).
There are three known selectins, each with a highly specific
pattern of cellular expression. Forgoing the listing of
all of their earlier more descriptive names, they are known
today by single letters designating the cell type by which
they were first identified. L-selectin (CD62L) is expressed
by leukocytes, E-selectin (CD62E) expression is limited to
endothelial cells, and P-selectin (CD62P) is expressed by
platelets as well as endothelial cells.