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

References
345
is thought to be due to the fact that activated neutrophils are
rigid and tend to lodge in capillary beds.
Limited neutrophil activation while in contact with the
endothelium is probably a normal process. This results
from binding of neutrophil adhesion molecules to endothelial
cells. Although not completely elucidated, these signaling
pathways appear to involve the Src-family of tyrosine
kinases, mitogen-activated protein kinases, and phosphatidylinositol
3-kinase ( Lee and Downey, 2001 ). However,
excessive activation of neutrophils while attached to endothelium
can result in direct release of oxygen radicals and
granule contents onto the endothelial surface. A variety of
factors, including platelet-activating factor, IL-8, LTB 4 ,
and complement, have been incriminated as neutrophil
activating agents. Platelet activating factor and IL-8 are
produced by activated endothelial cells and expressed on
the cell surface. Neutralization of platelet activating factor
both in vitro and in vivo has been reported to attenuate
bovine neutrophil-induced endothelial injury ( McClenahan
et al. , 2000, 2002 ). Multiple mediators are involved in neutrophil-mediated
endothelial injury. Mediators implicated
in various experimental models of ARDS include oxygen
radicals, activated complement factors, nitric oxide, proteolytic
enzymes, and metalloproteinases ( Lee and Downey,
2001 ). Consequences of this endothelial injury include (1)
massive leakage of plasma into alveoli, (2) vasodysregulation
leading to maldistribution of blood flow, and (3) disturbances
of oxygen transport and utilization. All of these
lead to dyspnea and hypoxemia.
As in ischemia/reperfusion injury, capillary plugging
by activated neutrophils appears to play a central role in
ARDS and MODS. Activated neutrophils are stiff because
of the assembly of F-actin filaments and tend to lodge in
capillaries. Additionally activated neutrophils form neutrophil-neutrophil
and neutrophil-platelet aggregates, which
form microvascular plugs in larger vessels. This leads to
microvascular thrombosis, tissue necrosis, and release of
additional toxic substances.
D . Role of Neutrophils in Microvascular
Thrombosis
Local and disseminated activation of coagulation frequently
accompanies sepsis and endotoxemia ( Weiss and Rashid,
1998 ). The mechanism responsible for this sepsis-induced
procoagulant effect is complex. The role of neutrophils in
microvascular thrombosis appears to be in their capacity to
induce endothelial injury and to bind and activate platelets.
Endothelial injury results in conversion of the endothelial
cell surface from an anticoagulant surface to a procoagulant
surface ( Fig. 11-5 ). Destruction of endothelial cells activates
the intrinsic clotting system through exposure of subendothelial
collagen and activates the extrinsic coagulation system
through contact with tissue factor.
Platelets also frequently become activated during sepsis
and endotoxemia. Both activated neutrophils and activated
endothelial cells express platelet activating factor that is a
potent platelet agonist. When activated platelets degranulate,
P-selectin is transported from alpha granules to the cell
membrane. P-selectin interacts with PSGL-1 on the neutrophil
surface forming platelet-neutrophil aggregates. Plateletneutrophil
aggregates are rigid and therefore lodge in
capillary beds and initiate microvascular inflammatory and
thrombotic events. Platelet-neutrophil aggregates have been
detected in horses undergoing near-maximal treadmill exercise
and in horses and ponies with carbohydrate overloadinduced
laminitis ( Weiss et al. , 1998a, 1998b ). The potential
causative role of activated platelets/platelet-neutrophil aggregates
in laminitis was inferred from in vivo studies in which
ponies were treated with a competitive inhibitor of platelet
aggregation before administration of carbohydrate overload.
The platelet aggregation inhibitor prevented the formation
of platelet-neutrophil aggregates and the prevented onset of
lameness in all eight ponies tested ( Weiss et al. , 1998a ).
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