Biomedical Engineering Reference
In-Depth Information
CD11b/CD18 cleavage may serve as an anti-inflammatory measure to reverse
spontaneous neutrophil adhesion to microvessels. Based on the role of CD11b/
CD18 in neutrophil adhesion, our findings [
104
-
106
] suggest that shear-induced
CD11b/CD18 shedding averts cell adhesion during non-inflamed states. In doing so,
the ability of shear stress to reduce neutrophil adhesion may be a key determinant of
microvascular resistance.
For suspended neutrophils, mechanisms must also be in place to prevent F-actin
polymerization and pseudopod extension, both of which serve to alter cell stiffness
and size [
138
]. Presumably, shear-induced pseudopod retraction and F-actin
depolymerization likely serve to minimize the tumbling behavior of the neutrophils
in the parabolic velocity field of microvascular blood. In doing so, intercellular
collisions of neutrophils with other cells, such as the RBCs, are minimized. Thus,
shear-induced neutrophil deactivation, by preventing this tumbling, may serve to
optimize microvessel flow in the non-capillary microvasculature, i.e., prevent the
Viscous effect on peripheral resistance (Fig.
3
). In contrast, a failure to retract
pseudopods by neutrophils under shear likely enhances blood viscosity that trans-
lates into elevations in flow resistance in line with a viscous effect (Fig.
3
). Thus,
the mechanosensitivity of neutrophils flowing in the blood may also serve as a
determinant of microvascular resistance.
5 Impaired Neutrophil Shear Response and Microvascular
Dysfunction in Obesity
The wide range of fluid shear stresses that neutrophils experience as they circulate
from site to site and from one moment to another implies that these cells function
''normally'' under complex and time-variant shear distributions. It also challenges the
notion that pathological changes in shear distributions within the local environment of
the neutrophil alone are what alter their behavior and lead to dysfunction. Another
possibility is that the state of the neutrophil mechanosensitivity to local flow condi-
tions determines the health status of these cells which, if pathological, promotes a
chronic inflammatory state leading to microvascular dysfunction.
Notably, obesity is a risk factor for hypertension and hypercholesterolemia,
both of which are associated with a chronic inflammatory phenotype. Several
studies have implicated dysregulated neutrophil behavior as a contributing factor
for microvascular dysfunction due to hypertension or hypercholesterolemia.
Reportedly, neutrophil behavior within obese individuals is also dysregulated
[
139
]. Thus, due to the link between obesity and either hypertension or hyper-
cholesterolemia, it is possible that dysregulated neutrophil behavior in obesity
stems from an impaired sensitivity to fluid shear stress.
In the case of hypertension, circulating neutrophils from obese individuals exist
in an activated state as indicated by their enhanced expression of MPO, calprotectin,
and CD66b, all of which are markers of activated granulocytes [
28
]. Conceivably,
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