Biomedical Engineering Reference
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Fig. 6 Regulation of neutrophil activity. The blue arrows represent the progression and
resolution of inflammation under physiologic (i.e., non-pathogenic) conditions. Under non-
inflamed conditions, neutrophils remain quiescent due to the deactivating effects of fluid shear
stress. Upon inflammatory stimulation, neutrophils activate and adhere to substrates. The high
levels of neutrophil agonists likely serve to prevent shear-induced cell deactivation. However,
when agonist levels subside during resolution of inflammation, neutrophils are once again capable
of responding to shear-induced deactivation. The red arrows represent the potential effects of
obesity on various aspects related to the physiologic control of the inflammatory response. Obesity
involves elevated levels of cytokines/agonists in the circulation, interferes with the resolution
stage of inflammation, and may interfere with neutrophil mechanotransduction. As activated
neutrophils accumulate in the blood and microcirculation, a chronic inflammatory state may ensue,
leading to microvascular dysfunction and downstream cardiovascular diseases. Neutrophils are
depicted in gray, platelets are depicted in yellow, and red blood cells are outlined in red
Presumably, the excess cholesterol in the blood accumulates in the membranes
of flowing neutrophils and alters their shear sensitivity via an impact on lipid
bilayer fluidity. In support of this, hypercholesterolemia has been reported to raise
cholesterol levels in blood cell membranes [ 143 - 146 ]. Conceivably, conforma-
tional activity of FPRs and CD18 integrins, both of which have been reported to
exhibit shear sensitivity for neutrophils, may be influenced by membrane cho-
lesterol levels that potentially interfere with mechanotransduction processes [ 138 ].
Moreover, there is substantial evidence [ 58 , 60 , 147 - 149 ] demonstrating a rela-
tionship between hypercholesterolemia and enhanced leukocyte activity in the
microcirculation. Thus, similar to the case for hypertension, elevated leukocyte
activity in the microcirculation may be linked to microvascular dysfunction and
impaired tissue perfusion. This may result from either the development of a sys-
temic inflammatory state promoting arteriolar endothelial dysregulation or a
change in the rheological behavior of leukocytes in the microcirculation due to an
impaired neutrophil mechanosensitivity to shear (Fig. 6 ).
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