Page 967 - Williams Hematology ( PDFDrive )

942 Part VII: Neutrophils, Eosinophils, Basophils, and Mast Cells Chapter 61: Production, Distribution, and Fate of Neutrophils 943

contains approximately 50-fold more neutrophils and even more lym- TABLE 61–3. Definitions and Calculations Relating to
phocytes and monocytes. Videomicroscopic study of these vessels
70
in animal models has revealed the transit of neutrophils through this Blood Neutrophil Kinetics
network required a median time of 26 seconds and mean time of 6.1 Circulating neutrophil pool (CNP) = Blood neutrophil concentration
seconds. 71,72 In contrast, the transit times of red blood cells ranges from × blood volume
1.4 to 4.2 seconds. The increased transit time results primarily from the Total blood neutrophil pool (TBNP) = All neutrophils in the circulation
time neutrophils are stopped within this vascular network. The longer Marginal neutrophil pool (MNP) = TBNP – CNP
time required for the neutrophils to pass through this bed apparently
accounts for their increased concentration. Blood clearance half-time (T ) = Disappearance time of half
1/2
Recruitment of neutrophils into the lungs through the alveolar the labeled neutrophils from
capillary network contrasts with the recruitment of neutrophils through circulation
postcapillary venules at sites of inflammation in a number of important Neutrophil turnover rate (NTR) = 0.693 × TBNP
ways. The tethering mechanisms required to capture neutrophils from T
flowing blood in larger vessels apparently are not necessary in the alve- 1/2
olar capillary bed. The diameters of spherical neutrophils (6 to 8 µm)
are larger than the diameters of many capillary segments (2 to 15 µm).
Approximately 50 percent of the capillary segments would require neu-
trophils to change their shape in order to pass through. 72–75 Given the steady state, NTR measures the rate of effective neutrophil production.
large number of capillary segments through which a neutrophil must Table 61–3 lists the definitions and calculations related to blood neu-
pass (often more than 50), most neutrophils must change shape during trophil kinetics. Table 61–4 lists data for normal human blood neu-
transit from arteriole to venule. Morphometric analysis of neutrophils trophil kinetics. The high production rate of neutrophils under normal
in the alveolar capillary beds has revealed significant deviation from conditions is remarkable, especially given that the rate may increase
spherical shape. 72,73 Computational models of the capillary bed describ- several fold in response to inflammatory stimuli.
ing flow, hematocrit, pressure gradients, and the effects of deformation Glucocorticoids increase TBNP by increasing influx from the
on the capillary transit times of neutrophils support the concept that marrow and decreasing efflux from the circulation. Five hours after a
the structure of the capillary bed and the deformation of neutrophils are pharmacologic dose of glucocorticoid, the neutrophil count increases
critical under normal conditions. Thus, the enormous lung vascular bed by approximately 4000/µL because of release from the marrow, demar-
contains a substantial number of neutrophils that can be mobilized into gination, and prolongation of T to approximately 10 hours. 90–92 Con-
1/2
the systemic circulation with stimuli such as epinephrine or exercise. sistent with the increase in T , prednisone reduces the accumulation of
1/2
75
During inflammation, much of the sequestration and infiltration neutrophils at induced sites of skin inflammation. With alternate-day,
occur through vessels so narrow that physical tapping is sufficient to single-dose prednisone, neutrophil counts and kinetics are normal 24
93
stop the flowing neutrophil. 68,72,76,77 Binding of mediators such as che- hours after administration and during the day off. Endotoxin causes
motactic factors (e.g., C5a, the chemotactic fragment of complement a prompt neutropenia as a result of cell margination and sequestra-
component C5) to neutrophil receptors induces a transient resistance tion, followed in 2 to 4 hours by a rebound neutrophilia as a result
of the cells to deformation. 78–83 Because neutrophils must deform to of cell release from the marrow. The size of the neutrophilic response
pass through the capillary bed, leukocyte activation by inflammatory correlates with the functional marrow reserves. 94–97 After epinephrine
mediators could affect further concentration of neutrophils at the alve- administration, a peak leukocytosis occurs in 5 to 10 minutes and rarely
olar walls. 65,76 The role of mechanical factors in the initial sequestration lasts more than 20 minutes. This finding reflects a shift of cells from the
of neutrophils in the alveolar capillaries is supported by evidence that marginated to the circulating pool.
neither L-selectin nor β -integrins are required. 76,84,85 In contrast, both
2
selectins and β -integrins are required for localization of neutrophils in
2
postcapillary venules at sites of inflammation. MIGRATION OF NEUTROPHILS INTO TISSUES
The events following the initial sequestration of neutrophils within The migration of neutrophils from blood into tissue at sites of inflam-
alveolar capillary beds are influenced by adhesion molecules. For exam- mation involves a series of sequential adhesive steps proceeding from
ple, simple systemic activation of neutrophils by intravenous injection tethering (rolling adhesion) on endothelium under shear conditions in
of chemotactic factors (e.g., IL-8 or C5a) results in rapid (<1 minute)
neutropenia with massive sequestration of neutrophils within alveolar
capillaries. This event is not dependent on L-selectin or β -integrins,
2
but the retention times within this capillary bed are influenced by these TABLE 61–4. Data for Human Blood Neutrophil Kinetics
adhesion molecules. 76,85 Adhesion likely is an interaction of leukocyte
adhesion molecules and endothelial adhesion molecules. Blockade of Pool Mean Pool 95% Limits
Size × 10 kg
7
the adhesive mechanism (e.g., using blocking monoclonal antibodies)
results in release of neutrophils from the lungs. 76,84,86–88 Mediator-in- TBNP 70 14–160
duced decreases in deformability are temporally correlated with upreg- CNP 31 11–46
ulation of β -integrins (e.g., both occurring within approximately
2
1 minute of exposure to IL-8). This allows both physical trapping and MNP 39 0–85
sticking to the vascular wall within the alveolar capillary bed. A simi- Mean Value 95% Limits
lar phenomenon occurs in the liver where sequestration is the result of Blood clearance T 6.7 h 4–10 h
physical trapping and liver injury is heavily dependent on adhesion of 1/2 7 7
leukocytes through the β -integrins. 89 NTR 63 × 10 kg/day 50–340 × 10 kg/day
2
Assuming a random loss of neutrophils from the blood, NTR can CNP, circulating neutrophil pool; MNP, marginal neutrophil pool; NTR, neu-
be calculated from T and TBNP: NTR = 0.693 × TBNP/T . In the trophil turnover rate; T , half-time; TBNP, total blood neutrophil pool.
1/2
1/2
1/2

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