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

postcapillary venules. This model has been investigated in a variety of error and relatively poor correlation with kinetics, as measured by other
98
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99
vascular beds and in vitro with monolayers of endothelial cells in par- techniques. For example, the morphologic findings in the marrow of a
allel plate flow chambers. The tethering event in this model depends “maturation arrest,” with little neutrophil development beyond the pro-
98
on adhesion molecules in the selectin family, E-selectin and P-selectin myelocyte or myelocyte stage, does not distinguish between a defect in
on the endothelium, L-selectin on the neutrophil, and ligands for the precursor cell maturation and rapid mobilization of postmitotic cells
selectins expressed on both cell types. These adhesion molecules are from the marrow. Similarly, distinguishing by purely morphologic means
necessary to efficiently initiate the cascade of adhesive steps ultimately neutropenic conditions resulting from ineffective neutrophil produc-
leading to firm attachment of the neutrophils to endothelium. The cas- tion from conditions caused by peripheral destruction of neutrophils
cade appears to be necessary for neutrophils to move from blood to often is difficult. However, despite these limitations, when the absolute
tissues because the unstimulated neutrophil is not adhesive to endothe- neutrophil count and marrow cellularity are used together, they provide
lium. 98,100 The integrins necessary for firm adhesion and cell locomotion a useful guide in most clinical settings. If the absolute neutrophil count
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require stimulation to promote sufficient increases in avidity or affinity is less than 1.0 × 10 /L and multiple marrow aspirations and/or biopsies
to support these functions (Chap. 19). are hypocellular, the patient almost invariably has impaired production
of marrow neutrophils. Very low neutrophil counts predispose to infec-
LIFE SPAN OF NEUTROPHILS tions by bacteria and certain fungi (e.g., Candida and Aspergillus). Such
After emigrating into tissue, the life span of neutrophils can be signifi- infections become especially troublesome as the neutrophil count falls
below 0.5 × 10 /L (Chap. 65). Unfortunately, the converse is not true.
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cantly prolonged (24 to 48 hours). Programmed cell death (apoptosis) The finding of cellular marrow and neutrophil count >1.0 × 10 /L does
101
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accounts for significant removal of tissue neutrophils through phagocy- not mean production is normal. Nevertheless, when marrow cellularity
tosis by macrophages. The constitutive rate of apoptosis of neutrophils is and absolute neutrophil count are considered together, they provide the
altered by inflammatory cytokines and chemokines. For example, tumor most clinically useful assessment of neutrophil production.
necrosis factor-α (TNF-α) accelerates the rate, but endotoxin, G-CSF,
GM-CSF, IL-15, and IL-3 inhibit the rate of apoptosis. The balance of
these effects at specific inflammatory sites is poorly understood, but the FUNCTIONAL EVALUATION
functional life of neutrophils in tissue appears to be controlled by the Several agents that increase neutrophil numbers in circulation,
rate of apoptosis. Apoptotic neutrophils lose the ability to release gran- including glucocorticoids, endotoxin, and etiocholanolone, have
ular enzymes in response to external stimuli (see below), and marked been used to evaluate neutrophil reserves in a clinical setting. These
changes in cell surface proteins occur (e.g., CD16, CD43, CD62L are agents have been supplanted by recombinant human G-CSF, a
greatly reduced). Although the loss of responsiveness may contribute to remarkably nontoxic cytokine that, when given in therapeutic doses
resolution of the inflammatory process, evidence indicates macrophages (5 to 8 mcg/kg), increases the blood neutrophil count by stimulat-
also are altered by the phagocytosis of apoptotic neutrophils. In con- ing neutrophil production and accelerating neutrophil release from
trast to the macrophage response to phagocytosis of microbes, where the marrow storage compartment (Chap. 65). The increase in neu-
secretion of proinflammatory cytokines (e.g., IL-1β) and chemokines trophil production results from a threefold increase in the number
(e.g., IL-8) is stimulated, phagocytosis of apoptotic neutrophils fails to of cell divisions in the mitotic compartment and shortening of the
provoke secretion of proinflammatory factors; instead, phagocytosis maturation time from myelocyte to neutrophil from 4 to 5 days to
stimulates release of factors that may suppress inflammatory responses less than 1 day. 102,103 Thus, as a byproduct of its therapeutic action,
(e.g., transforming growth factor-β and prostaglandin E ). Macrophage G-CSF administration directly tests an individual’s capacity to pro-
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recognition of apoptotic neutrophils is partially understood to involve duce neutrophils. This effect of G-CSF makes obsolete most of the
the vitronectin receptor α β and the thrombospondin receptor CD36 older methods for evaluating neutrophil compartments.
V 3
on the macrophage surface. In addition, phosphatidylserine residues on G-CSF does not test the distribution of neutrophils between the
the neutrophil are involved. 98 marginated and circulating pools. On the rare occasions when such
Neutrophils are capable of phenotypic changes depending on the information is desirable, epinephrine stimulation can be used to assess
tissue and cytokine/chemokine milieu at the time of their migration the distribution. For this purpose, epinephrine 0.1 mg infused intra-
into tissue (Chap. 60). Because our understanding of neutrophil physi- venously over 5 minutes has been used, and blood for white counts is
ology is relatively new, knowing the extent of this phenomenon on neu- obtained before and 1, 3, and 5 minutes after completion of the epi-
trophil life span in tissues is not possible at present.
nephrine infusion. Normally the neutrophils increase by approximately
50 percent after epinephrine infusion. 104
EVALUATION OF ADEQUACY OF
NEUTROPHIL RESERVES REFERENCES
1. Kondo M, Wagers AJ, Manz MG, et al: Biology of hematopoietic stem cells and progen-
itors: Implications for clinical application. Annu Rev Immunol 21:759, 2003.
WHITE CELL COUNT AND MARROW 2. Spangrude GJ: When is a stem cell really a stem cell? Bone Marrow Transplant 32 Suppl
CELLULARITY 1:S7, 2003.
3. Smaaland R, Sothern RB, Laerum OD, Abrahamsen JF: Rhythms in human bone mar-
White cell and absolute neutrophil counts are the most widely used row and blood cells. Chronobiol Int 19:101, 2002.
guides to the status of neutrophil production. They are useful in evalu- 4. Metcalf D: Hematopoietic stem cells: Old and new. Biomed Pharmacother 55:75, 2001.
ating the effects of cytotoxic chemotherapy, although they do not pro- 5. Athens JW: Neutrophilic granulocyte kinetics and granulopoiesis, in Regulation of
vide quantitative information on the rate of neutrophil production or Hematopoiesis, edited by Gordon AS, p 1143. Appleton-Century-Crofts, New York,
1961.
destruction, the status of marrow reserves, or the presence of abnormal- 6. Athens JW, Raab SO, Haab OP, et al: Leukokinetic studies. III. The distribution of gran-
ities in cell distribution. ulocytes in the blood of normal subjects. J Clin Invest 40:159, 1961.
Gauging neutrophil production by the appearance of marrow 7. Athens JW, Haab OP, Raab SO, et al: Leukokinetic studies. IV. The total blood, circu-
lating and marginal granulocyte pools and the granulocyte turnover rate in normal
films, clot sections, or biopsies suffers from the limitations of sampling subjects. J Clin Invest 40:989, 1961.

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