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CHAPTER 61 DEFINITION AND HISTORY

PRODUCTION, Neutrophils are produced in the marrow, where they arise from progen-
itor and precursor cells by a process of cellular proliferation and matu-
1,2
DISTRIBUTION, AND ration. They differentiate from the pluripotential stem cell through a
series of progressively more committed progenitor or colony-forming
units, including the granulocyte-monocyte colony-forming unit and the
FATE OF NEUTROPHILS granulocyte colony-forming unit, which give rise to neutrophils. The
3,4
early progenitor cells cannot be recognized under the microscope
but can be identified retrospectively by the type of colony formed in
culture of marrow cells (Chap. 18). The earliest morphologically recog-
C. Wayne Smith nizable neutrophil precursor is the myeloblast. From there, the formal
sequence of precursor development is myeloblast → promyelocyte →
myelocyte → metamyelocyte → band neutrophil → segmented neu-
SUMMARY trophil (Chap. 60). The term granulocyte often is loosely used to refer
to neutrophils but strictly speaking includes eosinophils and basophils.
Blood neutrophil levels are maintained in a normal steady state by Eosinophilic (Chap. 62) and basophilic granulocytes (Chap. 63) develop
hematopoiesis in the marrow, the distribution of neutrophils between from progenitors in a manner analogous to the neutrophils, although
the marginated pool in the microvasculature and the freely circulating commitment to neutrophilic, eosinophilic, or basophilic development
pool in the blood, and the rate of egress from blood to tissues. Marrow probably is established at an early progenitor stage, and are dependent
on the cytokines interleukin (IL)-5 and stem cell factor, respectively.
production of neutrophils is regulated by three principal glycoprotein The normal human neutrophil production rate is 0.85 to 1.6 × 10
9
hormones, or cytokines: interleukin-3, granulocyte-monocyte colony- cells/kg per day. Mature neutrophils are stored in the marrow before
stimulating factor, and granulocyte colony-stimulating factor (G-CSF), they are released into the blood. In the absence of an inflammatory
but only the genetic elimination of G-CSF has a measurable effect on focus, they leave the circulation randomly, with a half-disappearance
blood neutrophil levels. The latter two cytokines are available as recom- time of approximately 7 hours. The cells then enter the tissues and prob-
binant pharmaceutical products that can be administered therapeutically ably function for 1 or 2 days before their death or loss into the gastroin-
to ameliorate certain causes of neutropenia. Neutrophil interaction with testinal tract through mucosal surfaces.
endothelium is mediated by selectins, glycoproteins with sugar-bind- The marrow has an impressive capacity to produce neutrophils,
ing sites that support shear-dependent rolling on endothelium, and by yet it is carefully regulated both at steady state and in times of height-
integrins on the neutrophil binding to ligands on the endothelial cells, ened demand. This chapter outlines current concepts of neutrophil pro-
permitting firm attachment to endothelium and emigration into tissues. duction, distribution, and survival. For detailed data and methods, the
reader is referred to original articles and reviews on neutropoiesis and
Neutrophils have a short life span in blood, with a disappearance half- neutrophil kinetics. 5–17
time of approximately 7 hours. The process can be accelerated when
inflammation is present and highlights the need for a sustained rate of
production to maintain a normal blood neutrophil count. The pathogen- REGULATION OF NEUTROPHILIC
esis of neutropenia is more complex to analyze kinetically than anemia GRANULOPOIESIS
or thrombocytopenia because at least four compartments are involved:
marrow storage pool, circulating pool, marginated pool, and tissue pool. Although the primary cellular manifestation of commitment is the
The latter is particularly difficult to assay. Measurements can be further expression of receptors for lineage-specific hematopoietic growth fac-
complicated in the nonsteady state, when dramatic increases in turnover tors, the “decision” for a stem cell to self-renew is, at least partially, a
1,18
rates and distribution among the four principal pools are in disequilib- stochastic event. On the other hand, stromal elements, collectively
rium, as occurs during acute inflammatory states. referred to as the hematopoietic microenvironment, release short-range
signals that regulate the process of commitment from multipotential
stem cell pools. Although many details of hematopoietic stem cell reg-
ulation (Chap. 18) remain to be elucidated, much is known regarding
the interaction of hematopoietic cytokines with their receptors and
actions on the committed granulocyte progenitor cells and their mature
progeny. 19–24
Acronyms and Abbreviations: β -Integrin, a member of family of recep-
2
tors that mediate attachment between a cell and the tissues surrounding it; C5a,
chemotactic fragment of complement component C5; CD, one of the cluster of dif- HUMORAL REGULATORS
ferentiation antigens; CSF, colony-stimulating factor; DF P, diisopropyl fluorophos- The humoral regulators involved in granulopoiesis have been
32
phate; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-monocyte defined by in vitro culture systems. 20,21 Originally identified by their
colony-stimulating factor; IL, interleukin; L-selectin (and other selectins), a member ability to stimulate colony formation from marrow progenitor cells,
of selectin family of proteins, which are leukocyte cell-adhesion molecules; Mr, rela- the hemopoietic cytokines were initially termed colony-stimulating
tive molecular mass; NTR, neutrophil turnover rate; T , half-time; TBNP, total blood factors (CSFs) based on this assay system. With regard to neu-
25
1/2
neutrophil pool; TNF-α, tumor necrosis factor-α. trophil production, at least four human CSFs have been defined.
Granulocyte-monocyte colony-stimulating factor (GM-CSF) is a

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