DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1068 Individual growth factors then were isolated based on their activities
in clonal in vitro assays. Many of these same assays were instrumental
in purifying a hierarchy of progenitor cells committed to
individual and combinations of mature blood cells (Akashi, 2000;
Nakorn, 2003).
The existence of a circulating growth factor that controls red
blood cell development was first suggested by the experiments of
Paul Carnot in 1906. He observed an increase in the red-cell count
in rabbits injected with serum obtained from anemic animals and
postulated the existence of a factor that he called hemopoietin.
However, it was not until the 1950s that Reissmann, Erslev, and
Jacobsen and coworkers defined the origin and actions of the hormone,
now called erythropoietin. Subsequently, extensive studies of
erythropoietin were carried out in patients with anemia and polycythemia,
leading to the purification of erythropoietin from urine
and the subsequent cloning of the erythropoietin gene. The highlevel
expression of erythropoietin in cell lines has allowed for its
purification and use in humans with anemia.
Similarly, the existence of specific leukocyte growth factors
was suggested by the capacity of different conditioned culture media
to induce the in vitro growth of colonies containing different combinations
of granulocytes and monocytes. An activity that stimulated
the production of both granulocytes and monocytes was purified
from murine lung-conditioned medium, leading to cloning of
granulocyte/macrophage colony-stimulating factor (G-CSF), first
from mice (Gough et al., 1984) and subsequently from humans
(Wong, 1985). Finding an activity that stimulated the exclusive production
of neutrophils permitted the cloning of granulocyte colonystimulating
factor (G-CSF) (Welte et al., 1985). Subsequently, a
megakaryocyte colony-stimulating factor termed thrombopoietin
was purified and cloned (Kaushansky, 1998).
The growth factors that support lymphocyte growth were not
identified using in vitro colony-forming assays but rather using
assays that measured the capacity of the cytokine to promote lymphocyte
proliferation in vitro. This permitted the identification of the
growth-promoting properties of interleukin (Il)-7, Il-4, or Il-15 for all
lymphocytes, B cells, or NK cells, respectively (Goodwin et al.,
1989; Grabstein et al., 1994). Again, recombinant expression of these
cDNAs permitted production of sufficient quantities of biologically
active growth factors for clinical investigations, allowing for the
demonstration of the potential clinical utility of such factors.
SECTION IV
INFLAMMATION. IMMUNOMODULATION, AND HEMATOPOIESIS
Growth Factor Physiology. Steady-state hematopoiesis
encompasses the production of >400 billion blood cells
each day. This production is tightly regulated and can
be increased several fold with increased demand. The
hematopoietic organ also is unique in adult physiology
in that several mature cell types are derived from a
much smaller number of multipotent progenitors,
which develop from a more limited number of pluripotent
hematopoietic stem cells. Such cells are capable of
maintaining their own number and differentiating under
the influence of cellular and humoral factors to produce
the large and diverse number of mature blood cells.
Stem cell differentiation can be described as a
series of steps that produce so-called burst-forming
units (BFU) and colony-forming units (CFU) for each
of the major cell lines. These early progenitors (BFU
and CFU) are capable of further proliferation and differentiation,
increasing their number by some 30-fold.
Subsequently, colonies of morphologically distinct cells
form under the control of an overlapping set of additional
growth factors (G-CSF, M-CSF, erythropoietin,
and thrombopoietin). Proliferation and maturation of
the CFU for each cell line can amplify the resulting
mature cell product by another 30-fold or more, generating
>1000 mature cells from each committed stem
cell.
Hematopoietic and lymphopoietic growth factors
are glycoproteins produced by a number of marrow
cells and peripheral tissues. They are active at
very low concentrations and typically affect more
than one committed cell lineage. Most interact synergistically
with other factors and also stimulate production
of additional growth factors, a process called
networking. Growth factors generally exert actions at
several points in the processes of cell proliferation
and differentiation and in mature cell function.
However, the network of growth factors that contributes
to any given cell lineage depends absolutely
on a nonredundant, lineage-specific factor, such that
absence of factors that stimulate developmentally
early progenitors is compensated for by redundant
cytokines, but loss of the lineage-specific factor leads
to a specific cytopenia. Some of the overlapping and
nonredundant effects of the more important hematopoietic
growth factors are illustrated in Figure 37–1 and
listed in Table 37–1.
ERYTHROPOIESIS STIMULATING
AGENTS
Erythropoiesis stimulating agent (ESA) is the term
given to a pharmacological substance that stimulates
red blood cell production. Although erythropoietin is
not the sole growth factor responsible for erythropoiesis,
it is the most important regulator of the proliferation
of committed erythroid progenitors (CFU-E)
and their immediate progeny. In its absence, severe anemia
is invariably present, commonly seen in patients with
renal failure. Erythropoiesis is controlled by a feedback
system in which a sensor in the kidney detects changes
in oxygen delivery to modulate the erythropoietin
secretion. The sensor mechanism is now understood at
the molecular level (Maxwell et al., 2001). Hypoxiainducible
factor (HIF-1) is a heterodimeric (HIF-1α and