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

ERYTHROPOIETIN
1069
SCF / FL
Totipotent/pluripotent
stem cells
GM-CSF / IL-3
CFU-GM
BFU-E/CFU-E
Red
blood
cells
GM-CSF / G-CSF
Granulocytes
Eosinophils
CHAPTER 37
CFU-GEMM
CFU-Meg
Basophils
GM-CSF / M-CSF
Monocytes
HEMATOPOIETIC AGENTS
Lymphocyte
Progenitor
B cells
NK cells
Platelets
T cells
IL-1 / IL-2 / IL-3 / IL-4 / IL-6 Megakaryocyte
IL-6 / IL-11 / THROMBOPOIETIN
Figure 37–1. Sites of action of hematopoietic growth factors in the differentiation and maturation of marrow cell lines. A self-sustaining
pool of marrow stem cells differentiates under the influence of specific hematopoietic growth factors to form a variety of hematopoietic
and lymphopoietic cells. Stem cell factor (SCF), ligand (FL), interleukin-3 (IL-3), and granulocyte-macrophage colony-stimulating
factor (GM-CSF), together with cell–cell interactions in the marrow, stimulate stem cells to form a series of burst-forming units (BFU)
and colony-forming units (CFU): CFU-GEMM (granulocyte, erythrocyte, monocyte and megakaryocyte), CFU-GM (granulocyte and
macrophage), CFU-Meg (megakaryocyte), BFU-E (erythrocyte), and CFU-E (erythrocyte). After considerable proliferation, further
differentiation is stimulated by synergistic interactions with growth factors for each of the major cell lines—granulocyte
colony–stimulating factor (G-CSF), monocyte/macrophage-stimulating factor (M-CSF), thrombopoietin, and erythropoietin. Each of
these factors also influences the proliferation, maturation, and in some cases the function of the derivative cell line (Table 37–1).
HIF-1β) transcription factor that enhances expression
of multiple hypoxia-inducible genes, such as vascular
endothelial growth factor and erythropoietin. HIF-1α
is labile due to its prolyl hydroxylation and subsequent
polyubiquitination and degradation, aided by the von
Hippel-Lindau (VHL) protein. During states of
hypoxia, the prolyl hydroxylase is inactive, allowing
the accumulation of HIF-1α and activating erythropoietin
expression, which in turn stimulates a rapid expansion
of erythroid progenitors. Specific alteration of
VHL leads to an oxygen-sensing defect, characterized
by constitutively elevated levels of HIF-1α and erythropoietin,
with a resultant polycythemia (Gordeuk et al.,
2004). Recently, a potential role for a second isoform of
HIF, HIF-2α, was identified in erythropoiesis because
genetic gain-of-function mutation of that gene induces
erythrocytosis in patients (Percy et al., 2008).
Erythropoietin is encoded by a single copy gene on
human chromosome 7 that is expressed primarily in peritubular
interstitial cells of the kidney. Erythropoietin contains
193 amino acids, of which the first 27 are cleaved
during secretion. The final hormone is heavily glycosylated
and has a molecular mass of ~30,000 Da. After
secretion, erythropoietin binds to a receptor on the surface
of committed erythroid progenitors in the marrow
and is internalized. With anemia or hypoxemia, synthesis
rapidly increases by 100-fold or more, serum erythropoietin
levels rise, and marrow progenitor cell survival,