Erythrocyte Part 2

Question 1

is the term describing the dynamics of RBC production and destruction.

Answer 1

Erythrokinetics

Question 2

To understand erythrokinetics, it is helpful to appreciate the concept of the ______.

_____is the name given to the collection of all stages of erythrocytes throughout the body: the developing precursors in the bone marrow and the circulating erythrocytes in the peripheral blood and vascular spaces within organs, such as the spleen.

Answer 2

Erythron

Question 3

When the term______ is used, it conveys the concept of a unified functional tissue.

It is distinguished from the______

Answer 3

erythron

RBC mass

Question 4

The_______ is the entirety of erythroid cells in the body, whereas the_____ refers only to the cells in circulation.

Answer 4

erythron

RBC mass

Question 5

The primary oxygen-sensing system of the body is located in ________

Hypoxia, too little tissue oxygen, is detected by it, which then produce_______, the major stimulatory cytokine for RBCs.

Answer 5

peritubular fibroblasts of the kidney.

erythropoietin (EPO)

Question 6

Under normal circumstances, the amount of EPO produced______ very little, maintaining a level of RBC production that is sufficient to replace the approximately_____ of RBCs that normally die each day (discussed in section on erythrocyte destruction).

When there is______, increased RBC destruction, or other factors that diminish the oxygen-carrying capacity of the blood, the production of EPO is increased.

Answer 6

fluctuates

1%

hemorrhage

Question 7

Increased EPO production, caused by hypoxia, is regulated by a family of transcription factor proteins, called__________.

It respond to hypoxia by binding to kidney hypoxia responsive elements located at the 5’ flanking region of the EPO gene.

This results in increased EPO gene transcription, EPO production, and ultimately increased RBC production

Answer 7

hypoxia-inducible factors (HIFs)

Question 8

Erythropoietin Structure.

EPO is a thermostable, nondialyzable, glycoprotein hormone with a molecular weight of______.

It consists of a______ unit and a terminal ______unit, both of which play a role in the biologic activity of the hormone.

Answer 8

34 kD

carbohydrate

sialic acid

Question 9

EPO

It is a growth factor (or cytokine) that initiates an intracellular message to the developing erythroid cells; this process is called_______

Answer 9

signal transduction

Question 10

EPO (the ligand) must bind to its receptor (EPOR) on the surface of__________ to initiate the signal or message.

The interaction of EPO with its receptor initiates a cascade of intracellular events that ultimately leads to increased cell division and matu-ration, increased intestinal iron absorption and hemoglobin synthesis, and more RBCs entering the circulation.

Answer 10

EPO-responsive immature erythroid cells

Question 11

The_______ is the body’s hypoxia sensor and provides early detection when oxygen levels decline.

Regardless of the cause of the hypoxia (e.g., decreased RBC number, defective hemoglobin, poor lung function), stimulation of RBC production is warranted because the number of RBCs present are not meeting the oxygen need.

Answer 11

kidney

Question 12

The physiologic response to hypoxia is regulated by ________ that result in gene expression changes, which ultimately lead to promotion of erythropoiesis.

They are a family of proteins that are continually produced and degraded in non-hypoxic condi-tions.

Fundamentally, in hypoxic conditions, the proteins build up and activate the transcription of genes that will promote adaptation to the hypoxic condition.

This promotion of erythropoiesis, regulated by it, includes increased production of renal erythropoietin (EPO), enhanced iron uptake and intestinal absorption, and stimulation of erythroid progenitor maturation and proliferation.

Answer 12

hypoxia-inducible factors (HIFs)

Question 13

Erythropoietin binds to its receptors on erythroid progenitors and early precursors, ultimately increasing the production of RBCs by:

Answer 13

(1) allowing early release of reticulocytes from the bone marrow,

(2) preventing apoptotic cell death, and

(3) reducing the time needed for cells to mature in the bone marrow.

Question 14

In severe anemia, EPO production can be increased by up to_______-fold.

Answer 14

1000

Question 15

A physiologic adaptation to hypoxia occurs in the fetus and newborn as a result of the predominance of_______, which has a higher affinity for oxygen and less readily releases oxygen to the tissues compared with adult hemoglobin A.

To compensate for this hypoxia, more RBCs are produced, mediated by the action of erythropoietin.

Answer 15

hemoglobin F

Question 16

T or F

normal newborn has a relatively higher concentration of RBCs and hemoglobin compared with most adults.

Answer 16

True

Question 17

The binding of EPO to the________ (on erythrocyte progenitors and early precursors) results in a change in the conformation of the receptor.

This activates_______ signal transducers that are associated with the cytoplasmic domains of the EPO receptor.

Answer 17

extracellular domain of the EPO receptor

Janus-activated tyrosine kinase 2 (JAK2)

Question 18

JAK2 then activates downstream signal transduction pathways (such as the signal transduction and activator of transcription 5 or STAT5 pathway) that ultimately promotes________ of specific genes in the RBC nucleus

Answer 18

transcription

Question 19

EPO has three major effects:

Answer 19

(1) allowing early release of reticulocytes from the bone marrow,

(2) preventing apoptotic cell death, and

(3) reducing the time needed for cells to mature in the bone mar-row.

Question 20

Early release of reticulocytes.

EPO promotes early release of developing erythroid precursors from the bone marrow by two mechanisms.

EPO induces changes in the_____ layer of the bone marrow/sinus barrier that increase the width of the spaces for RBC egress into the sinus. This mechanism alone, however, is insufficient for cells to leave the marrow.

RBCs are held in the marrow because they express surface membrane receptors for adhesive molecules located on the bone marrow stroma, such as______.

EPO downregulates the expression of these receptors so that cells can exit the marrow earlier than they normally would.

Answer 20

adventitial cell

fibronectin

Question 21

The result is the presence in the circulation of reticulocytes that are still very basophilic because they have not spent as much time degrading their ribosomes and RNA or making hemoglobin as they normally would before entering the bloodstream.

These are called ________because they have been shifted from the bone marrow early

Their bluish cytoplasm with Wright stain is evident, so the overall blood picture is said to have_________.

Answer 21

shift reticulocytes

polychromasia

Question 22

Inhibition of apoptosis.

A second, and probably more im-portant, mechanism by which EPO increases the number of circulating RBCs is by increasing the number of cells that will be able to mature into circulating erythrocytes.

It does this by_______, the programmed death of_______.

Answer 22

decreasing apoptosis

RBC progenitors

Question 23

Apoptosis: programmed cell death.

As noted previously, it takes about______ days to produce an RBC from stimulation of the earliest erythroid progenitor (BFU-E) to release from the bone marrow.

In times of increased need for RBCs, such as when there is loss from the circulation during hemorrhage, this time lag would be a significant problem.

One way to prepare for such a need would be to maintain a store of mature RBCs in the body for emergencies.

RBCs cannot be stored in the body for this sort of eventuality, however, because they have a limited life span.

Therefore instead of storing mature cells for emergencies, the body produces more______ than needed at all times.

When there is a steady-state demand for RBCs, the extra progenitors are allowed to die.

When there is an increased demand for RBCs, however, the erythroid progenitors have about an ______day head start in the production process.

This process of intentional wastage of cells occurs by apoptosis, and it is part of the cell’s genetic program.

Answer 23

18 to 21

CFU-Es

8- to 10-

Question 24

_________ is a sequential process characterized by, among other things, the degradation of chromatin into fragments of varying size that are multiples of 180 to 185 base pairs long; protein clustering; and activation of transgluta-mase.

This is in contrast to_______, in which cell injury causes swelling and lysing with release of cytoplasmic contents that stimulate an inflammatory response.

_______is not associated with inflammation.

Answer 24

Apoptosis

necrosis

Apoptosis

Question 25

During the sequential process of apoptosis, the following morphologic changes can be seen:

Answer 25

condensation of the nucleus, causing increased basophilic staining of the chromatin;

nucleolar disintegration;

shrinkage of cell volume with concomitant increase in cell density and compaction of cytoplasmic organ-elles, whereas mitochondria remain normal

Question 26

The last stage of degradation produces______ consisting of multimers of 180 to 185 base pair segments.

Characteristic_____ of the plasma membrane is observed.

The apoptotic cell contents remain membrane bound and are ingested by macrophages, which prevents an inflammatory reaction.

The membrane-bound vesicles display so-called eat me signals on the membrane surface, which promote macrophage ingestion.

Answer 26

nuclear DNA fragments

blebbing

Question 27

Thus under normal circumstances, many erythroid progenitors will undergo_______.

However, when increased numbers of RBCs are needed, apoptosis can be avoided.

One effect of EPO is an indirect avoidance of apoptosis by removing an apoptosis induction signal.

Apoptosis of erythroid precursors and progenitors is a cellular process that depends on a signal from either the inside or outside of the cell.

Answer 27

apoptosis

Question 28

Among the crucial molecules in the external messaging system is the death receptor_______ on the membrane of the earliest erythroid precursors, whereas its ligand,_____, is expressed by more mature erythroid precursors.

Answer 28

Fas

FasL

Question 29

When EPO levels are low, cell production should be at a low rate because hypoxia is not present. The excess early erythroid precursors should undergo apoptosis.

This occurs when the older FasL-bearing erythroid precursors, such as________, cross-link with Fas-marked immature erythroid pre-cursors, such as_______ and_______, which are then stimulated to undergo apoptosis.

Answer 29

polychromatic normoblasts

pronormoblasts and basophilic normoblasts

Question 30

As long as the more mature erythroid precursors with FasL are present in the marrow,_________ is subdued.

If the FasL-bearing cells are depleted, as when EPO stimulates early bone marrow release, the younger Fas-positive precursors are allowed to develop, which increases the overall output of RBCs from the marrow.

Thus early release of older precursors in response to EPO indirectly allows more of the younger precursors to mature.

Answer 30

erythropoiesis

Question 31

A second mechanism for escaping apoptosis exists for erythroid progenitors:

direct EPO rescue from apoptosis.

This is the major way in which EPO is able to increase RBC production.

When EPO binds to its receptor on the CFU-E, one of the effects is to reduce production of______.

Thus the younger cells avoid the apoptotic signal from the older cells.

Additionally, EPO is able to stimulate production of various antiapoptotic molecules, which allows the cell to survive and mature.

Answer 31

Fas ligand

Question 32

The cell that has the most EPO receptors and is most sensitive to EPO rescue is the_______, although the late BFU-E and early pronormoblast have some receptors.

Without EPO, the_____ does not survive.

Answer 32

CFU-E

CFU-E

Question 33

binding of EPO to its transmembrane receptors on erythroid progenitors and precursors activates_____ protein associated with its cytoplasmic domain.

Activated JAK2 then phosphorylates (activates) the______ pathway, leading to the production of the antiapop-totic molecule_____ (now called Bcl-2-like protein 1).

EPO-stimulated cells develop this molecule on their mitochondrial membranes, preventing release of_______, an apoptosis initiator.

EPO’s effect is mediated by the transcription factor,_____, which is essential to red cell survival.

Answer 33

JAK2

STAT5

Bcl-XL

cytochrome c

GATA1

Question 34

Reduced marrow transit time.

Apoptosis rescue is the major way in which EPO increases RBC mass, that is by increasing the number of erythroid cells that survive and mature to enter the circulation.

Another effect of EPO is to increase the rate at which the surviving precursors can_________.

This is accomplished by two means:

Answer 34

enter the circulation

increased rate of cellular processes
decreased cell cycle times