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Alicia M. Mohr, MD, is a volunteer faculty member
in the Department of Surgery at UMDNJ-New Jersey
Medical School (NJMS). |
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Adrenergic Modulation
of Erythropoiesis Following Trauma
by By
Alicia M. Mohr, MD 
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In research conducted in the Division of Trauma at
UMDNJUniversity Hospital’s trauma center, I have
pursued a separate line of investigation on erythropoietic
dysfunction following severe injury. Erythropoiesis
and the formation of red blood cells is a complex process
involving bone marrow stem cells, progenitor cells,
and stromal cells. Severe traumatic injury is a stress
state, commonly associated with a “fight or flight
response.” During this time, the stress hormones
epinephrine and norepinephrine are released and bind
to adrenergic receptors. It is the impact of this stress
or “adrenergic state” on erythropoiesis
and its subsequent dysfunction that is the focus of
my research.
Persistent anemia is a common occurrence in critically
injured patients and multiple transfusions are frequently
needed. Anemia has associated adverse effects and the
safety of transfusions is uncertain. An understanding
of the pathophysiology of anemia in the intensive care
unit (ICU) patient facilitates selection of an optimal
treatment strategy. Adrenergic modulation of erythropoiesis
is known to occur under normal conditions and typically
red blood cell growth is enhanced. Yet, following traumatic
injury, red blood cell growth is suppressed and the
presence of anemia is persistent. Adrenergic stimulation
is known to accompany traumatic injury but there is
no information on its effects on bone marrow during
trauma. We hypothesize that since adrenergic stimulation
occurs with trauma, the anemia associated with injury
may be related to the cells’ altered ability to
proliferate and differentiate into red blood cells.
This response is due to either the magnitude or the
persistence of adrenergic stimulation that occurs with
injury. If true, an investigation of the contributions
of bone marrow stroma and the mediators involved in
altered erythropoiesis after injury, as well as the
use of adrenergic antagonists, may produce important
advances in trauma care by suggesting a clinical approach
to anemia that could diminish its current morbidity.
My work regarding the adrenergic modulation of erythropoiesis
following trauma is an extension of the research that
I began in the laboratory of David Livingston, MD. That
research provided the groundwork and background for
my current studies. Knowing that persistent anemia follows
severe injury, and that the defect lies in the bone
marrow rather than in peripheral blood, allows us to
analyze the specific impact of the stress state on bone
marrow erythropoiesis. My initial studies have focused
on hormonally replicating in vitro the stress state
using normal bone marrow. We are also expanding our
study to include trauma patients admitted to the Surgical
Trauma ICU at UMDNJ-University Hospital.
In one of our studies, we have demonstrated that urine
norepinephrine levels from critically injured patients
are significantly elevated as compared to a control
group (Figure 1). The initial elevation of norepinephrine
immediately following injury is six times that of normal
levels. This super-stimulated state lasts for seven
to 10 days following severe injury. Epinephrine levels
are also elevated but return to baseline levels more
quickly.
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Figure 1. Mean urine norepinephrine
levels (ug/day) are significantly increased in critically
ill patients compared to normal controls from the
date of admission up to day 10 post injury. |
Adrenergic agonists, epinephrine, norepinephrine and
isoproterenol, were added to bone marrow cultures in
vitro to assess their effect on erythropoietic progenitors,
specifically erythroid burst forming units (BFU-E) and
erythroid colony forming units (CFU-E). These adrenegic
agonists induced proliferation of BFU-E and CFU-E, which
were grown in the presence of bone marrow stroma. All
three adrenergic agents exerted their highest stimulatory
effect at lower doses. At the highest concentration,
most colony numbers dropped considerably, suggesting
that the adrenergic effect is dose-related. In our studies,
BFU-E colonies had a significantly higher response than
did CFU-E to adrenergic agonists. This differential
effect to catecholamine stimulation may be a hierarchical
response resulting from the adrenergic effect on the
terminal maturation at the BFU-E stage, which precedes
CFU-E in the erythropoietic maturation scheme. To determine
if the bone marrow stroma is essential for this proliferative
process associated with adrenergic stimulation, bone
marrow stroma was depleted. When these same adrenergic
agonists are added to bone marrow cultures of BFU-E
and CFU-E lacking bone marrow stroma, the proliferative
effect is abrogated (Figure 2).
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Figure 2. BFU-E colonies grown
with the addition of norepinephrine, epinephrine,
isoproterenol in cultures with the presence of stroma
(+ stroma) vs. stroma-depleted bone marrow (- stroma). |
Thus far, we have shown that there is a significant
and persistent hypercatecholamine state after severe
injury. Our in vitro analyses support the notion that
erythropoiesis is also modulated by the adrenergic system.
Our research discovered a dichotomy. On one hand there
is a hypercatecholamine period after severe injury that
is characterized by overt bone marrow dysfunction, seen
as anemia and leucopenia. Yet, on the other hand, our
data shows that the addition of adrenergic agents to
erythroid precursors in vitro leads to an overwhelming
pro-erythropoietic stimulus. Future studies will focus
on the mechanisms that account for the paradox of adrenergic
stimulation observed in trauma patients as opposed to
the in vitro effects on bone marrow cultures.
There may be a direct correlation between the magnitude
and duration of the stress response seen following injury
and resultant erythropoietic dysfunction. Perhaps with
the use of adrenergic antagonists, the adrenergic modulation
of erythropoiesis may be altered.
Alicia M. Mohr, MD, is a volunteer faculty member
in the Department of Surgery at UMDNJ-New Jersey Medical
School (NJMS). Dr. Mohr graduated from NJMS and completed
her surgical residency training at UMDNJ-University
Hospital. After completing a fellowship in trauma/critical
care surgery at the University of North Carolina, she
returned to join the faculty of the medical school in
2000. Dr. Mohr recently received the Wyeth Research
Scholarship from the Eastern Association for the Surgery
of Trauma for her research entitled Adrenergic Modulation
Of Erythropoiesis Following Severe Injury
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