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Even following successful resuscitation and
stabilization, a significant percentage of patients with
severe trauma or burns develop complications related to
infection. Further, it is generally accepted that this
increased risk of infection following major injury, is
related to dysfunction of host defense mechanisms.
A variety of factors certainly contribute to injury-induced
immune dysfunction. These include, primary cellular defects,
inadequate nutrition, shunting of metabolic energies to
maintain blood glucose and to initiate wound healing, and
release of endogenous immunosuppressive substances (wound
toxins, cytokines, and hormones).
It has been known for many years that glucocorticoids have
potent immunosuppressive effects on the immune system. In
spite of this fact, relative little work has been done
concerning the involvement of these hormones in
injury-induced immune dysfunction other than to establish
that these stress hormones are, not surprisingly, elevated
after injury. Therefore, my research has concentrated on the
role of glucocorticoids as mediators of post-injury immune
disorders.
My collaborators and I have been investigating
glucocorticoid-immune system interactions in several
different settings, 1) trauma patients in the surgical
intensive care unit, 2) human volunteers subjected to
hormonal manipulations, and 3) human volunteers administered
low doses of endotoxin.
Recently, and with the other investigators of the NIGMS-funded
large scale collaborative project entitled "Inflammation and
the Host Response to Injury" we have been evaluating the
genomic response to systemic inflammation in human
volunteers administered low doses of endotoxin. Our own
studies have followed a similar paradigm but with antecedent
treatment with counterregulatory hormones including
epinephrine and hydrocortisone. With microarray technology,
we have successfully been able to assess genome-wide changes
in blood leukocyte gene expression patterns after endotoxin
administration to human volunteers with or without
antecedent counter-regulatory hormone treatment. Most
recently, we have extended these studies to evaluation of
purified subsets of leukocytes including T-lymphocytes,
monocytes and neutrophils. Using the data so generated, we
are using network (Ingenuity) and canonical pathway (KEGG)
analyses to map the human response to endotoxin, a
prototypical inflammatory stimulus. Because inflammation can
play a pivotal beneficial or detrimental role in the
response to injury, and has recently been strongly linked to
progression of neoplastic disease, such studies have the
potential to provide novel directions for development of
intervention strategies in many different diseases. |
