Trauma Immunopathology Research Laboratory
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Research
γδ T-Cells and the Response to Traumatic Injury
Complications induced by major burn injury include immunosuppression,
increased septic complications and delayed wound healing. While
improvements in burn patient care have been made, the vast majority of
problems which develop for burn patients are associated with the healing
process. Wound healing is a complex process involving a series of
overlapping phases. However, for efficient tissue repair, it is
essential for inflammatory cells that include neutrophils, macrophages
and T-cells to infiltrate into the damaged tissue and orchestrate the
healing process. In this regard, a unique T-cell population expressing
the γ/δ T-cell receptor (γ/δ T-cells) has been shown to regulate
inflammation and play an important role in wound repair. Gamma/delta
T-cells are also important in the induction inducible nitric oxide
synthase (iNOS) expression and NO production in myeloid cells. Nitric
oxide is important in wound repair, as well as a major mediator of
post-burn immune dysfunction. Findings from our laboratory indicate that
γ/δ T-cells are important in post-burn immunopathology, as they
influence macrophage function and distal organ injury. Recently, we
have also shown that the production of growth factors at the burn site
is influenced by γ/δ T-cells. Thus, a number of common links exist
between γ/δ T-cells, wound repair and post-burn inflammation. Ongoing
studies in the laboratory are directed towards improving our
understanding of this unique T-cell population in the body's response to
traumatic injury.
Impact of Opiate Analgesics on Injury-Induced Immune
Complications
Opiate analgesics (i.e., morphine) are the preferred treatment for the
management of patient pain associated with burn injury, trauma, and
cancer. While opiates have excellent analgesic efficacy, it is also
well established that chronic or therapeutic use of these drugs
compromises a wide range of immune functional parameters.
Opiate-induced suppression in immune function has been demonstrated at
the level of lymphocyte and phagocytic cell functions, development of an
immunosuppressive type-2 cytokine profile and increased susceptibility
to infection. The majority of burn patients receive opiate analgesics
for the treatment of pain associated with the initial injury as well as
post-injury procedures. Since opiates have profound immunomodulatory
effects, it can be speculated that treatment of burn patients with these
drugs might alter immune responses to the injury. Studies have shown
that a sub-set of burn patients that received high levels of opiate
analgesics were more susceptible to infections. Experimental studies
suggest that this may be related to the immunosuppressive properties of
opiates.
Glucose Metabolism and Injury
Traumatic injuries often result in a hypermetabolic state in which
energy expenditure is increased. Hyperglycemia occurring during critical
illness in patients, with no previous history of diabetes, was thought
to be a part of a benign stress response. In addition to
hyperglycemia, this stress response also includes an increase in the
release of amino acids from skeletal muscle and an increase in the
synthesis of specific proteins involved in the acute phase of the
inflammatory response and are important for the repair of injured
tissues The hyperglycemia, sometimes referred to as "stress diabetes",
could be readily explained by insulin deficiency or insulin resistance.
There is now considerable evidence that insulin resistance occurs
following injury. The mechanisms of insulin resistance that develop
rapidly in trauma and infection are poorly understood, but appear to be
in part related to the pro-inflammatory response following injury. Thus,
an important link between post-injury hypermetabolism and the immune
system may exist.
Interactions between Coagulation and Inflammation Following
Trauma
Perturbations in the clotting system are often associated with
inflammatory conditions, such as major injury. A wide range of
inflammatory signals responsible for the induction of the humoral
(cytokines, chemokines) and cellular (neutrophils, monocytes, T-cells)
immune responses are also pro-coagulant in nature. These signals
include cytokines activated neutrophils and monocytes, and complement
activation. Inflammation in response to tissue injury activates the
clotting system and inhibits endogenous anticoagulants and the
fibrolytic response leading to a pro-coagulant state with deleterious
implications for the patient. Conversely, components of the coagulation
system can upregulate aspects of the innate immune response, which is
central in the early inflammatory response to traumatic injury.
Intravascular thrombin generation is highly inflammatory via the
interaction with specific receptors known as protease-activated
receptors (PARs). Studies have shown that the release of IL-6, a major
post-injury mediator, by T-cells or monocytes can be induced by
activation of PARs. T-cells can also trigger platelet activation,
creating a T-cell recruitment feedback loop and amplification of the
immune response. A further link between immune cells and coagulation
can be shown by the relationship between pro-thrombotic diseases, such
as Behcet syndrome and γ/δ T-cells. One of the goals of the laboratory
is to improve our understanding of the relationship(s) between the
post-injury immune response and coagulation.
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