Trauma Immunopathology Research Laboratory
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
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
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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