Abstract
BackgroundHemorrhagic shock results in systemic activation of the immune system and leads to ischemia-reperfusion injury. Lymphocytes have been identified as critical mediators of the early innate immune response to ischemia-reperfusion injury, and immunomodulation of lymphocytes may prevent secondary immunologic injury in surgical and trauma patients.MethodsYorkshire swine were anesthetized and underwent a grade III liver injury with uncontrolled hemorrhage to induce hemorrhagic shock. Experimental groups were treated with a lymphocyte depletional agent, porcine polyclonal anti-thymocyte globulin (PATG) (n = 8) and compared to a vehicle control group (n = 9). Animals were observed over a 3 day survival period. Circulating lymphocytes were examined with FACS analysis for CD3/CD4/CD8, and central lymphocytes with mesenteric lymph node and spleen staining for CD3. Circulating and lung tissue16 infiltrating neutrophils were measured. Circulating CD3 lymphocytes in the blood and in central lymphoid organs (spleen/lymph node) were stained and evaluated using FACS analysis. Immune-related gene expression from liver tissue was quantified using RT-PCR.ResultsThe overall survival was 22% (2/9) in the control and 75% (6/8) in the PATG groups, p = 0.09; during the reperfusion period (following hemorrhage) survival was 25% (2/8) in the control and 100% (6/6) in the PATG groups, p = 0.008. Mean blood loss and hemodynamic profiles were not significantly different between the experimental and control groups. Circulating CD3+CD4+ lymphocytes were significantly depleted in the PATG group compared to control. Lymphocyte depletion in the setting of hemorrhagic shock also significantly decreased circulating and lung tissue infiltrating neutrophils, and decreased expression of liver ischemia gene expression.ConclusionsLymphocyte manipulation with a depletional (PATG) strategy improves reperfusion survival in experimental hemorrhagic shock using a porcine liver injury model. This proof of principle study paves the way for further development of immunomodulation approaches to ameliorate secondary immune injury following hemorrhagic shock.
Highlights
Hemorrhagic shock results in systemic activation of the immune system and leads to ischemia-reperfusion injury
The role of T lymphocytes as critical cellular mediators of the innate immune response to ischemia-reperfusion injury (IRI) has been corroborated in multiple IRI models [10,11,12,13,14]
We developed a porcine specific Antithymocyte globulin (ATG) in order to determine if lymphocyte depletion improves survival following experimental hemorrhagic shock
Summary
Hemorrhagic shock results in systemic activation of the immune system and leads to ischemia-reperfusion injury. In two clinical trials testing humanized CD18 monoclonal antibodies in the setting of traumatic injury, mortality and other primary end points were not significantly affected [4,5]. These failures are likely the result of the redundancy of adhesion pathways, and suggest that the neutrophil is not central in the innate immune response to IRI. Mice deficient in CD4+ and CD8+ lymphocytes demonstrated less tissue neutrophil infiltration, suggesting that lymphocytes orchestrate cell-mediated innate responses to ischemia These studies demonstrate a novel, innate function of lymphocytes in the setting of ischemic injury. Thereby, immunomodulation of lymphocytes may offer a novel approach to attenuate detrimental immune responses to severe traumatic injury
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