IMMUNOLOGICAL ASPECTS OF HEMORRHAGE

DESCRIPTION (provided by applicant): A major feature of trauma is immune depression. Studies demonstrate immune depression is severe in aged and ovariectomized (OVX) females and adult males, as opposed to maintained immune functions in proestrus females, after trauma-hemorrhage and resuscitation (T-H). Administration of 17beta-estradiol (E2) in OVX females and males, or prolactin or steroid enzyme activity modulators (SEAM) in males after T-H restores immune functions. Moreover, survival rate of proestrus females subjected to sepsis after T-H is significantly higher than age-matched males or OVX females. Studies also show that increased 5alpha-dihydrotestosterone synthesis in T cells is the likely cause for immune depression in males, while continued E2 synthesis maintains immune functions in proestrus females, following T-H. Similarly, hypoxemia also causes immune depression in mice. Recent studies show that in males, (a) pattern recognition receptors TREM 1, 2 and 3 are expressed in CD11b+ macrophages from bone marrow, PBMC, spleen and liver, in the absence of LPS stimulation, and their expressions are enhanced following T-H, and (b) there is a Th1 to Th2 shift in T cell cytokine release following T-H, implying that the depression in immune function may be due phenotypic changes in MPh and T cells. Since immune response following T-H is gender-dimorphic, phenotypic changes occurring in the immune cells early following T-H may be different in males and proestrus females. Therefore, the hypothesis is that the sex steroid hormonal milieu prevailing at the time of injury induces phenotypic changes in macrophages and T cells whose altered functions, evidenced in the release of mediators, lead to either depression or maintenance of immune functions after T-H. Since macrophages and T cells express receptors for sex steroids, and T cells synthesize active steroids in situ, it is also hypothesized that modulation of immune functions early following T-H with sex steroid receptor-specific antagonists/agonists or SEAM will lead to restoration and maintenance of immune functions and decrease mortality from subsequent sepsis in both genders. The specific aims are to: characterize phenotypic changes in macrophages and dendritic and T cells in the inflammatory microenvironment early following T-H; delineate the mechanism(s) for the release of inflammatory mediators by immune and endothelial cells; determine the contribution of hypophysis-pituitary-adrenal-gonad axis to immune depression; and evaluate the effects of steroidogenic enzyme and sex steroid receptor-specific modulators for restoring immune functions in males and estrus cycle-specific females after T-H or hypoxemia. Detailed analysis of phenotypic changes in immune cells and understanding their functions in T-H induced milieu, using recent cellular/molecular biological techniques, delineating sex steroid immune functions and assessing how they can be modulated by exogenous steroidal/ nonsteroidal modulators to improve immune responses should lead to innovative approaches for preventing immune depression and reducing mortality from sepsis in trauma victims with low E2 levels.

DESCRIPTION (provided by applicant): A major feature of trauma is immune depression. Studies demonstrate immune depression is severe in aged and ovariectomized (OVX) females and adult males, as opposed to maintained immune functions in proestrus females, after trauma-hemorrhage and resuscitation (T-H). Administration of 17beta-estradiol (E2) in OVX females and males, or prolactin or steroid enzyme activity modulators (SEAM) in males after T-H restores immune functions. Moreover, survival rate of proestrus females subjected to sepsis after T-H is significantly higher than age-matched males or OVX females. Studies also show that increased 5alpha-dihydrotestosterone synthesis in T cells is the likely cause for immune depression in males, while continued E2 synthesis maintains immune functions in proestrus females, following T-H. Similarly, hypoxemia also causes immune depression in mice. Recent studies show that in males, (a) pattern recognition receptors TREM 1, 2 and 3 are expressed in CD11b+ macrophages from bone marrow, PBMC, spleen and liver, in the absence of LPS stimulation, and their expressions are enhanced following T-H, and (b) there is a Th1 to Th2 shift in T cell cytokine release following T-H, implying that the depression in immune function may be due phenotypic changes in MPh and T cells. Since immune response following T-H is gender-dimorphic, phenotypic changes occurring in the immune cells early following T-H may be different in males and proestrus females. Therefore, the hypothesis is that the sex steroid hormonal milieu prevailing at the time of injury induces phenotypic changes in macrophages and T cells whose altered functions, evidenced in the release of mediators, lead to either depression or maintenance of immune functions after T-H. Since macrophages and T cells express receptors for sex steroids, and T cells synthesize active steroids in situ, it is also hypothesized that modulation of immune functions early following T-H with sex steroid receptor-specific antagonists/agonists or SEAM will lead to restoration and maintenance of immune functions and decrease mortality from subsequent sepsis in both genders. The specific aims are to: characterize phenotypic changes in macrophages and dendritic and T cells in the inflammatory microenvironment early following T-H; delineate the mechanism(s) for the release of inflammatory mediators by immune and endothelial cells; determine the contribution of hypophysis-pituitary-adrenal-gonad axis to immune depression; and evaluate the effects of steroidogenic enzyme and sex steroid receptor-specific modulators for restoring immune functions in males and estrus cycle-specific females after T-H or hypoxemia. Detailed analysis of phenotypic changes in immune cells and understanding their functions in T-H induced milieu, using recent cellular/molecular biological techniques, delineating sex steroid immune functions and assessing how they can be modulated by exogenous steroidal/ nonsteroidal modulators to improve immune responses should lead to innovative approaches for preventing immune depression and reducing mortality from sepsis in trauma victims with low E2 levels.