IMMUNOLOGICAL ASPECTS OF HEMORRHAGE

出血的免疫学方面

• 批准号: 7038220
• 负责人: IRSHAD H CHAUDRY
• 金额: $ 46.02万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7038220
• 关键词: Kupffer' s cell; T lymphocyte; biological signal transduction; cellular immunity; cytokine; dendritic cells; dihydrotestosterone; enzyme activity; enzyme linked immunosorbent assay; estradiol; estrogen receptors; estrus; flow cytometry; gel mobility shift assay; hemorrhage; high performance liquid chromatography; hormone regulation /control mechanism; hypothalamic pituitary axis; immunomodulators; laboratory mouse; macrophage; polymerase chain reaction; prolactin; tissue /cell culture; trauma; vascular endothelium; western blottings

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.

描述(由申请人提供)： 创伤的一个主要特征是免疫抑制。研究表明，在老年和卵巢切除(OVX)的女性和成年男性中，免疫抑制是严重的，与动情前期女性在创伤-出血和复苏(T-H)后保持的免疫功能相反。在T-H恢复免疫功能后，在OVX雌性和雄性体内注射17β-雌二醇(E_2)，或在雄性体内应用催乳素或类固醇酶活性调节剂(SEAM)。此外，动情前期雌性动物经T-H后发生脓毒症的存活率显著高于年龄匹配的雄性动物或卵巢切除的雌性动物。研究还表明，T细胞中5α-双氢睾酮合成增加可能是导致男性免疫抑制的原因，而持续的E2合成维持了发情前期女性的免疫功能。同样，低氧血症也会导致小鼠的免疫抑制。最近的研究表明，在男性，(A)在没有内毒素刺激的情况下，骨髓、PBMC、脾和肝脏的CD11b+巨噬细胞表达模式识别受体Trem1、2和3，并在T-H后表达增强；(B)T-H后T细胞细胞因子释放发生Th1向Th2的转变，提示免疫功能的抑制可能是由于MPH和T细胞表型的变化所致。由于T-H后的免疫反应是性别二型性的，T-H后早期免疫细胞的表型变化在雄性和发情前期的雌性中可能是不同的。因此，假设损伤时普遍存在的性类固醇激素环境会诱导巨噬细胞和T细胞的表型变化，这些细胞和T细胞的功能变化表现为介质的释放，导致T-H后免疫功能的抑制或维持。由于巨噬细胞和T细胞表达性激素受体，而T细胞在原位合成活性类固醇，也假设T-H后早期使用性类固醇受体特异性拮抗剂/激动剂或SEAM调节免疫功能将导致免疫功能的恢复和维持，并降低随后发生的脓毒症的死亡率。其具体目的是：表征T-H后早期炎症微环境中巨噬细胞、树突状细胞和T细胞的表型变化；阐明免疫细胞和内皮细胞释放炎症介质的机制(S)；确定垂体-垂体-肾上腺-性腺轴在免疫抑制中的作用；以及评估类固醇生成酶和性类固醇受体特异性调节剂在T-H或低氧后恢复雄性和动情周期特异性雌性动物免疫功能方面的作用。详细分析免疫细胞的表型变化并了解它们在T-H诱导环境中的功能，利用最新的细胞/分子生物学技术，描绘性激素免疫功能，并评估如何通过外源性类固醇/非类固醇调节剂调节它们以改善免疫反应，将有助于在低E2水平的创伤患者中预防免疫抑制和降低脓毒症死亡率的创新方法。