Neuropeptides, Immunity, and Lung Injury

描述（由申请人提供）： 我们的总体假设是BLP是BPD肺损伤、肺泡化受阻和免疫缺陷的早期介质。患有BPD的婴儿出生后不久尿BLP水平升高。BLP可介导肺损伤：抗BLP阻断抗体2A11在两种狒狒模型中均保护BPD。我们正在探索这种情况发生的机制，特别是促炎级联反应。我们最近的数据表明，免疫缺陷可能有助于BPD：2A11治疗消除胸腺皮质退化，并增加胸腺护士细胞，其功能是对自身反应性T细胞的负选择。我们将使用五个特定目的来检验我们的假设：目的1：确定2A11在125天/PRN × 21天BPD模型中的最佳剂量方案和剂量反应。我们将2A11与人源化抗蛙皮素抗体进行比较。目标2：在BPD的125 d/PRN模型中，使用最佳剂量和治疗方案，确定给予抗BLP抗体后6个月的长期结局。目标3：分析狒狒肺、脾和胸腺免疫系统的正常个体发育，包括先天性和获得性免疫[巨噬细胞/树突状细胞（M/DC）、内皮细胞和T细胞。功能测定可包括细胞增殖、凋亡、细胞分化标志物的表达、细胞因子产生、趋化性、呼吸爆发、吞噬作用和体外抗原呈递。我们还将评估三种BLP受体和所示其他标志物的RNA水平。目的4：检验125 d/PRN狒狒免疫缺陷的假设，这有助于BPD，2A11消除这种免疫缺陷。我们将在免疫缺陷小鼠（scid-boon）体内建立功能性狒狒免疫系统：将在宿主小鼠+BLP、2A11、抗氧化剂或其他BPD干预措施中测试狒狒免疫力。在AIM 5中，我们将确定是否可以实现更大的治疗效果，使用治疗的组合，显示单独改善BPD：2A11，抗氧化剂模拟物和一氧化氮（NO）的125天/PRN模型的结果。我们还计划进行合作研究，以确定2A11恢复发育中肺微血管形成的机制。这项调查应进一步澄清BPD的潜在细胞缺陷，并允许引入新的多模态治疗。

DESCRIPTION (provided by applicant): Our overall hypothesis is that BLP is an early mediator of lung injury, arrested alveolarization and immunodeficiency in BPD. Urine BLP levels are elevated shortly after birth in infants who develop BPD. BLP can mediate lung injury: anti-BLP blocking antibody 2A11 protects against BPD in both baboon models. We are exploring the mechanisms by which this occurs, especially pro-inflammatory cascades. Our recent data suggest that immunodeficiency might contribute to BPD: 2A11 treatment abrogates thymic cortical involution and increases thymic nurse cells, which function in negative selection against self-reactive T cells. We will test our hypothesis using five Specific Aims: AIM 1: To determine the optimal dosage schedule and dose-response for 2A11 in the 125d/PRN x 21 days model of BPD. We will compare 2A11 to a humanized antibombesin antibody. AIM 2: To determine long-term outcomes at 6 months after giving anti-BLP antibodies in the 125d/PRN model of BPD using the optimal dose and treatment schedule. AIM 3: To analyze normal ontogeny of the baboon immune system in lung, spleen and thymus, including both innate and acquired immunity [macrophage/dendritic cells (M/DC), endothelial cells, and T cells. Functional assays may include cell proliferation, apoptosis, expression of cell differentiation markers, cytokine production, chemotaxis, respiratory burst, phagocytosis and antigen presentation in vitro. We will also assess RNA levels for the three BLP receptors and other markers as indicated. AIM 4: To test the hypotheses that 125d/PRN baboons are immunodeficient, that this contributes to BPD, and that 2A11 abrogates this immunodeficiency. We will establish functional baboon immune systems in vivo in immunodeficient mice (scid-boon): Baboon immunity will be tested in the host mice + BLP, 2A11, antioxidants, or other interventions for BPD. In AIM 5 we will determine whether greater therapeutic efficacy can be achieved using combinations of treatments shown to individually improve outcomes in the 125d/PRN model of BPD: 2A11, antioxidant mimetics, and nitric oxide (NO). We also plan collaborative studies to determine mechanisms by which 2A11 restores microvasculature formation in developing lung. This investigation should further clarify underlying cellular defects in BPD and permit the introduction of novel multi-modality treatments.