An Autoimmune Basis for Pulmonary Hypertension

肺动脉高压的自身免疫基础

• 批准号: 8903549
• 负责人: Mark Robert Nicolls
• 金额: $ 38.73万
• 依托单位: PALO ALTO VETERANS INSTIT FOR RESEARCH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8903549
• 关键词: Adenoviruses; Alveolar; Anabolism; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antigen-Presenting Cells; Apoptosis; Apoptotic; Appearance; Autoimmune Process; Bacteriophages; Biological Markers; Biology; Blood Vessels; Breathing; Cell Proliferation; Cessation of life; Clinical; Coculture Techniques; Coupled; Data; Development; Disease; Disease Progression; Down-Regulation; Eicosanoids; Enzymes; Event; Evolution; GTP-Binding Proteins; Gene Transfer; Generations; Grant; Health; Hypertrophy; Immune; Immune response; Immunity; In Vitro; Infiltration; Inflammation; Inflammation Mediators; Inflammatory Response; Injury; Interleukin-10; LTB4R gene; Leukotriene B4; Leukotriene B4 Receptors; Leukotrienes; Lung; Mediating; Mediator of activation protein; Molecular; Monocrotaline; Nitric Oxide; Nude Rats; Oral; Pathogenesis; Pathway interactions; Patients; Phenotype; Phosphorylation; Play; Population; Protein Dephosphorylation; Proteins; Protocols documentation; Pulmonary Hypertension; Pulmonary artery structure; Pulmonary vessels; Rattus; Regulatory T-Lymphocyte; Research; Resistance; Resolution; Role; SPHK1 enzyme; Serum; Signal Transduction; Smooth Muscle Myocytes; T-Lymphocyte; TP53 gene; Testing; Vascular Endothelial Growth Factor Receptor-2; Work; advanced disease; arteriole; base; bone morphogenetic protein receptors; cytokine; effective therapy; heme oxygenase-1; human NOS3 protein; in vivo; inhibitor/antagonist; interstitial; killings; knock-down; leukotriene A4 hydrolase; lung vascular injury; macrophage; migration; mutant; prevent; pulmonary arterial hypertension; pulmonary artery endothelial cell; receptor; reconstitution; therapeutic target

DESCRIPTION (provided by applicant): This project is a revised, competing renewal R01 application that focuses on the contribution of immune dysregulation to pulmonary arterial hypertension (PH). PH is a serious condition frequently associated with autoimmune conditions and perivascular inflammation. Regulatory T cells (Tregs) normally serve a protective function by promoting injury resolution through several anti-inflammatory mechanisms including the induction of anti-inflammatory macrophages. When Treg function is compromised, as it is in a number of PH-associated conditions, injury evolution occurs with inflammatory responses that are overly exuberant, notably with activated perivascular M1 macrophages. Accordingly, athymic rats which lack all T cell populations, including Tregs, develop severe perivascular inflammation and PH when treated with monocrotaline or with a vascular endothelial growth factor receptor 2 antagonist. PH, in these animals, is prevented if Tregs are restored through immune reconstitution; in these rescued rats, the hallmark of protection is an early influx of Tregs expressing the anti-inflammatory cytokine IL-10. Infiltrating IL-10+ Tregs in the lungs are associated with increased anti-inflammatory macrophages which secrete the immunomodulatory protein heme oxygenase 1 (HO-1). IL-10, a known inducer of HO-1, may be a key Treg-derived mediator promoting the appearance of anti-inflammatory Mox (HO-1+) macrophages. The absence of these Tregs in non-reconstituted athymic rats results in a significant inflammatory response with notable M1 macrophage infiltration, similar to clinical PH. Activated macrophages in experimental and clinical PH strongly express the leukotriene, LTB4, which mediates pulmonary artery endothelial cell (PAEC) apoptosis and PA smooth muscle cell (PASMC) proliferation and hypertrophy. Inhibiting macrophage-derived biosynthesis of LTB4 or blocking the LTB4 receptor, BLT1, prevents PAEC apoptosis, a key early event in PH pathogenesis. Accordingly, systemic, oral or inhaled LTB4 antagonists not only prevent PH but also reverse advanced disease. LTB4 mediates PAEC apoptosis through inhibition of the sphingosine kinase 1-endothelial nitric oxide (eNOS) survival pathway. Specific Aim 1 will be to determine whether pulmonary vascular injury resolution associated with the induction of anti-inflammatory macrophages requires IL-10 dependent Treg activity. Specific Aim 2 will be to determine how macrophage- derived LTB4 mediates PH-relevant vascular injury evolution. This aim will determine whether LTB4 inhibits endothelial pro-survival Smad/BMPR2 signaling through NF?B. Additionally, this aim will test whether macrophage-derived LTB4 blocks endothelial Sphk1-eNOS survival signaling through p53. Finally, Aim 2 will assess whether macrophage-derived LTB4 induces PASMC proliferation, hypertrophy, migration and survival in a BLT1-dependent manner. LTB4 antagonism may be a highly effective therapy for a subset of PH patients with immune dysregulation. This project integrates evolving concepts about pulmonary immunity with vascular biology to provide a better understanding of how the immune response contributes to health and disease.

描述（由申请人提供）：该项目是一项修订后的竞争性更新 R01 申请，重点关注免疫失调对肺动脉高压 (PH) 的影响。 PH 是一种严重疾病，通常与自身免疫性疾病和血管周围炎症相关。调节性 T 细胞 (Treg) 通常通过多种抗炎机制（包括诱导抗炎巨噬细胞）促进损伤消退，从而发挥保护功能。当 Treg 功能受损时，就像在许多 PH 相关病症中一样，损伤演变会伴随过度旺盛的炎症反应，特别是血管周围 M1 巨噬细胞的激活。因此，缺乏所有 T 细胞群（包括 Tregs）的无胸腺大鼠在用野百合碱或血管内皮生长因子受体 2 拮抗剂治疗时会出现严重的血管周围炎症和 PH。如果通过免疫重建恢复 Tregs，则可以预防这些动物的 PH。在这些获救的大鼠中，保护的标志是表达抗炎细胞因子 IL-10 的 Tregs 的早期涌入。肺部浸润的 IL-10+ Tregs 与分泌免疫调节蛋白血红素加氧酶 1 (HO-1) 的抗炎巨噬细胞增加有关。 IL-10 是一种已知的 HO-1 诱导剂，可能是促进抗炎 Mox (HO-1+) 巨噬细胞出现的关键 Treg 衍生介质。未重建的无胸腺大鼠中这些 Tregs 的缺失会导致显着的炎症反应，并伴有显着的 M1 巨噬细胞浸润，与临床 PH 类似。实验和临床 PH 中激活的巨噬细胞强烈表达白三烯 LTB4，其介导肺动脉内皮细胞 (PAEC) 凋亡和 PA 平滑肌细胞 (PASMC) 增殖和肥大。抑制巨噬细胞衍生的 LTB4 生物合成或阻断 LTB4 受体 BLT1，可防止 PAEC 细胞凋亡，这是 PH 发病机制中的一个关键早期事件。因此，全身、口服或吸入 LTB4 拮抗剂不仅可以预防 PH，还可以逆转晚期疾病。 LTB4 通过抑制鞘氨醇激酶 1-内皮一氧化氮 (eNOS) 存活途径介导 PAEC 凋亡。具体目标 1 是确定与抗炎巨噬细胞诱导相关的肺血管损伤的缓解是否需要 IL-10 依赖性 Treg 活性。具体目标 2 是确定巨噬细胞衍生的 LTB4 如何介导 PH 相关血管损伤的演变。该目标将确定 LTB4 是否通过 NF?B 抑制内皮促存活 Smad/BMPR2 信号传导。此外，该目标将测试巨噬细胞衍生的 LTB4 是否通过 p53 阻断内皮 Sphk1-eNOS 存活信号传导。最后，目标 2 将评估巨噬细胞衍生的 LTB4 是否以 BLT1 依赖性方式诱导 PASMC 增殖、肥大、迁移和存活。 LTB4 拮抗剂对于免疫失调的 PH 患者可能是一种高效的治疗方法。该项目将不断发展的肺免疫概念与血管生物学相结合，以更好地了解免疫反应如何影响健康和疾病。