An Autoimmune Basis for Pulmonary Hypertension

描述（由申请人提供）：该项目是一项修订的竞争性更新R 01申请，重点关注免疫失调对肺动脉高压（PH）的贡献。PH是一种严重的疾病，经常与自身免疫性疾病和血管周围炎症相关。调节性T细胞（Tcells）通常通过几种抗炎机制（包括诱导抗炎巨噬细胞）促进损伤消退来发挥保护功能。当Treg功能受损时，正如在许多PH相关疾病中一样，损伤演变伴随过度旺盛的炎症反应发生，特别是活化的血管周围M1巨噬细胞。因此，当用野百合碱或用血管内皮生长因子受体2拮抗剂治疗时，缺乏所有T细胞群（包括TcB）的无胸腺大鼠发生严重的血管周围炎症和PH。在这些动物中，如果通过免疫重建恢复Tcl 3，则PH被预防;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Tcl 3的早期流入。肺中的IL-10+ T细胞浸润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。在非重建的无胸腺大鼠中这些Tcl 3的缺乏导致显著的炎症反应，具有显著的M1巨噬细胞浸润，类似于临床PH。在实验和临床PH中活化的巨噬细胞强烈表达白三烯，LTB 4，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。抑制巨噬细胞来源的LTB 4生物合成或阻断LTB 4受体BLT 1可防止PAEC凋亡，这是PH发病机制中的关键早期事件。因此，全身、口服或吸入的LTB 4拮抗剂不仅可以预防PH，而且可以逆转晚期疾病。LTB 4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将是确定与抗炎巨噬细胞的诱导相关的肺血管损伤消退是否需要IL-10依赖性Treg活性。具体目标2将是确定巨噬细胞衍生的LTB 4如何介导PH相关的血管损伤演变。这一目标将确定LTB 4是否通过NF抑制内皮促存活Smad/BMPR 2信号传导？B。此外，这一目标将测试巨噬细胞衍生的LTB 4是否通过p53阻断内皮Sphk 1-eNOS存活信号传导。最后，目标2将评估巨噬细胞来源的LTB 4是否以BLT 1依赖的方式诱导PASMC增殖、肥大、迁移和存活。LTB 4拮抗剂可能是一种非常有效的治疗PH患者的免疫失调的子集。该项目将肺免疫的概念与血管生物学相结合，以更好地了解免疫反应如何促进健康和疾病。

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.