An Autoimmune Basis for Pulmonary Hypertension

描述(由申请人提供)：这个项目是一个修订的，竞争性更新的R01申请，重点是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有关。调节性T细胞(Tregs)通常通过几种抗炎机制，包括诱导抗炎巨噬细胞，促进损伤的消退，从而发挥保护作用。当Treg功能受损时，就像在许多PH相关的条件下一样，损伤演变发生在过度活跃的炎症反应中，尤其是血管周围M1巨噬细胞被激活。因此，当使用野百合碱或血管内皮生长因子受体2拮抗剂治疗时，缺乏包括Tregs在内的所有T细胞群的无菌大鼠会出现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Tregs，就可以防止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早期涌入。肺中IL-10+Tregs的渗入与抗炎巨噬细胞的增加有关，抗炎巨噬细胞分泌免疫调节蛋白血红素加氧酶1(HO-1)。IL-10是已知的HO-1诱导剂，可能是促进抗炎Mox(HO-1+)巨噬细胞产生的Treg来源的关键介质。在未重建的无性系大鼠中，这些Tregs的缺失导致了显著的炎症反应，并伴有明显的M1巨噬细胞浸润，类似于临床上的PH。活化的巨噬细胞在实验性和临床性PH中强烈表达白三烯、LTB4，它介导了肺动脉内皮细胞(PAEC)的凋亡和PA平滑肌细胞(PASMC)的增殖和肥大。抑制巨噬细胞来源的LTB4的生物合成或阻断LTB4受体BLT1可以防止PAEC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-内皮型一氧化氮合酶(ENOS)生存通路介导PAEC的凋亡。具体目标1将确定肺血管损伤的解决与抗炎巨噬细胞的诱导是否需要IL-10依赖的Treg活性。具体目标2将是确定巨噬细胞来源的LTB4如何介导与PH相关的血管损伤演变。这一目的将决定LTB4是否通过核因子？B抑制内皮细胞促生存信号Smad/BMPR2。此外，这一目的还将检测巨噬细胞来源的LTB4是否通过P53阻断内皮细胞Sphk1-eNOS生存信号。最后，AIM 2将评估巨噬细胞来源的LTB4是否以BLT1依赖的方式诱导PASMC增殖、肥大、迁移和存活。LTB4拮抗剂可能是治疗部分伴有免疫紊乱的PH患者的一种高效治疗方法。该项目将有关肺免疫的不断发展的概念与血管生物学相结合，以更好地了解免疫反应如何对健康和疾病做出贡献。

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.