Project 3 of this Program Project Grant application focuses on the consequences of immune dysregulation on pulmonary 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; immune dysregulation occurs when Treg function is compromised. Accordingly, athymic rats, which lack Tregs, develop severe perivascular inflammation and PH when treated with monocrotaline or with a vascular endothelial growth factor receptor 2 (VEGFR2) antagonist. PH, in these animals, is abrogated if Tregs are restored through immune reconstitution (IR) prior to vascular injury. In these rescued rats, the hallmark of protection is an early influx of anti-inflammatory cells, such as Tregs and Mox macrophages, expressing Fox- P3, IL-10 and HO-1. This model is relevant to patients because abnormal Treg function is also observed in conditions associated with clinical PH. In PH associated with immune dysregulation, activated macrophages infiltrate the lungs expressing the leukotriene, LTB4, which mediates pulmonary artery endothelial cell (PAEC) apoptosis, pulmonary artery smooth muscle cell (PASMC) growth and fibroblast proliferation. Inhibiting macrophage biosynthesis of LTB4 prevents PAEC apoptosis which is otherwise a key early event in PH pathogenesis. Systemic, oral or inhaled LTB4 antagonists not only prevent PH but also reverse advanced experimental PH, and LTB4 is now a viable therapeutic target.
Specific Aim 1 will test the possibility that normal resolution of pulmonary vascular injury associated with the induction of anti-inflammatory Ms requires IL-10- and Programmed Death-1 Ligand (PD-L1)-dependent Treg activity.
Specific Aim 2 will test the idea that injury evolution in PH, occurring in the absence of Treg-mediated control of inflammation, involves M-derived LTB4 triggering of key signaling pathways leading to specific pathologies in three vascular cell types: PAECs (apoptosis), PASMCs (growth) and pulmonary artery adventitial fibroblasts (proliferation). Finally, Specific Aim 3 will test the possibility that plasma LTB4 levels and lung LTB4 biosynthesis in PH patients correlate with clinical activity.
Pulmonary hypertension (PH) is serious disease without a known cure that can develop after vascular injury.The research proposed in this project will examine how the normal resolution of pulmonary vascular injury requires specialized cells known as Tregs. In the absence of normal immune suppression by these cells, an inflammatory molecule, called leukotriene B4, promotes vascular injury evolution and PH
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