Role of Interleukin 1 Beta in Flow-Induced Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) specifies the primary lesion in the pulmonary arterial system caused by genetic defect such as congenital heart diseases, and others. Nearly 30% of congenital heart patients developed PAH, due to the high pulmonary vascular flow from intra-cardiac shunts. Among those with congenital heart defects, the presence of PAH adversely impact the quality of life and long term survival. In the modern era of well-developed medication for PAH, there is still an increased risk of procedure or surgery for atrial septal defect with significant PAH. Additionally, treatment of those congenital defects such as atrial septal defect (ASD) may not necessary comfort the progression of PAH. These suboptimal long-term results of congenital heart associated, or flow-induced, PAH indicate a niche for research. The underlying mechanism of flow-induced PAH also requires investigation. Perivascular cell infiltrates such as macrophages, are characteristic in animal models of pulmonary hypertension (animal models are still referred to as having pulmonary hypertension rather than PAH) and patients with PAH. Cytokines are important mediators in the cross-talk between these inflammatory cells. Controlling the cytokines might re-organize the dysregulated pulmonary artery inflammation, and thus hamper the hypertrophy of pulmonary vessels in PAH. Inflammatory cytokines such as interleukin (IL)-1 contribute to the increased pulmonary resistance and remodeling. The applicant postulated that IL-1 may be an important mediator in flow-induced PAH. Moreover, Administration of anakinra, an IL-1 receptor antagonist, had been shown to improve endothelial function in aorta of diabetic rats. The effects of IL-1 receptor antagonist over flow-induced PAH has yet to be determined. This proposal aim to elucidate possible role of IL-1 in flow-induced PAH using the animal model and clinical specimens. The study results might be an important step toward clinical application of IL-1R antagonists for flow-induced PAH patients who are at high risk for surgical procedures.