Abstract 9814: Nf-?B Inhibition Prevents Vascular Obliteration and Improves Immune Regulation in Severe Pulmonary Arterial Hypertension

Nuclear factor-κB (NF-κB) and interleukin-6 (IL-6), a NF-κB downstream mediator, play a central role in inflammatory response and vascular cell growth. Inflammation and a dysregulated immune response are found in many forms of severe pulmonary arterial hypertension (PAH), but how the NF-κB pathway contributes to PAH development is unclear. The SU5416 and chronic hypoxia (Su/Hx) rat PAH model is, like severe human PAH, characterized by obliterative pulmonary vascular lesions and right ventricular failure. We hypothesized that activation of the classical NF-κB pathway in severe PAH promotes ongoing vascular lesion cell apoptosis and proliferation, as well as dysregulation of the immune system. We aimed to determine the role of NF-κB in severe PAH induced by Su/Hx in rats. PAH was induced by a single injection of SU5416 and exposure to chronic hypoxia. Su/Hx rats were treated from day 1-21 with the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) and/or anti-IL-6 antibody. After hemodynamic assessment at day 21, cytokine/chemokine expression, NF-κB activation, lymphocyte accumulation, as well as pulmonary arterial cell apoptosis and proliferation were evaluated by Western blot, Flow cytometry and immunohistochemistry. The classical NF-κB pathway was activated in pulmonary arterial lesions SuHx rats. NF-κB inhibition with PDTC prevented the development of pulmonary arterial obliteration and in part PAH without reducing muscularization. However, the elevated lung levels of IL-6 were not reduced in PDTC-treated SuHx animals. Apoptosis of pulmonary artery wall cells and pulmonary arterial obliteration was prevented by PDTC or by PDTC+IL-6 inhibition and partially by IL-6 inhibition alone. Pulmonary arterial media wall thickness was not affected by any of these treatments. In Su/Hx rats, CD4 + T cells were reduced and perivascular CD8 + T lymphocytes and CD45RA + B lymphocytes were increased. NF-κB inhibition promoted immune regulation by increasing the number of perivascular CD4 + T cells and reducing the number of perivascular CD8 + T lymphocytes and CD45RA + B lymphocytes. Inhibition of NF-κB may represent a therapeutic option for pulmonary arterial obliteration via reduced vessel wall cell apoptosis and improved immune regulation.