Abstract 973: A Novel Anti-Inflammatory Therapeutic Approach for Pulmonary Arterial Hypertension: Blockade of NF-kB by Nano-DDS of NF-kB decoy to the lung ameliorates monocrotaline-induced PAH

Abstract

Background: Inflammatory mechanisms are implicated in the pathogenesis of pulmonary arterial hypertension (PAH), and thus can be a promising therapeutic target of the devastating disease. Nuclear factor-κB (NF-κB) is a redox-sensitive transcription factor that controls expression of important inflammatory cytokines. However, no prior study addressed the role of NF-κB in PAH. We have developed nanotechnology-based drug delivery system (Nano-DDS) to the lung using intratracheal injection of bioabsorbable polymeric PLGA nanoparticle (NP, a mean diameter of 50 nm) for clinical application. Hypothesis: Blockade of NF-κB by Nano-DDS of NF-κB decoy to the lung ameliorates monocrotaline (MCT)-induced PAH. Methods and Results: [Immunohistochemical studies in human samples from autopsy] Immunohistochemical study using an antibody against activated form (α-p65) showed that activation of NF-κB was noted in the alveolar macrophage and pulmonary vasculature with medial hypertrophy from lung cross-sections from patients with severe PAH. These pathologic changes were associated with increased staining of IL-6 and MCP-1. [Experimental animal studies] Single intratracheal injection of NP incorporated with fluorescence labeled NF-κB decoy in rats resulted in sustained intracellular delivery into macrophages and pulmonary vasculature until 7 days. After MCT injection, rats were divided into no treatment (No Tx) group, and those received single intratracheal decoy alone (50 μg), blank NPs alone, or decoy NP (n=6 – 8, each). No Tx group developed significant PAH, pulmonary arterial remodeling, and increased infiltration of macrophages 3 weeks after MCT injection. These pathologic changes were ameliorated by treatment with decoy NP, but not with decoy only or blank NP only. Increased activity of NF-κB in alveolar macrophages in No Tx group was attenuated by intratracheal decoy NP, but not by decoy only or blank NP only. Conclusions: We have developed a novel Nano-DDS of NF-κB decoy into the lung using bioabsorbable NP, and demonstrated its therapeutic benefit associated with anti-inflammatory effects in MCT-induced PAH. This study provides an innovative future direction of less invasive and dependable Nano-DDS for patients with severe PAH.