Abstract 225: Evaluating Pro-Inflammatory and Pro-Resolving Lipid Modulations in an Oral 15-HETE Model of Pulmonary Hypertension

Abstract

Pulmonary arterial hypertension (PH) is a chronic lung disease with a mortality rate of 50% at 5 years after diagnosis. PH is characterized by progressive increase in pulmonary arterial pressure leading to right ventricular (RV) increase in afterload, hypertrophy, and failure. Despite the availability of multiple animal models of PH, finding relief or cure for PH patients has been elusive to date. Recent studies in our laboratory have shown that levels of hydroxyeicosatetraenoic acids (HETEs) and hydroxyoctadecadienoic acids (HODEs) are elevated in the lungs and plasma of patients with PH as well as in animal models of PH. In testing for causality, we showed that administration of 5 μg of 15-HETE/day to wild type male mice for 3 weeks was sufficient to cause increase in pulmonary pressure, vascular resistance, plasma levels of HETEs and HODEs, right ventricle hypertrophy, and right ventricle systolic pressure (RVSP), consistent with PH. We set out to utilize this new mouse model of PH to understand the mechanisms in PH pathology by first examining the role of lipid mediators of inflammation in the development of PH. Our lab has developed a mass spectrometry method for measuring the levels of 39 inflammatory pathway lipid mediators from the cyclooxygenase (COX) and lipoxygenase (LOX) pathways that has been validated for use in tissue, plasma, and cell supernatant. Utilizing this panel with samples from mice fed 15-HETE and supernatant from an intestinal epithelial cell line; IEC-6 cells treated with 15-HETE, we have observed significant changes in multiple lipid mediators of inflammation. In addition to seeing increases in HETEs and HODEs with 15-HETE treatment, we observed significant increases in leukotriene C4 (LTC4) and 14(S)-hydroxy docosahexaenoic acid (14S-HDHA) and trending increases in thromboxane B2 (TXB2), and leukotriene E4 (LTE4) in the plasma, significant increases in 20 different lipids in lung tissue, including LTC4, TXB2, and LTE4, and significant increases in LTC4 and 5-oxo-eicosatetraenoic acid (5-oxoETE) in the supernatant of IEC-6 cells incubated with 15-HETE for 12 hours. These results indicate that novel inflammatory lipids and pathways may play an important in the development of hypertension and help identify new targets for therapies.