Increased Eicosanoid Levels in the Sugen/Chronic Hypoxia Model of Severe Pulmonary Hypertension

Abstract

Inflammation and altered immunity are recognized components of severe pulmonary arterial hypertension in human patients and in animal models of PAH. While eicosanoid metabolites of cyclooxygenase and lipoxygenase pathways have been identified in the lungs from pulmonary hypertensive animals their role in the pathogenesis of severe angioobliterative PAH has not been examined. Here we investigated whether a cyclooxygenase-2 (COX-2) inhibitor or diethylcarbamazine (DEC), that is known for its 5-lipoxygenase inhibiting and antioxidant actions, modify the development of PAH in the Sugen 5416/hypoxia (SuHx) rat model. The COX-2 inhibitor SC-58125 had little effect on the right ventricular pressure and did not prevent the development of pulmonary angioobliteration. In contrast, DEC blunted the muscularization of pulmonary arterioles and reduced the number of fully obliterated lung vessels. DEC treatment of SuHx rats, after the lung vascular disease had been established, reduced the degree of PAH, the number of obliterated arterioles and the degree of perivascular inflammation. We conclude that the non-specific anti-inflammatory drug DEC affects developing PAH and is partially effective once angioobliterative PAH has been established.

Formulation and Characterization of Solid Lipid Nanoparticles Loading RF22-c, a Potent and Selective 5-LO Inhibitor, in a Monocrotaline-Induced Model of Pulmonary Hypertension

“…The significant elevation in PAP, the increasing of RV afterload, and decreasing of endurance induced right ventricular hypertrophy and subsequently right ventricular failure (RVF). A growing number of evidences support the leukotrienes implication in cardiomyocytes' remodeling (Qian et al, 2015), demonstrating a significant reduction in the degree of hypertrophy of the RV and right ventricular systolic pressure (RVSP) induced by agents that affect lipoxygenase metabolite production (Al-Husseini et al, 2015). In our study, the pressure decrease induced by RF22-c treatment resulted in a reduction of heart overload and RV hypertrophy.…”

Challenges and opportunities in treating inflammation associated with pulmonary hypertension

“…The targeting of several inflammatory pathways and the resulting modulation of chronic PAH, based on such successful targeting (35 –37), all support the notion that inflammation plays an important role in the pathobiology of hypoxia-induced PAH. An important aspect of chronic hypoxic PAH models is that the PAH is reversible upon withdrawal of the hypoxic stimulus.…”

Vascular Endothelial Growth Factor Receptor 3 Signaling Contributes to Angioobliterative Pulmonary Hypertension

“…Because treatment of rats with the VEGFR1 and VEGFR2 receptor blocker combined with chronic hypoxia generates angioobliterative PAH that is associated with accumulation of inflammatory cells, activation of inflammatory cells in the lungs, and activation of inflammatory eicosanoid mediator-generating pathways, 44 we postulated that the tissue expression profile of VEGF isoforms and/or VEGF receptors would be altered because of inflammation or as a consequence of chronic VEGF receptor blockade. Lung tissue samples harvested from SuHx rats 4 weeks after the initiation of the experimental protocol were surveyed, and the expression of VEGF ligand isoforms was assessed by Western blotting.…”