Targeting Inflammation in Pulmonary Artery Hypertension: Is It Time to Forget About the Lungs ?

The quest to identify and develop new therapies for the treatment of pulmonary artery hypertension (PAH) has resulted in the approval of 14 therapies by the U.S. Food and Drug Administration. Thus far therapies have targeted endothelin type A and B receptors, soluble guanylate cyclase, phosphodiesterase V inhibitors and prostacyclin analogs.¹ Despite the advances in the treatment of PAH, many patients will become refractory to treatment with these agents, insofar as these vasodilators do not target the underlying mechanisms that are responsible for disease progression in PAH. Given the inherent limitations of current pulmonary vasodilator therapies, there is a compelling need to develop new therapies that target the specific mechanisms that contribute to disease progression in PAH.¹ Germane to this discussion, there has been considerable interest in the role of inflammation as an important mechanism for disease progression in PAH.² Among the many cytokines and inflammatory mediators that have been implicated in PAH, interleukin-6 (IL-6) has emerged as one of the important pro-inflammatory cytokines, both in experimental models² and in observational clinical studies.³ IL-6 is the first and prototypical member of the IL-6 family of cytokines that share a common signaling receptor, glycoprotein 130 (gp130), that transduces a variety of pleiotropic effects in mammalian cells.

In the current issue of the Journal, Prisco and colleagues investigate the role of gp130 inhibition in a monocrotaline (MCT) induced model of pulmonary hypertension in rats.⁴ Beginning 2 weeks after a single injection of MCT, rats were treated for 10 consecutive days with intraperitoneal injections of a gp130 antagonist, SC-144 (10 mg/kg),⁵ or a vehicle control. Treatment with SC-144 decreased signal transducer and activator of transcription 3 (STAT3) activation in myocardial extracts from the right ventricle (RV), consistent with inhibition of gp130 signaling.⁵ Treatment with SC-144 also prevented the upregulation of tubulin isoforms and microtubule associated protein, resulting in normalization of junctophilin-2 levels, which the authors have previously shown are important for maintaining T-tubule architecture in the heart.⁶ Intriguingly, these changes were more prominent in the RV than in the left ventricle. Global metabolomic profiling of RV free wall specimens revealed that treatment with SC-144 prevented the MCT-induced decrease in fatty acid oxidation and increase in glycolysis, as well as prevented the development of abnormalities within complexes I-V of the electron transport chain. Transmission electron microscopy identified that mitochondria were significantly larger and more spherical in shape in the vehicle treated MCT rats, whereas mitochondrial morphology was normalized in the SC-144 treated rats. To address the mechanisms for this finding, the authors showed that there was a decrease in the abundance of pro-fusion mitochondrial proteins and increased expression of the pro-fission proteins in the vehicle treated MCT rats, whereas treatment with SC-144 prevented the decrease in pro-fusion mitochondrial proteins and was associated with increased levels of pro-fission proteins, suggesting that inhibition of gp130 mediated signaling prevented mitochondrial fission. Echocardiography and pressure-volume loops showed that treatment with SC-144 had no effect on adverse pulmonary artery remodeling, but did improve RV function, including RV ejection fraction, end-systolic elastance, and RV-PA coupling. Additionally, treatment with SC-144 led to decreased RV mass, decreased RV fibrosis, and a decrease in RV cardiac myocyte cell area. Interestingly, vehicle control and SC-144 treated rats had similar pathological remodeling of the pulmonary artery vasculature. Lastly, the authors evaluated serum levels of IL-6 in patients with PAH (n=73). They showed that patients with IL-6 levels above the median had higher N-terminal pro B-type natriuretic peptide levels and lower RV fractional area change by 2D-echocardiography. When the authors plotted the relationship between RV fractional area change and mean pulmonary arterial pressure or RV fractional area change and pulmonary vascular resistance, they observed that patients with higher IL-6 levels had lower RV fractional area change, regardless of the corresponding pulmonary artery pressures or levels of pulmonary vascular resistance, which they interpreted as suggesting that elevated levels of IL-6 were associated with RV dysfunction. The authors appropriately acknowledge a major limitation of their study, which is the that they did not confirm their results using an second model of PAH (e.g. Sugen-hypoxia model).

The study by Prisco and colleagues in this issue of the Journal represents a technical tour de force that combines proteomics and metabolomics in the evaluation of a small molecule inhibitor of gp130 signaling in the MCT-induced PAH model. Their findings suggest that inhibition of gp130 signaling enhances RV function independent of changes in the pulmonary artery vasculature. Apart from the novelty of these findings, the study raises the interesting question of whether it may be possible to move beyond therapeutic targeting of vasodilation in PAH, by targeting gp130 mediated inflammatory signaling pathways.

By way of review, gp130 is a transmembrane protein that is ubiquitously expressed in mammalian cells. As noted, gp130 serves as receptor subunit for cytokines that belong to the IL-6 family, including IL-6, IL-11, interleukin-27, leukemia inhibitory factor, cardiotrophin-1, cardiotrophin-like cytokine, oncostatin M, neuropoietin and ciliary neurotrophic factor.⁷ The interaction of gp130 with an IL-6 family member ligand and its cognate receptor triggers the activation of several downstream cytoprotective signaling cascades including Janus associated kinase (JAK)/STAT, mitogen-activated protein kinases, and phosphatidylinositol 3-kinase (PI3K)/AKT pathways. Given the central role of gp130 mediated cytoprotective signaling, strategies that globally target gp130 signaling (e.g. SC-144, gp130 antibodies) have not been tested in clinical trials thus far,⁷ given the concerns related to potential severe side effects, especially in the heart, wherein gp130 receptor mediated JAK/STAT signaling plays a critical role in promoting cell survival in cardiac myocytes, as well as promoting angiogenesis.^8-10 In this regard it is important to note the studies by Prisco et al. were completed within 10 days,⁴ and would therefore been too short term to observe the deleterious effects of global inhibition of gp130 mediated signaling. In contrast to strategies for globally antagonizing gp130, antagonizing individual cytokines that signal through gp130 has been proven to be an effective strategy for treating patients with rheumatoid arthritis, as well as the inflammation associated with cytokine storm. Tocilizumab is an anti-IL-6 receptor monoclonal antibody that is FDA approved for treating adults with moderately to severely active rheumatoid arthritis and treating patients with the cytokine release syndrome following chimeric antigen receptor T cell (CAR T-cell) therapy. Germane to this discussion, tocilizumab was evaluated in the TRANSFORM-UK (Therapeutic Open Label Study of Tocilizumab in the Treatment of Pulmonary Arterial Hypertension) trial, which was a 6 month open label phase II trial evaluating the safety and efficacy of 23 patients with group 1 PAH. Although the TRANSFORM-UK trial showed that treatment with tocilizumab altered C-reactive protein levels, consistent with effective target engagement, treatment with tocilizumab did not reduce pulmonary vascular resistance (primary end point) through 6 months of therapy.^{11, 12} Unfortunately, RV function was not assessed in TRANSFORM-UK. Given the very small sample size of the TRANSFORM-UK trial, it is premature to speculate on whether the neutral results of the trial indicate that inflammation does or does not play an role in the pathogenesis of inflammation in PAH. In this regard it is interesting to note that Prisco and colleagues also did not observe a decrease in pulmonary vascular resistance with SC-144, but did observe an increase in RV function, suggesting that inflammation plays a role in the pathogenesis of PAH. These provocative findings further suggest that future clinical trials that target inflammation in PAH should include an assessment of RV structure and function in addition to the traditional measurements of pulmonary artery hemodynamics.