IL-1 Blockade Reduces Inflammation in Pulmonary Arterial Hypertension and Right Ventricular Failure: A Single-Arm, Open-Label, Phase IB/II Pilot Study

Trankle, Cory R.; Canada, Justin M.; Kadariya, Dinesh; Markley, Roshanak; Chazal, Horacio Medina de; Pinson, Janet; Fox, Adam; Tassell, Benjamín W. Van; Abbate, Antonio; Grinnan, Daniel

doi:10.1164/rccm.201809-1631le

Cited by 82 publications

(56 citation statements)

References 11 publications

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“…In an adult rat inflammatory PH model, daily IL-1Ra treatment brings about a significant reduction of PH (57), and neonatal piglets have been shown to be protected from neonatal PH when treated with IL-1Ra (58). A recent single-arm, open label study has reported IL-1Ra successfully treats human adult PH (59).…”

Section: Discussionmentioning

confidence: 99%

Interleukin-1 Receptor Antagonist Protects Newborn Mice Against Pulmonary Hypertension

et al. 2019

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Pulmonary hypertension secondary to bronchopulmonary dysplasia (BPD-PH) represents a major complication of BPD in extremely preterm infants for which there are currently no safe and effective interventions. The abundance of interleukin-1 (IL-1) is strongly correlated with the severity and long-term outcome of BPD infants and we have previously shown that IL-1 receptor antagonist (IL-1Ra) protects against murine BPD; therefore, we hypothesized that IL-1Ra may also be effective against BPD-PH. We employed daily injections of IL-1Ra in a murine model in which BPD/BPD-PH was induced by antenatal LPS and postnatal hyperoxia of 65% O 2 . Pups reared in hyperoxia for 28 days exhibited a BPD-PH-like disease accompanied by significant changes in pulmonary vascular morphology: micro-CT revealed an 84% reduction in small vessels (4–5 μm diameter) compared to room air controls; this change was prevented by IL-1Ra. Pulmonary vascular resistance, assessed at day 28 of life by echocardiography using the inversely-related surrogate marker time-to-peak-velocity/right ventricular ejection time (TPV/RVET), increased in hyperoxic mice (0.27 compared to 0.32 in air controls), and fell significantly with daily IL-1Ra treatment (0.31). Importantly, in vivo cine-angiography revealed that this protection afforded by IL-1Ra treatment for 28 days is maintained at day 60 of life. Despite an increased abundance of mediators of pulmonary angiogenesis in day 5 lung lysates, namely vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1), no difference was detected in ex vivo pulmonary vascular reactivity between air and hyperoxia mice as measured in precision cut lung slices, or by immunohistochemistry in alpha-smooth muscle actin (α-SMA) and endothelin receptor type-A (ET A ) at day 28. Further, on day 28 of life we observed cardiac fibrosis by Sirius Red staining, which was accompanied by an increase in mRNA expression of galectin-3 and CCL2 (chemokine (C-C motif) ligand 2) in whole hearts of hyperoxic pups, which improved with IL-1Ra. In summary, our findings suggest that daily administration of the anti-inflammatory IL-1Ra prevents the increase in pulmonary vascular resistance and the pulmonary dysangiogenesis of murine BPD-PH, thus pointing to IL-1Ra as a promising candidate for the treatment of both BPD and BPD-PH.

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Section: Discussionmentioning

confidence: 99%

Interleukin-1 Receptor Antagonist Protects Newborn Mice Against Pulmonary Hypertension

et al. 2019

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“…A pilot study evaluating the safety and feasibility of anakinra for treatment of PAH was recently completed [ 12 ]. Six patients completed the study without any serious adverse events, and there was some improvement in the biomarkers and symptoms of heart failure [ 12 ]. These encouraging data will form the basis of a larger trial.…”

Section: Inflammatory Mediators and Their Effects On Vascular Remomentioning

confidence: 99%

Perivascular Inflammation in Pulmonary Arterial Hypertension

Chi

Kuebler

et al. 2020

Cells

142

109

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Perivascular inflammation is a prominent pathologic feature in most animal models of pulmonary hypertension (PH) as well as in pulmonary arterial hypertension (PAH) patients. Accumulating evidence suggests a functional role of perivascular inflammation in the initiation and/or progression of PAH and pulmonary vascular remodeling. High levels of cytokines, chemokines, and inflammatory mediators can be detected in PAH patients and correlate with clinical outcome. Similarly, multiple immune cells, including neutrophils, macrophages, dendritic cells, mast cells, T lymphocytes, and B lymphocytes characteristically accumulate around pulmonary vessels in PAH. Concomitantly, vascular and parenchymal cells including endothelial cells, smooth muscle cells, and fibroblasts change their phenotype, resulting in altered sensitivity to inflammatory triggers and their enhanced capacity to stage inflammatory responses themselves, as well as the active secretion of cytokines and chemokines. The growing recognition of the interaction between inflammatory cells, vascular cells, and inflammatory mediators may provide important clues for the development of novel, safe, and effective immunotargeted therapies in PAH.

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“…These observations indicate that IL-1Ra attenuates murine BPD and PH. The antagonist was also recently shown to be safe and effective in adult patients with PH and right ventricular failure (119), emphasizing the translational potential of this compound for BPD infants with PH.…”

Section: Interleukin-1 Receptor Antagonistmentioning

confidence: 99%

Novel Strategies to Reduce Pulmonary Hypertension in Infants With Bronchopulmonary Dysplasia

El-Saie

Shivanna

2020

Front. Pediatr.

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Bronchopulmonary dysplasia (BPD) is a developmental lung disorder of preterm infants primarily caused by the failure of host defense mechanisms to prevent tissue injury and facilitate repair. This disorder is the most common complication of premature birth, and its incidence remains unchanged over the past few decades. Additionally, BPD increases long-term cardiopulmonary and neurodevelopmental morbidities of preterm infants. Pulmonary hypertension (PH) is a common morbidity of BPD. Importantly, the presence of PH increases both the short-and long-term morbidities and mortality in BPD infants. Further, there are no curative therapies for this complex disease. Besides providing an overview of the pathogenesis and diagnosis of PH associated with BPD, we have attempted to comprehensively review and summarize the current literature on the interventions to prevent and/or mitigate BPD and PH in preclinical studies. Our goal was to provide insight into the therapies that have a high translational potential to meaningfully manage BPD patients with PH.

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IL-1 Blockade Reduces Inflammation in Pulmonary Arterial Hypertension and Right Ventricular Failure: A Single-Arm, Open-Label, Phase IB/II Pilot Study

Cited by 82 publications

References 11 publications

Interleukin-1 Receptor Antagonist Protects Newborn Mice Against Pulmonary Hypertension

Interleukin-1 Receptor Antagonist Protects Newborn Mice Against Pulmonary Hypertension

Perivascular Inflammation in Pulmonary Arterial Hypertension

Novel Strategies to Reduce Pulmonary Hypertension in Infants With Bronchopulmonary Dysplasia

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