Interleukin-1 Receptor Antagonist Protects Newborn Mice Against Pulmonary Hypertension.

Abstract

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% O2. 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 (ETA) 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.

• Authors: Christine B Bui, Magdalena Kolodziej, Emma Lamanna, Kirstin Elgass, Arvind Sehgal, Ina Rudloff, Daryl O Schwenke, Hirotsugu Tsuchimochi, Maurice A G M Kroon, Steven X Cho, Anton Maksimenko, Marian Cholewa, Philip J Berger, Morag J Young, Jane E Bourke, James T Pearson, Marcel F Nold, Claudia A Nold-Petry
• Journal: Frontiers in immunology (Front Immunol) Vol. 10 Pg. 1480 ( 2019) ISSN: 1664-3224 [Electronic] Switzerland
• PMID: 31354700 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents
• Endothelin-1
• Il1rn protein, mouse
• Interleukin 1 Receptor Antagonist Protein
• Lipopolysaccharides
• Vascular Endothelial Growth Factor A
• vascular endothelial growth factor A, mouse

Topics

• Animals
• Animals, Newborn
• Anti-Inflammatory Agents (pharmacology)
• Bronchopulmonary Dysplasia (pathology, prevention & control)
• Disease Models, Animal
• Endothelin-1 (metabolism)
• Hyperoxia
• Hypertension, Pulmonary (prevention & control)
• Interleukin 1 Receptor Antagonist Protein (pharmacology)
• Lipopolysaccharides (toxicity)
• Mice
• Mice, Inbred C57BL
• Vascular Endothelial Growth Factor A (metabolism)
• Vascular Resistance (drug effects)