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Title: | Interleukin-1 receptor antagonist protects newborn mice against pulmonary hypertension. | Authors: | Nold-Petry C.A. ;Cholewa M.;Berger P.J.;Young M.J.;Bourke J.E.;Pearson J.T.;Nold M.F.;Sehgal A. ;Bui C.B.;Kolodziej M.;Lamanna E.;Elgass K.;Rudloff I.;Schwenke D.O.;Tsuchimochi H.;Kroon M.A.G.M.;Cho S.X.;Maksimenko A. | Institution: | (Bui, Rudloff, Cho, Berger, Nold, Nold-Petry) Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia (Bui, Sehgal, Rudloff, Cho, Berger, Nold, Nold-Petry) Department of Paediatrics, Monash University, Clayton, VIC, Australia (Kolodziej) Faculty of Medicine, University of Rzeszow, Rzeszow, Poland (Lamanna, Kroon, Bourke) Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia (Elgass) Monash Micro Imaging, Hudson Institute of Medical Research, Clayton, VIC, Australia (Sehgal) Monash Newborn, Monash Children's Hospital, Melbourne, VIC, Australia (Schwenke) Department of Physiology-Heart Otago, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand (Tsuchimochi, Pearson) Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan (Kroon) Department of Pharmacy, Amsterdam UMC, Amsterdam, Netherlands (Maksimenko) Imaging and Medical Beamline, Australian Synchrotron, Clayton, VIC, Australia (Cholewa) Centre for Innovation and Transfer of Natural Sciences and Engineering Knowledge, University of Rzeszow, Rzeszow, Poland (Young) Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Clayton, VIC, Australia (Pearson) Department of Physiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia | Issue Date: | 26-Jul-2019 | Copyright year: | 2019 | Publisher: | Frontiers Media S.A. (E-mail: info@frontiersin.org) | Place of publication: | Switzerland | Publication information: | Frontiers in Immunology. 10 (JULY) (no pagination), 2019. Article Number: 1480. Date of Publication: 2019. | Journal: | Frontiers in Immunology | 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 mum 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 (alpha-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.Copyright © 2019 Bui, Kolodziej, Lamanna, Elgass, Sehgal, Rudloff, Schwenke, Tsuchimochi, Kroon, Cho, Maksimenko, Cholewa, Berger, Young, Bourke, Pearson, Nold and Nold-Petry. | DOI: | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.3389/fimmu.2019.01480 | ISSN: | 1664-3224 (electronic) | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/36042 | Type: | Article | Subjects: | mouse mRNA expression level newborn nonhuman phase contrast microscopy protein analysis *pulmonary hypertension/dt [Drug Therapy] real time polymerase chain reaction reverse transcription polymerase chain reaction spectrophotometry synchrotron radiation X ray analysis 15 hydroxy 11alpha,9alpha epoxymethanoprosta 5,13 dienoic acid alpha smooth muscle actin/ec [Endogenous Compound] endothelin 1/ec [Endogenous Compound] endothelin receptor/ec [Endogenous Compound] galectin 3/ec [Endogenous Compound] interleukin 1/ec [Endogenous Compound] *interleukin 1 receptor blocking agent/dt [Drug Therapy] *interleukin 1 receptor blocking agent/sc [Subcutaneous Drug Administration] lipopolysaccharide monocyte chemotactic protein 1/ec [Endogenous Compound] thromboxane vasculotropin/ec [Endogenous Compound] vasculotropin A/ec [Endogenous Compound] intravascular ultrasound system phase contrast microscope spectrophotometer time to peak velocity Eclipse Ti U NanoDrop 100 ViVid 7 micro-computed tomography heart left ventricle function heart muscle fibrosis heart rate heart right ventricle function heart ventricle ejection time heart ventricle enddiastolic pressure heart ventricle remodeling hyperoxia image analysis immunohistochemistry lung artery pressure lung dysplasia/dt [Drug Therapy] algorithm angiogenesis animal experiment animal model animal tissue arterial pressure article blood vessel diameter cardiovascular parameters carditis chorioamnionitis cineangiocardiography echocardiography enzyme linked immunosorbent assay gene expression gestational age lung vascular resistance mean arterial pressure echocardiography enzyme linked immunosorbent assay gene expression gestational age heart left ventricle function heart muscle fibrosis heart rate heart right ventricle function heart ventricle ejection time heart ventricle enddiastolic pressure heart ventricle remodeling hyperoxia image analysis immunohistochemistry lung artery pressure lung dysplasia / drug therapy lung vascular resistance mean arterial pressure micro-computed tomography mouse mRNA expression level newborn nonhuman phase contrast microscopy protein analysis *pulmonary hypertension / *drug therapy real time polymerase chain reaction reverse transcription polymerase chain reaction spectrophotometry synchrotron radiation X ray analysis animal model animal experiment animal tissue algorithm angiogenesis arterial pressure Article blood vessel diameter cardiovascular parameters carditis chorioamnionitis cineangiocardiography |
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