Interleukin-1 receptor antagonist protects newborn mice against pulmonary hypertension

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

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Article number1480
Number of pages15
JournalFrontiers in Immunology
Volume10
Issue numberJULY
DOIs
Publication statusPublished - 11 Jul 2019

Keywords

  • Anti-inflammatory therapy
  • Bronchopulmonary dysplasia
  • Interleukin-1 receptor antagonist
  • Interventional immunology
  • Neonatal immunity
  • Preterm infants
  • Pulmonary hypertension
  • Pulmonary vascular resistance

Cite this

Bui, Christine B. ; Kolodziej, Magdalena ; Lamanna, Emma ; Elgass, Kirstin ; Sehgal, Arvind ; Rudloff, Ina ; Schwenke, Daryl O. ; Tsuchimochi, Hirotsugu ; Kroon, Maurice A.G.M. ; Cho, Steven X. ; Maksimenko, Anton ; Cholewa, Marian ; Berger, Philip J. ; Young, Morag J. ; Bourke, Jane E. ; Pearson, James T. ; Nold, Marcel F. ; Nold-Petry, Claudia A. / Interleukin-1 receptor antagonist protects newborn mice against pulmonary hypertension. In: Frontiers in Immunology. 2019 ; Vol. 10, No. JULY.
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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.",
keywords = "Anti-inflammatory therapy, Bronchopulmonary dysplasia, Interleukin-1 receptor antagonist, Interventional immunology, Neonatal immunity, Preterm infants, Pulmonary hypertension, Pulmonary vascular resistance",
author = "Bui, {Christine B.} and Magdalena Kolodziej and Emma Lamanna and Kirstin Elgass and Arvind Sehgal and Ina Rudloff and Schwenke, {Daryl O.} and Hirotsugu Tsuchimochi and Kroon, {Maurice A.G.M.} and Cho, {Steven X.} and Anton Maksimenko and Marian Cholewa and Berger, {Philip J.} and Young, {Morag J.} and Bourke, {Jane E.} and Pearson, {James T.} and Nold, {Marcel F.} and Nold-Petry, {Claudia A.}",
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Interleukin-1 receptor antagonist protects newborn mice against pulmonary hypertension. / Bui, Christine B.; Kolodziej, Magdalena; Lamanna, Emma; Elgass, Kirstin; Sehgal, Arvind; Rudloff, Ina; Schwenke, Daryl O.; Tsuchimochi, Hirotsugu; Kroon, Maurice A.G.M.; Cho, Steven X.; Maksimenko, Anton; Cholewa, Marian; Berger, Philip J.; Young, Morag J.; Bourke, Jane E.; Pearson, James T.; Nold, Marcel F.; Nold-Petry, Claudia A.

In: Frontiers in Immunology, Vol. 10, No. JULY, 1480, 11.07.2019.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Interleukin-1 receptor antagonist protects newborn mice against pulmonary hypertension

AU - Bui, Christine B.

AU - Kolodziej, Magdalena

AU - Lamanna, Emma

AU - Elgass, Kirstin

AU - Sehgal, Arvind

AU - Rudloff, Ina

AU - Schwenke, Daryl O.

AU - Tsuchimochi, Hirotsugu

AU - Kroon, Maurice A.G.M.

AU - Cho, Steven X.

AU - Maksimenko, Anton

AU - Cholewa, Marian

AU - Berger, Philip J.

AU - Young, Morag J.

AU - Bourke, Jane E.

AU - Pearson, James T.

AU - Nold, Marcel F.

AU - Nold-Petry, Claudia A.

PY - 2019/7/11

Y1 - 2019/7/11

N2 - 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.

AB - 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.

KW - Anti-inflammatory therapy

KW - Bronchopulmonary dysplasia

KW - Interleukin-1 receptor antagonist

KW - Interventional immunology

KW - Neonatal immunity

KW - Preterm infants

KW - Pulmonary hypertension

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