Interleukin-1 receptor antagonist prevents murine bronchopulmonary dysplasia induced by perinatal inflammation and hyperoxia

Marcel Friedrich Nold, Niamh Mangan, Ina Rudloff, Steven Cho, Nikeh Shariatian, Thilini Damsarani Samarasinghe, Elizabeth Michalina Skuza, John S Pedersen, Alex Veldman, Philip John Berger, Claudia Annelie Nold-Petry

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Abstract

Bronchopulmonary dysplasia (BPD) is a common lung disease of premature infants, with devastating short- and long-term consequences. The pathogenesis of BPD is multifactorial, but all triggers cause pulmonary inflammation. No therapy exists; therefore, we investigated whether the anti-inflammatory interleukin-1 receptor antagonist (IL-1Ra) prevents murine BPD. We precipitated BPD by perinatal inflammation (lipopolysaccharide injection to pregnant dams) and rearing pups in hyperoxia (65 or 85 O2). Pups were treated daily with IL-1Ra or vehicle for up to 28 d. Vehicle-injected animals in both levels of hyperoxia developed a severe BPD-like lung disease (alveolar number and gas exchange area decreased by up to 60 , alveolar size increased up to fourfold). IL-1Ra prevented this structural disintegration at 65 , but not 85 O2. Hyperoxia depleted pulmonary immune cells by 67 ; however, extant macrophages and dendritic cells were hyperactivated, with CD11b and GR1 (Ly6G/C) highly expressed. IL-1Ra partially rescued the immune cell population in hyperoxia (doubling the viable cells), reduced the percentage that were activated by up to 63 , and abolished the unexpected persistence of IL-1alpha and IL-1beta on day 28 in hyperoxia/vehicle-treated lungs. On day 3, perinatal inflammation and hyperoxia each triggered a distinct pulmonary immune response, with some proinflammatory mediators increasing up to 20-fold and some amenable to partial or complete reversal with IL-1Ra. In summary, our analysis reveals a pivotal role for IL-1alpha/beta in murine BPD and an involvement for MIP (macrophage inflammatory protein)-1alpha and TREM (triggering receptor expressed on myeloid cells)-1. Because it effectively shields newborn mice from BPD, IL-1Ra emerges as a promising treatment for a currently irremediable disease that may potentially brighten the prognosis of the tiny preterm patients.
Original languageEnglish
Pages (from-to)14384-14389
Number of pages6
JournalProceedings of the National Academy of Sciences
Volume110
Issue number35
DOIs
Publication statusPublished - 2013

Cite this

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title = "Interleukin-1 receptor antagonist prevents murine bronchopulmonary dysplasia induced by perinatal inflammation and hyperoxia",
abstract = "Bronchopulmonary dysplasia (BPD) is a common lung disease of premature infants, with devastating short- and long-term consequences. The pathogenesis of BPD is multifactorial, but all triggers cause pulmonary inflammation. No therapy exists; therefore, we investigated whether the anti-inflammatory interleukin-1 receptor antagonist (IL-1Ra) prevents murine BPD. We precipitated BPD by perinatal inflammation (lipopolysaccharide injection to pregnant dams) and rearing pups in hyperoxia (65 or 85 O2). Pups were treated daily with IL-1Ra or vehicle for up to 28 d. Vehicle-injected animals in both levels of hyperoxia developed a severe BPD-like lung disease (alveolar number and gas exchange area decreased by up to 60 , alveolar size increased up to fourfold). IL-1Ra prevented this structural disintegration at 65 , but not 85 O2. Hyperoxia depleted pulmonary immune cells by 67 ; however, extant macrophages and dendritic cells were hyperactivated, with CD11b and GR1 (Ly6G/C) highly expressed. IL-1Ra partially rescued the immune cell population in hyperoxia (doubling the viable cells), reduced the percentage that were activated by up to 63 , and abolished the unexpected persistence of IL-1alpha and IL-1beta on day 28 in hyperoxia/vehicle-treated lungs. On day 3, perinatal inflammation and hyperoxia each triggered a distinct pulmonary immune response, with some proinflammatory mediators increasing up to 20-fold and some amenable to partial or complete reversal with IL-1Ra. In summary, our analysis reveals a pivotal role for IL-1alpha/beta in murine BPD and an involvement for MIP (macrophage inflammatory protein)-1alpha and TREM (triggering receptor expressed on myeloid cells)-1. Because it effectively shields newborn mice from BPD, IL-1Ra emerges as a promising treatment for a currently irremediable disease that may potentially brighten the prognosis of the tiny preterm patients.",
author = "Nold, {Marcel Friedrich} and Niamh Mangan and Ina Rudloff and Steven Cho and Nikeh Shariatian and Samarasinghe, {Thilini Damsarani} and Skuza, {Elizabeth Michalina} and Pedersen, {John S} and Alex Veldman and Berger, {Philip John} and Nold-Petry, {Claudia Annelie}",
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doi = "10.1073/pnas.1306859110",
language = "English",
volume = "110",
pages = "14384--14389",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
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Interleukin-1 receptor antagonist prevents murine bronchopulmonary dysplasia induced by perinatal inflammation and hyperoxia. / Nold, Marcel Friedrich; Mangan, Niamh; Rudloff, Ina; Cho, Steven; Shariatian, Nikeh; Samarasinghe, Thilini Damsarani; Skuza, Elizabeth Michalina; Pedersen, John S; Veldman, Alex; Berger, Philip John; Nold-Petry, Claudia Annelie.

In: Proceedings of the National Academy of Sciences, Vol. 110, No. 35, 2013, p. 14384-14389.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Interleukin-1 receptor antagonist prevents murine bronchopulmonary dysplasia induced by perinatal inflammation and hyperoxia

AU - Nold, Marcel Friedrich

AU - Mangan, Niamh

AU - Rudloff, Ina

AU - Cho, Steven

AU - Shariatian, Nikeh

AU - Samarasinghe, Thilini Damsarani

AU - Skuza, Elizabeth Michalina

AU - Pedersen, John S

AU - Veldman, Alex

AU - Berger, Philip John

AU - Nold-Petry, Claudia Annelie

PY - 2013

Y1 - 2013

N2 - Bronchopulmonary dysplasia (BPD) is a common lung disease of premature infants, with devastating short- and long-term consequences. The pathogenesis of BPD is multifactorial, but all triggers cause pulmonary inflammation. No therapy exists; therefore, we investigated whether the anti-inflammatory interleukin-1 receptor antagonist (IL-1Ra) prevents murine BPD. We precipitated BPD by perinatal inflammation (lipopolysaccharide injection to pregnant dams) and rearing pups in hyperoxia (65 or 85 O2). Pups were treated daily with IL-1Ra or vehicle for up to 28 d. Vehicle-injected animals in both levels of hyperoxia developed a severe BPD-like lung disease (alveolar number and gas exchange area decreased by up to 60 , alveolar size increased up to fourfold). IL-1Ra prevented this structural disintegration at 65 , but not 85 O2. Hyperoxia depleted pulmonary immune cells by 67 ; however, extant macrophages and dendritic cells were hyperactivated, with CD11b and GR1 (Ly6G/C) highly expressed. IL-1Ra partially rescued the immune cell population in hyperoxia (doubling the viable cells), reduced the percentage that were activated by up to 63 , and abolished the unexpected persistence of IL-1alpha and IL-1beta on day 28 in hyperoxia/vehicle-treated lungs. On day 3, perinatal inflammation and hyperoxia each triggered a distinct pulmonary immune response, with some proinflammatory mediators increasing up to 20-fold and some amenable to partial or complete reversal with IL-1Ra. In summary, our analysis reveals a pivotal role for IL-1alpha/beta in murine BPD and an involvement for MIP (macrophage inflammatory protein)-1alpha and TREM (triggering receptor expressed on myeloid cells)-1. Because it effectively shields newborn mice from BPD, IL-1Ra emerges as a promising treatment for a currently irremediable disease that may potentially brighten the prognosis of the tiny preterm patients.

AB - Bronchopulmonary dysplasia (BPD) is a common lung disease of premature infants, with devastating short- and long-term consequences. The pathogenesis of BPD is multifactorial, but all triggers cause pulmonary inflammation. No therapy exists; therefore, we investigated whether the anti-inflammatory interleukin-1 receptor antagonist (IL-1Ra) prevents murine BPD. We precipitated BPD by perinatal inflammation (lipopolysaccharide injection to pregnant dams) and rearing pups in hyperoxia (65 or 85 O2). Pups were treated daily with IL-1Ra or vehicle for up to 28 d. Vehicle-injected animals in both levels of hyperoxia developed a severe BPD-like lung disease (alveolar number and gas exchange area decreased by up to 60 , alveolar size increased up to fourfold). IL-1Ra prevented this structural disintegration at 65 , but not 85 O2. Hyperoxia depleted pulmonary immune cells by 67 ; however, extant macrophages and dendritic cells were hyperactivated, with CD11b and GR1 (Ly6G/C) highly expressed. IL-1Ra partially rescued the immune cell population in hyperoxia (doubling the viable cells), reduced the percentage that were activated by up to 63 , and abolished the unexpected persistence of IL-1alpha and IL-1beta on day 28 in hyperoxia/vehicle-treated lungs. On day 3, perinatal inflammation and hyperoxia each triggered a distinct pulmonary immune response, with some proinflammatory mediators increasing up to 20-fold and some amenable to partial or complete reversal with IL-1Ra. In summary, our analysis reveals a pivotal role for IL-1alpha/beta in murine BPD and an involvement for MIP (macrophage inflammatory protein)-1alpha and TREM (triggering receptor expressed on myeloid cells)-1. Because it effectively shields newborn mice from BPD, IL-1Ra emerges as a promising treatment for a currently irremediable disease that may potentially brighten the prognosis of the tiny preterm patients.

UR - http://www.pnas.org/content/110/35/14384.full.pdf

U2 - 10.1073/pnas.1306859110

DO - 10.1073/pnas.1306859110

M3 - Article

VL - 110

SP - 14384

EP - 14389

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 35

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