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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72 Citations (Scopus)

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 of the United States of America
Volume110
Issue number35
DOIs
Publication statusPublished - 2013

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