Bronchopulmonary dysplasia (BPD) is a common, severe chronic lung disease of premature infants, with devastating short- and long-term consequences, including impaired neurodevelopment and increased mortality. The pathogenesis of BPD is multifactorial, but all triggers cause pulmonary inflammation. No therapy exists; therefore, we investigated whether the antiinflammatory interleukin 1 receptor antagonist (IL-1Ra) prevents murine BPD.
We precipitated BPD by perinatal inflammation (intraperitoneal injection of lipopolysaccharide to pregnant dams) and rearing pups in hyperoxia at 65% or 85% O2. The pups received daily subcutaneous injections of IL-1Ra or vehicle.
Vehicle-injected animals in both levels of hyperoxia developed a severe BPD-like lung disease, with an up to 60% decrease in alveolar number and in surface area available for gas exchange, as well as a 4-fold increase in alveolar size. IL-1Ra prevented this structural disintegration at 65%, but not at 85% O2. Hyperoxia depleted the pulmonary immune cells by 67%; however, the extant macrophages and dendritic cells were hyperactivated, with CD11b and GR1 highly expressed. IL-1Ra partially rescued the immune cell population in hyperoxia (doubling the number of viable cells), reduced the percentage that were activated by 63%, and abolished the unexpected persistence of IL-1alpha and IL-1beta that we observed 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 20-fold and some amenable to partial or complete reversal with IL-1Ra.
Our analysis reveals a pivotal role for IL-1alpha and IL-1beta in murine BPD, as well as an involvement for MIP-1alpha and TREM-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.