Interleukin-1 receptor antagonist prevents murine bronchopulmonary dysplasia induced by perinatal inflammation and hyperoxia.
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-1α and IL-1β 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-1α/β in murine BPD and an involvement for MIP (macrophage inflammatory protein)-1α 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.
Ritchie Centre, Monash Institute of Medical Research, Monash University, Clayton, Melbourne, VIC 3168, Australia.
Marcel F
MF
Nold
Niamh E
NE
Mangan
Ina
I
Rudloff
Steven X
SX
Cho
Nikeh
N
Shariatian
Thilini D
TD
Samarasinghe
Elizabeth M
EM
Skuza
John
J
Pedersen
Alex
A
Veldman
Philip J
PJ
Berger
Claudia A
CA
Nold-Petry
D000818:Animals; D001997:Bronchopulmonary Dysplasia / Q000209:etiology / Q000517:prevention & control*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D018496:Hyperoxia / Q000150:complications*; D007231:Infant, Newborn; D007249:Inflammation / Q000150:complications*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy
D053590:Interleukin 1 Receptor Antagonist Protein; D008070:Lipopolysaccharides
anti-inflammatory therapy; cytokines; neonatal immunity; receptor blockade