Refining anti-inflammatory therapy strategies for bronchopulmonary dysplasia
#MMPMID27957795
Rudloff I
; Cho SX
; Bui CB
; McLean C
; Veldman A
; Berger PJ
; Nold MF
; Nold-Petry CA
J Cell Mol Med
2017[Jun]; 21
(6
): 1128-1138
PMID27957795
show ga
Bronchopulmonary dysplasia (BPD) is a severe lung disease of preterm infants,
which is characterized by fewer, enlarged alveoli and increased inflammation. BPD
has grave consequences for affected infants, but no effective and safe therapy
exists. We previously showed that prophylactic treatment with interleukin-1
receptor antagonist (IL-1Ra) prevents murine BPD induced by perinatal
inflammation and hyperoxia. Here, we used the same BPD model to assess whether an
alternative anti-inflammatory agent, protein C (PC), is as effective as IL-1Ra
against BPD. We also tested whether delayed administration or a higher dose of
IL-1Ra affects its ability to ameliorate BPD and investigated aspects of drug
safety. Pups were reared in room air (21% O(2) ) or hyperoxia (65% or 85% O(2) )
and received daily injections with vehicle, 1200 IU/kg PC, 10 mg/kg IL-1Ra (early
or late onset) or 100 mg/kg IL-1Ra. After 3 or 28 days, lung and brain histology
were assessed and pulmonary cytokines were analysed using ELISA and cytokine
arrays. We found that PC only moderately reduced the severe impact of BPD on lung
structure (e.g. 18% increased alveolar number by PC versus 34% by IL-1Ra);
however, PC significantly reduced IL-1?, IL-1Ra, IL-6 and macrophage inflammatory
protein (MIP)-2 by up to 89%. IL-1Ra at 10 mg/kg prevented BPD more effectively
than 100 mg/kg IL-1Ra, but only if treatment commenced at day 1 of life. We
conclude that prophylactic low-dose IL-1Ra and PC ameliorate BPD and have
potential as the first remedy for one of the most devastating diseases preterm
babies face.
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