Abstract
Pulmonary hypertension secondary to bronchopulmonary dysplasia (BPD-PH) represents a major complication of BPD in extremely preterm infants for which there are currently no safe and effective interventions. The abundance of interleukin-1 (IL-1) is strongly correlated with the severity and long-term outcome of BPD infants and we have previously shown that IL-1 receptor antagonist (IL-1Ra) protects against murine BPD; therefore, we hypothesized that IL-1Ra may also be effective against BPD-PH. We employed daily injections of IL-1Ra in a murine model in which BPD/BPD-PH was induced by antenatal LPS and postnatal hyperoxia of 65% O2. Pups reared in hyperoxia for 28 days exhibited a BPD-PH-like disease accompanied by significant changes in pulmonary vascular morphology: micro-CT revealed an 84% reduction in small vessels (4–5 μm diameter) compared to room air controls; this change was prevented by IL-1Ra. Pulmonary vascular resistance, assessed at day 28 of life by echocardiography using the inversely-related surrogate marker time-to-peak-velocity/right ventricular ejection time (TPV/RVET), increased in hyperoxic mice (0.27 compared to 0.32 in air controls), and fell significantly with daily IL-1Ra treatment (0.31). Importantly, in vivo cine-angiography revealed that this protection afforded by IL-1Ra treatment for 28 days is maintained at day 60 of life. Despite an increased abundance of mediators of pulmonary angiogenesis in day 5 lung lysates, namely vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1), no difference was detected in ex vivo pulmonary vascular reactivity between air and hyperoxia mice as measured in precision cut lung slices, or by immunohistochemistry in alpha-smooth muscle actin (α-SMA) and endothelin receptor type-A (ETA) at day 28. Further, on day 28 of life we observed cardiac fibrosis by Sirius Red staining, which was accompanied by an increase in mRNA expression of galectin-3 and CCL2 (chemokine (C-C motif) ligand 2) in whole hearts of hyperoxic pups, which improved with IL-1Ra. In summary, our findings suggest that daily administration of the anti-inflammatory IL-1Ra prevents the increase in pulmonary vascular resistance and the pulmonary dysangiogenesis of murine BPD-PH, thus pointing to IL-1Ra as a promising candidate for the treatment of both BPD and BPD-PH.
Highlights
Improved survival of preterm infants with gestational ages as low as 23 weeks exposes ever more preterm infants to bronchopulmonary dysplasia (BPD)
To advance the prospects for an antiinflammatory treatment for pulmonary injury and cardiovascular complications, we extended our earlier study by examining whether the benefit interleukin-1 receptor antagonist (IL-1Ra) provides against BPD extends to the pulmonary vasculature and thereby improves pulmonary vascular resistance, cardiac inflammation and fibrosis
Having shown in our model that IL-1Ra prevents the loss of alveoli that is characteristic of BPD [19, 26], the aim of the current study was to determine if blocking inflammation with IL-1Ra for 28 days ameliorates rarefaction of the pulmonary vascular bed in mice with BPD and thereby reduces pulmonary hypertension
Summary
Improved survival of preterm infants with gestational ages as low as 23 weeks exposes ever more preterm infants to bronchopulmonary dysplasia (BPD). BPD is a severe inflammatory lung disease that affects up to 15,000 preterm infants each year in the USA [1, 2], with the highest incidence of 35–68% in the 0.5–1 kg birth weight group [3, 4]. The diminished lung function of the preterm infant calls for intensive care with mechanical ventilation and oxygen supplementation, which each contribute to the development of the multifactorial pathophysiology of BPD [5] and to health complications that persist into adulthood [6, 7]. Occurring in 15–30% of BPD patients [8], the deleterious consequences of BPD-PH are far worse than those of systemic hypertension, with a survival of just 50% 2 years after diagnosis in the severe cases [9]
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