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% O 2 ). 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% O 2 . 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.anti-inflammatory therapy | cytokines | receptor blockade | neonatal immunity

ObjectivesThe significance of blood pressure variability (BPV) for cerebral oxygenation in extremely preterm infants has not been explored, though BPV may well be associated with end organ injury. We hypothesized that increased BPV in sick preterm infants, by exceeding the cerebral autoregulatory capacity, is associated with cerebral oxygenation changes which closely follow the blood pressure fluctuations. We assessed the autoregulatory capacity in the early postnatal period, by determining the correlation between BPV (mmHg2) and coherence of mean arterial blood pressure (MABP mmHg) and cerebral oxygenation (tissue oxygenation index, TOI %).Study DesignThirty-two preterm infants of mean gestational age of 26.3 (±1.5) weeks were studied on the first 3 postnatal days. Spectral analysis (Coherence and transfer-function gain analysis) was used to calculate coherence of MABP and TOI; BPV was quantified using power spectral density of MABP.ResultsOverall, maximum Coherence showed a trend for positive correlation with BPV (n = 32, p = 0.06). Infants identified as clinically unstable with documented brain injury (n = 7) had high Coherence values at low BPV. Separate analysis of stable infants (excluding the 7 critically ill infants) revealed a significant association between maximum Coherence and BPV (n = 25, p = 0.006).ConclusionsFluctuation in cerebral oxygenation is closely associated with increased BPV in preterm infants undergoing intensive care. Moreover, in the critically sick preterm infant, blood pressure-dependent variations in cerebral oxygenation occur even with relatively lower BPV, suggesting they have severely impaired autoregulation, and placing them at greater vulnerability to cerebral injury arising from blood pressure fluctuations.

The impact of endotoxemia on cerebral endothelium and cerebral blood flow (CBF) regulation was studied in conscious newborn lambs. Bacterial endotoxin [LPS, 2 microg/kg iv] was infused on 3 consecutive days. Cerebrovascular function was assessed by monitoring CBF and cerebral vascular resistance (CVR) over 12 h each day and by the endothelium-dependent vasodilator bradykinin (BK) (n = 10). Inflammatory responses were assessed by plasma tumor necrosis factor-alpha (TNF-alpha, n = 5). Acutely, LPS disrupted the cerebral circulation within 1 h, with peak cerebral vasoconstriction at 3 h (CBF -28 and CVR +118%, P < 0.05) followed by recovery to baseline by 12 h. TNF-alpha and body temperature peaked approximately 1 h post-LPS. BK-induced vasodilatation (CVR -20%, P < 0.05) declined with each LPS infusion, was abolished after 3 days, and remained absent for at least the subsequent 5 days. Histological evidence of brain injury was found in four of five LPS-treated newborns. We conclude that endotoxin impairs cerebral perfusion in newborn lambs via two mechanisms: 1) acute vasoconstriction (over several hours); and 2) persistent endothelial dysfunction (over several days). Endotoxin-induced circulatory impairments may place the newborn brain at prolonged risk of CBF dysregulation and injury as a legacy of endotoxin exposure.

TOI corresponds with cerebral oxygenation. The variable agreement of TOIsrs with TOIcox may reflect changes in cerebral A:V ratio due to arterial oxygenation-related vasoreactivity.