Preterm birth occurs in 11% of live births globally and accounts for 35% of all newborn deaths. Preterm newborns have immature immune systems, with reduced innate and adaptive immunity; their immune systems may be further compromised by various factors associated with preterm birth. The immune systems of preterm infants have a smaller pool of monocytes and neutrophils, impaired ability of these cells to kill pathogens, and lower production of cytokines which limits T cell activation and reduces the ability to fight bacteria and detect viruses in cells, compared to term infants. Intrauterine inflammation is a major contributor to preterm birth, and causes premature immune activation and cytokine production. This can induce immune tolerance leading to reduced newborn immune function. Intrauterine inflammation is associated with an increased risk of early-onset sepsis and likely has long-term adverse immune consequences. Requisite medical interventions further impact on immune development and function. Antenatal corticosteroid treatment to prevent newborn respiratory disease is routine but may be immunosuppressive, and has been associated with febrile responses, reductions in lymphocyte proliferation and cytokine production, and increased risk of infection. Invasive medical procedures result in an increased risk of late-onset sepsis. Respiratory support can cause chronic inflammatory lung disease associated with increased risk of long-term morbidity. Colonization of the infant by microorganisms at birth is a significant contributor to the establishment of the microbiome. Caesarean section affects infant colonization, potentially contributing to lifelong immune function and well-being. Several factors associated with preterm birth alter immune function. A better understanding of perinatal modification of the preterm immune system will allow for the refinement of care to minimize lifelong adverse immune consequences.

The hypothesis examined was that contractions of the longitudinal muscle layer occurin the duodenum which are independent of those of the circular muscle layer and that they induce flow of duodenal contents. A segment of opossum duodenum isolated in vitro was marked and photographed during periods of longitudinal muscle contraction, when the circular muscle layer appeared inactive. The prequency of longitudinal oscillation of the marked points was 20.5 cycles/min. The longitudinal displacement wave spread caudad with an average velocity of 3.27 cm/s. Frequency and velocity of electrical slow waves were determined in similiar duodenal segments. Slow-wave frquencywas 18.9 cycles/min. In a two-dimensional mechanical model, flow induced by simulatedlongitudinal muscle layer appear to be driven by the electrical slow waves of the duodenum. They are capable of inducing a pattern of flow in which ocntents flow betweenthe core and the periphery of the intestinal conduit.

Key pointsr Erythropoietin is a neuroprotectant undergoing clinical trial for brain injury in term and preterm infants.r This is the first experimental study to assess the acute effects of erythropoietin on the cerebral white matter in preterm ventilated lambs.r Administration of erythropoietin within minutes of injurious ventilation onset amplified pro-inflammatory cytokine gene expression in both the periventricular and subcortical white matter compared to the ventilation alone group; erythropoietin had no effect on the area of microglial aggregations in white matter regions with a reduction in cellular density of aggregations in the subcortical white matter only.r Administration of erythropoietin in conjunction with injurious ventilation increased gene expression of tight junction proteins and reduced protein extravasation from blood vessels in the cerebral white matter.r Given the increase in inflammation after erythropoietin, we recommend further investigation into its use as a treatment for ventilated preterm babies prior to clinical translation.Abstract Inadvertently injurious ventilation of preterm neonates in the delivery room can cause cerebral white matter (WM) inflammation and injury. We investigated the impact of an early high dose of recombinant human erythropoietin (EPO) on ventilation-induced WM changes in preterm lambs. Injurious ventilation, targeting a V T of 15 ml kg −1 with no positive end-expiratory pressure, was initiated for 15 min in preterm lambs (0.85 gestation). Conventional ventilation was continued for a further 105 min. Lambs received either 5000 IU kg −1 of EPO (EPREX R ; Vent+EPO; n = 6) or vehicle (Vent; n = 8) via an umbilical vein at 4 ± 2 min. Markers of WM injury and inflammation were assessed using quantitative real-time PCR (qPCR) and immunohistochemistry and compared to a group of unventilated controls (UVC; n = 4). In Vent+EPO lambs compared to Vent lambs: (i) interleukin (IL)-1β and IL-6 mRNA levels in the periventricular WM and IL-8 mRNA levels in the subcortical WM were higher (P < 0.05 for all); (ii) the density of microglia within the aggregations was not different in the periventricular WM and was lower in the subcortical WM (P = 0.001); (iii) the density of astrocytes was lower in the subcortical WM (P = 0.002); (iv) occludin and claudin-1 mRNA levels were higher in the periventricular WM (P < 0.02 for all) and (vi) the number of blood vessels with protein G. R. Polglase and M. Tolcos contributed equally to this work. extravasation was lower (P < 0.05). Recombinant human EPO had variable regional effects within the WM when administered during injurious ventilation. The adverse short-term outcomes discourage the use of early high dose EPO administration in preterm ventilated babies.

Key pointsr Erythropoietin (EPO) has been suggested as a potential treatment for bronchopulmonary dysplasia (BPD) in preterm infants.r Ventilation-induced lung injury (VILI) is a major cause of BPD in preterm neonates. We investigated whether early high-dose EPO (I.V. 5000 IU kg −1 ) administration can reduce lung inflammation and injury resultant from VILI in ventilated preterm lambs.r Early high-dose EPO administration increased mRNA expression of early markers of lung inflammation and injury and systemic injury controls.r Early high-dose EPO worsened histological assessment of inflammation, airway wall thickness, haemorrhage and total injury compared to controls.r Early high-dose EPO may increase the incidence and severity of respiratory disease in ventilated, preterm neonates.Abstract Ventilation-induced lung injury (VILI) of preterm neonates probably contributes to the pathogenesis of bronchopulmonary dysplasia (BPD). Erythropoietin (EPO) has been suggested as a therapy for BPD. The aim of this study was to determine whether prophylactic administration of EPO reduces VILI in preterm newborn lambs. Lambs at 126 days of gestation (term is 147 days) were delivered and ventilated with a high tidal volume strategy for 15 min to cause lung injury, then received gentle ventilation until 2 h of age. Lambs were randomized to receive intravenous EPO (5000 IU kg −1 : Vent+EPO; n = 6) or phosphate-buffered saline (Vent; n = 7) soon after birth: unventilated controls (UVC; n = 8) did not receive ventilation or any treatment. Physiological parameters were recorded throughout the experimental procedure. Samples of lung were collected for histological and molecular assessment of inflammation and injury. Samples of liver were collected to assess the systemic acute phase response. Vent+EPO lambs received higher F IO 2 , P aO 2 and oxygenation during the first 10 min than Vent lambs. There were no differences in physiological indices beyond this time. Total lung injury score, airway wall thickness, inflammation and haemorrhage were higher in Vent+EPO lambs than in Vent lambs. Lung inflammation and early markers of lung and systemic injury were elevated in ventilated lambs relative to unventilated lambs; EPO administration further increased lung inflammation and markers of lung and systemic injury. Prophylactic EPO exacerbates VILI, which may increase the incidence and severity of long-term respiratory disease. More studies are required before EPO can be used for lung protection in preterm infants.