Abstract
Fetal growth restriction (FGR) and prematurity are often co-morbidities, and both are risk factors for lung disease. Despite advances in early delivery combined with supportive ventilation, rates of ventilation-induced lung injury (VILI) remain high. There are currently no protective treatments or interventions available that target lung morbidities associated with FGR preterm infants. Stem cell therapy, such as umbilical cord blood (UCB) cell administration, demonstrates an ability to attenuate inflammation and injury associated with VILI in preterm appropriately grown animals. However, no studies have looked at the effects of stem cell therapy in growth restricted newborns. We aimed to determine if UCB treatment could attenuate acute inflammation in the first 24 h of ventilation, comparing effects in lambs born preterm following FGR with those born preterm but appropriately grown (AG). Placental insufficiency (FGR) was induced by single umbilical artery ligation in twin-bearing ewes at 88 days gestation, with twins used as control (appropriately grown, AG). Lambs were delivered preterm at ~126 days gestation (term is 150 days) and randomized to either immediate euthanasia (unventilated controls, AGUVC and FGRUVC) or commenced on 24 h of gentle supportive ventilation (AGV and FGRV) with additional cohorts receiving UCB treatment at 1 h (AGCELLS, FGRCELLS). Lungs were collected at post-mortem for histological and biochemical examination. Ventilation caused lung injury in AG lambs, as indicated by decreased septal crests and elastin density, as well as increased inflammation. Lung injury in AG lambs was attenuated with UCB therapy. Ventilated FGR lambs also sustained lung injury, albeit with different indices compared to AG lambs; in FGR, ventilation reduced septal crest density, reduced alpha smooth muscle actin density and reduced cell proliferation. UCB treatment in ventilated FGR lambs further decreased septal crest density and increased collagen deposition, however, it increased angiogenesis as evidenced by increased vascular endothelial growth factor (VEGF) expression and vessel density. This is the first time that a cell therapy has been investigated in the lungs of growth restricted animals. We show that the uterine environment can alter the response to both secondary stress (ventilation) and therapy (UCB). This study highlights the need for further research on the potential impact of novel therapies on a growth restricted offspring.
Highlights
Fetal growth restriction (FGR) is a common complication of pregnancy, where a fetus fails to reach its expected growth potential, primarily due to placental insufficiency [1]
Our research demonstrates that after 24 h of ventilation, Umbilical cord blood (UCB) therapy shows differential effects in appropriately grown and growth restricted lambs, where protection from ventilation induced lung injury (VILI) was evident in AG lambs but not FGR lambs
We have previously shown that AG and FGR newborns do not have significantly different ventilator requirements in the first 2 h of life [4, 38], in this study we extended these findings to show that, with a prolonged period of ventilation, FGR lambs begin to require a greater Peak inspiratory pressure (PIP) to maintain VT, suggesting stiffer and less compliant lungs, a change that was subclinical throughout our experiment period as shown by dynamic compliance
Summary
Fetal growth restriction (FGR) is a common complication of pregnancy, where a fetus fails to reach its expected growth potential, primarily due to placental insufficiency [1]. It is evident that early and late onset FGR have differential effects [6], and animal studies to date have primarily induced FGR during late gestation, and it is, possible that crucial lung development has already occurred at this stage [7]; whereas preclinical studies of long term growth restriction describe altered surfactant protein [8, 9] disrupted alveolarization, with thickened parenchyma [10] and large alveoli resulting in reduced alveolar and vascular density [11]. Whilst ventilation is usually essential for survival in such scenarios, it has the potential to exacerbate pathology in FGR lungs, since lung development may already be adversely affected by the chronic hypoxemia caused by placental insufficiency [11]. Current treatment focuses on ensuring the survival of the FGR infant while ameliorating the detrimental effects of FGR on the lungs
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