The Ritchie Centre, Hudson Institute of Medical Research & Department of Obstetrics and Gynaecology, Monash University , Melbourne , Australia.
The Florey Institute of Neuroscience and Mental Health, University of Melbourne , Parkville, Victoria , Australia.
J Appl Physiol (1985). 2019 Jan 1;126(1):44-50. doi: 10.1152/japplphysiol.00800.2018. Epub 2018 Nov 1.
Erythropoietin (EPO) is being trialled in preterm infants to reduce brain injury, but high doses increase lung injury in ventilated preterm lambs. We aimed to determine whether early administration of lower doses of EPO could reduce ventilation-induced lung injury and systemic inflammation in preterm lambs. Ventilation was initiated in anaesthetized preterm lambs [125 ± 1 (SD) days gestation] using an injurious strategy for the first 15 min. Lambs were subsequently ventilated with a protective strategy for a total of 2 h. Lambs were randomized to receive either intravenous saline (Vent; n = 7) or intravenous 300 ( n = 5), 1,000 (EPO; n = 5), or 3,000 (EPO; n = 5) IU/kg of human recombinant EPO via an umbilical vein. Lung tissue was collected for molecular and histological assessment of inflammation and injury and compared with unventilated control lambs (UVC; n = 8). All ventilated groups had similar blood gas and ventilation parameters, but EPO lambs had a lower fraction of inspired oxygen requirement and lower alveolar-arterial difference in oxygen. Vent and EPO lambs had increased lung interleukin (IL)-1β, IL-6, and IL-8 mRNA, early lung injury genes connective tissue growth factor, early growth response protein 1, and cysteine-rich 61, and liver serum amyloid A3 mRNA compared with UVCs; no difference was observed between Vent and EPO groups. Histological lung injury was increased in Vent and EPO groups compared with UVCs, but EPO lambs had increased lung injury scores compared with VENT only. Early low-doses of EPO do not exacerbate ventilation-induced lung inflammation and injury and do not provide any short-term respiratory benefit. High doses (≥3,000 IU/kg) likely exacerbate lung inflammation and injury in ventilated preterm lambs. NEW & NOTEWORTHY Trials are ongoing to assess the efficacy of erythropoietin (EPO) to provide neuroprotection for preterm infants. However, high doses of EPO increase ventilation-induced lung injury (VILI) in preterm lambs. We investigated whether early lower doses of EPO may reduce VILI. We found that lower doses did not reduce, but did not increase, VILI, while high doses (≥3,000 IU/kg) increase VILI. Therefore, lower doses of EPO should be used in preterm infants, particularly those receiving respiratory support.
促红细胞生成素（EPO）正在早产儿中进行试验，以减少脑损伤，但高剂量会增加通气早产儿肺损伤。我们旨在确定早期给予较低剂量的 EPO 是否可以减少通气诱导的早产儿肺损伤和全身炎症。使用损伤性策略对麻醉早产儿（胎龄 125 ± 1 [SD] 天）进行通气 15 分钟，然后使用保护性策略进行总共 2 小时的通气。随机分配羔羊接受静脉内生理盐水（Vent；n = 7）或静脉内 300（EPO；n = 5）、1,000（EPO；n = 5）或 3,000（EPO；n = 5）IU/kg 人重组 EPO。收集肺组织进行炎症和损伤的分子和组织学评估，并与未通气对照羔羊（UVC；n = 8）进行比较。所有通气组的血气和通气参数相似，但 EPO 羔羊的吸氧分数和肺泡-动脉氧差较低。与 UVC 相比，Vent 和 EPO 羔羊的肺白细胞介素（IL）-1β、IL-6 和 IL-8 mRNA、早期肺损伤基因结缔组织生长因子、早期生长反应蛋白 1 和富含半胱氨酸 61 以及肝血清淀粉样蛋白 A3 mRNA 增加；Vent 和 EPO 组之间没有差异。与 UVC 相比，Vent 和 EPO 组的组织学肺损伤增加，但 EPO 羔羊的肺损伤评分高于仅 Vent 组。早期低剂量的 EPO 不会加重通气诱导的肺炎症和损伤，也不会提供任何短期呼吸益处。高剂量（≥3,000 IU/kg）可能会加重通气早产儿的肺炎症和损伤。正在进行试验以评估促红细胞生成素（EPO）对早产儿提供神经保护的疗效。然而，高剂量的 EPO 会增加早产儿通气引起的肺损伤（VILI）。我们研究了早期给予较低剂量的 EPO 是否可以减轻 VILI。我们发现，较低剂量不会减轻，但不会增加，VILI，而高剂量（≥3,000 IU/kg）会增加 VILI。因此，应在早产儿中使用较低剂量的 EPO，尤其是那些接受呼吸支持的早产儿。
