Differential short-term regional effects of early high dose erythropoietin on white matter in preterm lambs after mechanical ventilation.
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®; 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 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.
The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, 3168, Australia.
Samantha K
SK
Barton
The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, 3168, Australia.|Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, 3168, Australia.
Annie R A
AR
McDougall
The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, 3168, Australia.
Jacqueline M
JM
Melville
The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, 3168, Australia.|Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, 3168, Australia.
Timothy J M
TJ
Moss
The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, 3168, Australia.
Valerie A
VA
Zahra
The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, 3168, Australia.
Tammy
T
Lim
The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, 3168, Australia.
Kelly J
KJ
Crossley
The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, 3168, Australia.|Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, 3168, Australia.
Graeme R
GR
Polglase
The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, 3168, Australia.|Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, 3168, Australia.
Mary
M
Tolcos
D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D004921:Erythropoietin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D002534:Hypoxia, Brain / Q000188:drug therapy* / Q000209:etiology; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011247:Pregnancy; D012123:Pulmonary Ventilation; D012121:Respiration, Artificial / Q000009:adverse effects*; D012756:Sheep; D062725:Tight Junction Proteins / Q000235:genetics / Q000378:metabolism; D066127:White Matter / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
D007378:Interleukins; D018696:Neuroprotective Agents; D062725:Tight Junction Proteins; D004921:Erythropoietin