Differential short-term regional effects of early high dose erythropoietin on white matter in preterm lambs after mechanical ventilation

Samantha K Barton, Annie RA McDougall, Jacqueline M Melville, Timothy JM Moss, Valerie A Zahra, Tammy Lim, Kelly J Crossley, Graeme R Polglase, Mary Tolcos

Research output: Contribution to journalArticleResearchpeer-review

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. METHODS: Injurious ventilation, targeting a VT of 15 ml kg-1 with no positive end-expiratory pressure (PEEP), 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). RESULTS: In Vent+EPO lambs compared to Vent lambs: (i) IL-1beta and IL-6 levels in the periventricular WM and IL-8 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). CONCLUSIONS: 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. This article is protected by copyright. All rights reserved.
Original languageEnglish
Pages (from-to)1437-1449
Number of pages13
JournalThe Journal of Physiology
Volume594
Issue number5
DOIs
Publication statusPublished - 2016

Cite this

@article{a42bd8c7760f4bee97806d1776629437,
title = "Differential short-term regional effects of early high dose erythropoietin on white matter in preterm lambs after mechanical ventilation",
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. METHODS: Injurious ventilation, targeting a VT of 15 ml kg-1 with no positive end-expiratory pressure (PEEP), 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). RESULTS: In Vent+EPO lambs compared to Vent lambs: (i) IL-1beta and IL-6 levels in the periventricular WM and IL-8 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). CONCLUSIONS: 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. This article is protected by copyright. All rights reserved.",
author = "Barton, {Samantha K} and McDougall, {Annie RA} and Melville, {Jacqueline M} and Moss, {Timothy JM} and Zahra, {Valerie A} and Tammy Lim and Crossley, {Kelly J} and Polglase, {Graeme R} and Mary Tolcos",
year = "2016",
doi = "10.1113/JP271376",
language = "English",
volume = "594",
pages = "1437--1449",
journal = "The Journal of Physiology",
issn = "0022-3751",
publisher = "Wiley-Blackwell",
number = "5",

}

Differential short-term regional effects of early high dose erythropoietin on white matter in preterm lambs after mechanical ventilation. / Barton, Samantha K; McDougall, Annie RA; Melville, Jacqueline M; Moss, Timothy JM; Zahra, Valerie A; Lim, Tammy; Crossley, Kelly J; Polglase, Graeme R; Tolcos, Mary.

In: The Journal of Physiology, Vol. 594, No. 5, 2016, p. 1437-1449.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Differential short-term regional effects of early high dose erythropoietin on white matter in preterm lambs after mechanical ventilation

AU - Barton, Samantha K

AU - McDougall, Annie RA

AU - Melville, Jacqueline M

AU - Moss, Timothy JM

AU - Zahra, Valerie A

AU - Lim, Tammy

AU - Crossley, Kelly J

AU - Polglase, Graeme R

AU - Tolcos, Mary

PY - 2016

Y1 - 2016

N2 - 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. METHODS: Injurious ventilation, targeting a VT of 15 ml kg-1 with no positive end-expiratory pressure (PEEP), 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). RESULTS: In Vent+EPO lambs compared to Vent lambs: (i) IL-1beta and IL-6 levels in the periventricular WM and IL-8 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). CONCLUSIONS: 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. This article is protected by copyright. All rights reserved.

AB - 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. METHODS: Injurious ventilation, targeting a VT of 15 ml kg-1 with no positive end-expiratory pressure (PEEP), 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). RESULTS: In Vent+EPO lambs compared to Vent lambs: (i) IL-1beta and IL-6 levels in the periventricular WM and IL-8 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). CONCLUSIONS: 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. This article is protected by copyright. All rights reserved.

UR - http://onlinelibrary.wiley.com/doi/10.1113/JP271376/epdf

U2 - 10.1113/JP271376

DO - 10.1113/JP271376

M3 - Article

VL - 594

SP - 1437

EP - 1449

JO - The Journal of Physiology

JF - The Journal of Physiology

SN - 0022-3751

IS - 5

ER -