Vitamin A protects the preterm lamb diaphragm against adverse effects of mechanical ventilation

Yong Song, Mar Janna Dahl, Wendy Leavitt, Jeremy Alvord, Calan Y. Bradford, Kurt H. Albertine, J. Jane Pillow

Research output: Contribution to journalArticle

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Abstract

Background: Preterm infants are deficient in vitamin A, which is essential for growth and development of the diaphragm. Preterm infants often require mechanical ventilation (MV) for respiratory distress. In adults, MV is associated with the development of ventilation-induced diaphragm dysfunction and difficulty weaning from the ventilator. We assessed the impact of MV on the preterm diaphragm and the protective effect of vitamin A during MV. Methods: Preterm lambs delivered operatively at ~131 days gestation (full gestation: 150 days) received respiratory support by synchronized intermittent mandatory ventilation for 3 days. Lambs in the treated group received daily (24 h) enteral doses of 2500 IU/kg/day vitamin A combined with 250 IU/kg/day retinoic acid (VARA) during MV, while MV control lambs received saline. Unventilated fetal reference lambs were euthanized at birth, without being allowed to breathe. The fetal diaphragm was collected to quantify mRNA levels of myosin heavy chain (MHC) isoforms, atrophy genes, antioxidant genes, and pro-inflammatory genes; to determine ubiquitin proteasome pathway activity; to measure the abundance of protein carbonyl, and to investigate metabolic signaling. Results: Postnatal MV significantly decreased expression level of the neonatal MHC gene but increased expression level of MHC IIx mRNA level (p < 0.05). Proteasome activity increased after 3 days MV, accompanied by increased MuRF1 mRNA level and accumulated protein carbonyl abundance. VARA supplementation decreased proteasome activity and FOXO1 signaling, down-regulated MuRF1 expression, and reduced reactive oxidant production. Conclusion: These findings suggest that 3 days of MV results in abnormal myofibrillar composition, activation of the proteolytic pathway, and oxidative injury of diaphragms in mechanically ventilated preterm lambs. Daily enteral VARA protects the preterm diaphragm from these adverse effects.

Original languageEnglish
Article number1119
JournalFrontiers in Physiology
Volume9
Issue numberAUG
DOIs
Publication statusPublished - 13 Aug 2018

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Diaphragm
Vitamin A
Artificial Respiration
Myosin Heavy Chains
Proteasome Endopeptidase Complex
Premature Infants
Messenger RNA
Small Intestine
Ventilation
Ventilator Weaning
Genes
Pregnancy
Ubiquitin
Tretinoin
Growth and Development
Oxidants
Atrophy
Protein Isoforms
Proteins
Antioxidants

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Song, Yong ; Dahl, Mar Janna ; Leavitt, Wendy ; Alvord, Jeremy ; Bradford, Calan Y. ; Albertine, Kurt H. ; Pillow, J. Jane. / Vitamin A protects the preterm lamb diaphragm against adverse effects of mechanical ventilation. In: Frontiers in Physiology. 2018 ; Vol. 9, No. AUG.
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title = "Vitamin A protects the preterm lamb diaphragm against adverse effects of mechanical ventilation",
abstract = "Background: Preterm infants are deficient in vitamin A, which is essential for growth and development of the diaphragm. Preterm infants often require mechanical ventilation (MV) for respiratory distress. In adults, MV is associated with the development of ventilation-induced diaphragm dysfunction and difficulty weaning from the ventilator. We assessed the impact of MV on the preterm diaphragm and the protective effect of vitamin A during MV. Methods: Preterm lambs delivered operatively at ~131 days gestation (full gestation: 150 days) received respiratory support by synchronized intermittent mandatory ventilation for 3 days. Lambs in the treated group received daily (24 h) enteral doses of 2500 IU/kg/day vitamin A combined with 250 IU/kg/day retinoic acid (VARA) during MV, while MV control lambs received saline. Unventilated fetal reference lambs were euthanized at birth, without being allowed to breathe. The fetal diaphragm was collected to quantify mRNA levels of myosin heavy chain (MHC) isoforms, atrophy genes, antioxidant genes, and pro-inflammatory genes; to determine ubiquitin proteasome pathway activity; to measure the abundance of protein carbonyl, and to investigate metabolic signaling. Results: Postnatal MV significantly decreased expression level of the neonatal MHC gene but increased expression level of MHC IIx mRNA level (p < 0.05). Proteasome activity increased after 3 days MV, accompanied by increased MuRF1 mRNA level and accumulated protein carbonyl abundance. VARA supplementation decreased proteasome activity and FOXO1 signaling, down-regulated MuRF1 expression, and reduced reactive oxidant production. Conclusion: These findings suggest that 3 days of MV results in abnormal myofibrillar composition, activation of the proteolytic pathway, and oxidative injury of diaphragms in mechanically ventilated preterm lambs. Daily enteral VARA protects the preterm diaphragm from these adverse effects.",
keywords = "BPD, Bronchopulmonary dysplasia, Disuse atrophy, Retinoids, Retinol, Ventilator-induced diaphragm dysfunction, VIDD",
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Vitamin A protects the preterm lamb diaphragm against adverse effects of mechanical ventilation. / Song, Yong; Dahl, Mar Janna; Leavitt, Wendy; Alvord, Jeremy; Bradford, Calan Y.; Albertine, Kurt H.; Pillow, J. Jane.

In: Frontiers in Physiology, Vol. 9, No. AUG, 1119, 13.08.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Vitamin A protects the preterm lamb diaphragm against adverse effects of mechanical ventilation

AU - Song, Yong

AU - Dahl, Mar Janna

AU - Leavitt, Wendy

AU - Alvord, Jeremy

AU - Bradford, Calan Y.

AU - Albertine, Kurt H.

AU - Pillow, J. Jane

PY - 2018/8/13

Y1 - 2018/8/13

N2 - Background: Preterm infants are deficient in vitamin A, which is essential for growth and development of the diaphragm. Preterm infants often require mechanical ventilation (MV) for respiratory distress. In adults, MV is associated with the development of ventilation-induced diaphragm dysfunction and difficulty weaning from the ventilator. We assessed the impact of MV on the preterm diaphragm and the protective effect of vitamin A during MV. Methods: Preterm lambs delivered operatively at ~131 days gestation (full gestation: 150 days) received respiratory support by synchronized intermittent mandatory ventilation for 3 days. Lambs in the treated group received daily (24 h) enteral doses of 2500 IU/kg/day vitamin A combined with 250 IU/kg/day retinoic acid (VARA) during MV, while MV control lambs received saline. Unventilated fetal reference lambs were euthanized at birth, without being allowed to breathe. The fetal diaphragm was collected to quantify mRNA levels of myosin heavy chain (MHC) isoforms, atrophy genes, antioxidant genes, and pro-inflammatory genes; to determine ubiquitin proteasome pathway activity; to measure the abundance of protein carbonyl, and to investigate metabolic signaling. Results: Postnatal MV significantly decreased expression level of the neonatal MHC gene but increased expression level of MHC IIx mRNA level (p < 0.05). Proteasome activity increased after 3 days MV, accompanied by increased MuRF1 mRNA level and accumulated protein carbonyl abundance. VARA supplementation decreased proteasome activity and FOXO1 signaling, down-regulated MuRF1 expression, and reduced reactive oxidant production. Conclusion: These findings suggest that 3 days of MV results in abnormal myofibrillar composition, activation of the proteolytic pathway, and oxidative injury of diaphragms in mechanically ventilated preterm lambs. Daily enteral VARA protects the preterm diaphragm from these adverse effects.

AB - Background: Preterm infants are deficient in vitamin A, which is essential for growth and development of the diaphragm. Preterm infants often require mechanical ventilation (MV) for respiratory distress. In adults, MV is associated with the development of ventilation-induced diaphragm dysfunction and difficulty weaning from the ventilator. We assessed the impact of MV on the preterm diaphragm and the protective effect of vitamin A during MV. Methods: Preterm lambs delivered operatively at ~131 days gestation (full gestation: 150 days) received respiratory support by synchronized intermittent mandatory ventilation for 3 days. Lambs in the treated group received daily (24 h) enteral doses of 2500 IU/kg/day vitamin A combined with 250 IU/kg/day retinoic acid (VARA) during MV, while MV control lambs received saline. Unventilated fetal reference lambs were euthanized at birth, without being allowed to breathe. The fetal diaphragm was collected to quantify mRNA levels of myosin heavy chain (MHC) isoforms, atrophy genes, antioxidant genes, and pro-inflammatory genes; to determine ubiquitin proteasome pathway activity; to measure the abundance of protein carbonyl, and to investigate metabolic signaling. Results: Postnatal MV significantly decreased expression level of the neonatal MHC gene but increased expression level of MHC IIx mRNA level (p < 0.05). Proteasome activity increased after 3 days MV, accompanied by increased MuRF1 mRNA level and accumulated protein carbonyl abundance. VARA supplementation decreased proteasome activity and FOXO1 signaling, down-regulated MuRF1 expression, and reduced reactive oxidant production. Conclusion: These findings suggest that 3 days of MV results in abnormal myofibrillar composition, activation of the proteolytic pathway, and oxidative injury of diaphragms in mechanically ventilated preterm lambs. Daily enteral VARA protects the preterm diaphragm from these adverse effects.

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KW - Bronchopulmonary dysplasia

KW - Disuse atrophy

KW - Retinoids

KW - Retinol

KW - Ventilator-induced diaphragm dysfunction

KW - VIDD

UR - http://www.scopus.com/inward/record.url?scp=85051632466&partnerID=8YFLogxK

U2 - 10.3389/fphys.2018.01119

DO - 10.3389/fphys.2018.01119

M3 - Article

VL - 9

JO - Frontiers in Physiology

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SN - 1664-042X

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