Pulmonary vascular changes in extremely preterm sheep after intra-amniotic exposure to Ureaplasma parvum and lipopolysaccharide

Monique G. M. Willems; Matthew W. Kemp; Laura A. Fast; Nick M. M. Wagemaker; Leon E. W. Janssen; John P. Newnham; Matt S. Payne; Owen B. Spiller; Suhas G. Kallapur; Alan H. Jobe; Tammo Delhaas; Boris W. Kramer; Tim G. A. M. Wolfs

doi:10.1371/journal.pone.0180114

Pulmonary vascular changes in extremely preterm sheep after intra-amniotic exposure to Ureaplasma parvum and lipopolysaccharide

Monique G. M. Willems, Matthew W. Kemp, Laura A. Fast, Nick M. M. Wagemaker, Leon E. W. Janssen, John P. Newnham, Matt S. Payne, Owen B. Spiller, Suhas G. Kallapur, Alan H. Jobe, Tammo Delhaas, Boris W. Kramer, Tim G. A. M. Wolfs^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Background

Chorioamnionitis can induce pulmonary inflammation and promote bronchopulmonary dysplasia development, distinguished by alveolar simplification and impaired vascular growth. Chorioamnionitis is more common during the extremely preterm canalicular lung stage (crucial for vascular development); and increases the risk for subsequent sepsis. We hypothesized that single/combined exposure to chronic and/or acute inflammation induces pulmonary inflammatory responses and vascular changes.

Methods

Ovine fetuses were intra-amniotically exposed to chronic Ureaplasma parvum (UP) at 24 days (d) before extreme preterm delivery at 94d (term 147d) and/or to lipopolysaccharide (LPS) 7 or 2d before delivery. Pulmonary inflammation, vascular remodeling and angiogenic factors were assessed.

Results

LPS exposure increased CD3-positive and myeloperoxidase-positive cells. Combined UP-LPS exposure increased pulmonary inflammation compared with 2d LPS or UP groups. The UP+2d LPS group had an increased adventitial fibrosis score when compared with UP-treated animals. A reduced wall-to-lumen ratio was found in the 7d LPS animals when compared to the 2d LPS-treated animals. Exposure to UP+2d LPS reduced VEGF and VEGFR2 levels compared with 2d LPS-treated animals. Angiopoietin-1 (Ang1) and tunica interna endothelial cell kinase 2 (Tie-2) levels were decreased after UP+7d LPS as well as after 7d LPS, but not with UP alone.

Conclusion

Chronic UP and subsequent LPS exposure increased pulmonary inflammation and decreased expression of angiogenic growth factors and receptors when compared to single

Original language	English
Article number	0180114
Number of pages	16
Journal	PLOS ONE
Volume	12
Issue number	6
DOIs	https://doi.org/10.1371/journal.pone.0180114
Publication status	Published - 30 Jun 2017

Keywords

ENDOTHELIAL GROWTH-FACTOR
BRONCHOPULMONARY DYSPLASIA
TRAINED IMMUNITY
FETAL SHEEP
OVINE MODEL
LUNG
CHORIOAMNIONITIS
ENDOTOXIN
HYPERTENSION
INFLAMMATION

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Cite this

Willems, M. G. M., Kemp, M. W., Fast, L. A., Wagemaker, N. M. M., Janssen, L. E. W., Newnham, J. P., Payne, M. S., Spiller, O. B., Kallapur, S. G., Jobe, A. H., Delhaas, T., Kramer, B. W., & Wolfs, T. G. A. M. (2017). Pulmonary vascular changes in extremely preterm sheep after intra-amniotic exposure to Ureaplasma parvum and lipopolysaccharide. PLOS ONE, 12(6), Article 0180114. https://doi.org/10.1371/journal.pone.0180114

@article{3f51c0a739b74865ba392b152dd4b7ba,

title = "Pulmonary vascular changes in extremely preterm sheep after intra-amniotic exposure to Ureaplasma parvum and lipopolysaccharide",

abstract = "BackgroundChorioamnionitis can induce pulmonary inflammation and promote bronchopulmonary dysplasia development, distinguished by alveolar simplification and impaired vascular growth. Chorioamnionitis is more common during the extremely preterm canalicular lung stage (crucial for vascular development); and increases the risk for subsequent sepsis. We hypothesized that single/combined exposure to chronic and/or acute inflammation induces pulmonary inflammatory responses and vascular changes.MethodsOvine fetuses were intra-amniotically exposed to chronic Ureaplasma parvum (UP) at 24 days (d) before extreme preterm delivery at 94d (term 147d) and/or to lipopolysaccharide (LPS) 7 or 2d before delivery. Pulmonary inflammation, vascular remodeling and angiogenic factors were assessed.ResultsLPS exposure increased CD3-positive and myeloperoxidase-positive cells. Combined UP-LPS exposure increased pulmonary inflammation compared with 2d LPS or UP groups. The UP+2d LPS group had an increased adventitial fibrosis score when compared with UP-treated animals. A reduced wall-to-lumen ratio was found in the 7d LPS animals when compared to the 2d LPS-treated animals. Exposure to UP+2d LPS reduced VEGF and VEGFR2 levels compared with 2d LPS-treated animals. Angiopoietin-1 (Ang1) and tunica interna endothelial cell kinase 2 (Tie-2) levels were decreased after UP+7d LPS as well as after 7d LPS, but not with UP alone.ConclusionChronic UP and subsequent LPS exposure increased pulmonary inflammation and decreased expression of angiogenic growth factors and receptors when compared to single",

keywords = "ENDOTHELIAL GROWTH-FACTOR, BRONCHOPULMONARY DYSPLASIA, TRAINED IMMUNITY, FETAL SHEEP, OVINE MODEL, LUNG, CHORIOAMNIONITIS, ENDOTOXIN, HYPERTENSION, INFLAMMATION",

author = "Willems, {Monique G. M.} and Kemp, {Matthew W.} and Fast, {Laura A.} and Wagemaker, {Nick M. M.} and Janssen, {Leon E. W.} and Newnham, {John P.} and Payne, {Matt S.} and Spiller, {Owen B.} and Kallapur, {Suhas G.} and Jobe, {Alan H.} and Tammo Delhaas and Kramer, {Boris W.} and Wolfs, {Tim G. A. M.}",

year = "2017",

month = jun,

day = "30",

doi = "10.1371/journal.pone.0180114",

language = "English",

volume = "12",

journal = "PLOS ONE",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "6",

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Willems, MGM, Kemp, MW, Fast, LA, Wagemaker, NMM, Janssen, LEW, Newnham, JP, Payne, MS, Spiller, OB, Kallapur, SG, Jobe, AH, Delhaas, T, Kramer, BW & Wolfs, TGAM 2017, 'Pulmonary vascular changes in extremely preterm sheep after intra-amniotic exposure to Ureaplasma parvum and lipopolysaccharide', PLOS ONE, vol. 12, no. 6, 0180114. https://doi.org/10.1371/journal.pone.0180114

TY - JOUR

T1 - Pulmonary vascular changes in extremely preterm sheep after intra-amniotic exposure to Ureaplasma parvum and lipopolysaccharide

AU - Willems, Monique G. M.

AU - Kemp, Matthew W.

AU - Fast, Laura A.

AU - Wagemaker, Nick M. M.

AU - Janssen, Leon E. W.

AU - Newnham, John P.

AU - Payne, Matt S.

AU - Spiller, Owen B.

AU - Kallapur, Suhas G.

AU - Jobe, Alan H.

AU - Delhaas, Tammo

AU - Kramer, Boris W.

AU - Wolfs, Tim G. A. M.

PY - 2017/6/30

Y1 - 2017/6/30

N2 - BackgroundChorioamnionitis can induce pulmonary inflammation and promote bronchopulmonary dysplasia development, distinguished by alveolar simplification and impaired vascular growth. Chorioamnionitis is more common during the extremely preterm canalicular lung stage (crucial for vascular development); and increases the risk for subsequent sepsis. We hypothesized that single/combined exposure to chronic and/or acute inflammation induces pulmonary inflammatory responses and vascular changes.MethodsOvine fetuses were intra-amniotically exposed to chronic Ureaplasma parvum (UP) at 24 days (d) before extreme preterm delivery at 94d (term 147d) and/or to lipopolysaccharide (LPS) 7 or 2d before delivery. Pulmonary inflammation, vascular remodeling and angiogenic factors were assessed.ResultsLPS exposure increased CD3-positive and myeloperoxidase-positive cells. Combined UP-LPS exposure increased pulmonary inflammation compared with 2d LPS or UP groups. The UP+2d LPS group had an increased adventitial fibrosis score when compared with UP-treated animals. A reduced wall-to-lumen ratio was found in the 7d LPS animals when compared to the 2d LPS-treated animals. Exposure to UP+2d LPS reduced VEGF and VEGFR2 levels compared with 2d LPS-treated animals. Angiopoietin-1 (Ang1) and tunica interna endothelial cell kinase 2 (Tie-2) levels were decreased after UP+7d LPS as well as after 7d LPS, but not with UP alone.ConclusionChronic UP and subsequent LPS exposure increased pulmonary inflammation and decreased expression of angiogenic growth factors and receptors when compared to single

AB - BackgroundChorioamnionitis can induce pulmonary inflammation and promote bronchopulmonary dysplasia development, distinguished by alveolar simplification and impaired vascular growth. Chorioamnionitis is more common during the extremely preterm canalicular lung stage (crucial for vascular development); and increases the risk for subsequent sepsis. We hypothesized that single/combined exposure to chronic and/or acute inflammation induces pulmonary inflammatory responses and vascular changes.MethodsOvine fetuses were intra-amniotically exposed to chronic Ureaplasma parvum (UP) at 24 days (d) before extreme preterm delivery at 94d (term 147d) and/or to lipopolysaccharide (LPS) 7 or 2d before delivery. Pulmonary inflammation, vascular remodeling and angiogenic factors were assessed.ResultsLPS exposure increased CD3-positive and myeloperoxidase-positive cells. Combined UP-LPS exposure increased pulmonary inflammation compared with 2d LPS or UP groups. The UP+2d LPS group had an increased adventitial fibrosis score when compared with UP-treated animals. A reduced wall-to-lumen ratio was found in the 7d LPS animals when compared to the 2d LPS-treated animals. Exposure to UP+2d LPS reduced VEGF and VEGFR2 levels compared with 2d LPS-treated animals. Angiopoietin-1 (Ang1) and tunica interna endothelial cell kinase 2 (Tie-2) levels were decreased after UP+7d LPS as well as after 7d LPS, but not with UP alone.ConclusionChronic UP and subsequent LPS exposure increased pulmonary inflammation and decreased expression of angiogenic growth factors and receptors when compared to single

KW - ENDOTHELIAL GROWTH-FACTOR

KW - BRONCHOPULMONARY DYSPLASIA

KW - TRAINED IMMUNITY

KW - FETAL SHEEP

KW - OVINE MODEL

KW - LUNG

KW - CHORIOAMNIONITIS

KW - ENDOTOXIN

KW - HYPERTENSION

KW - INFLAMMATION

U2 - 10.1371/journal.pone.0180114

DO - 10.1371/journal.pone.0180114

M3 - Article

C2 - 28666032

SN - 1932-6203

VL - 12

JO - PLOS ONE

JF - PLOS ONE

IS - 6

M1 - 0180114

ER -