Brief, large tidal volume ventilation initiates lung injury and a systemic response in fetal sheep

Am J Respir Crit Care Med. 2007 Sep 15;176(6):575-81. doi: 10.1164/rccm.200701-051OC. Epub 2007 Jul 19.


Rationale: Premature infants are exposed to potentially injurious ventilation in the delivery room. Assessments of lung injury are confounded by effects of subsequent ventilatory support.

Objectives: To evaluate the injury response to a brief period of large tidal volume (Vt) ventilation, simulating neonatal resuscitation in preterm neonates.

Methods: Preterm lambs (129 d gestation; term is150 d) were ventilated (Vt = 15 ml/kg, no positive end-expiratory pressure) for 15 minutes to simulate delivery room resuscitation, either with the placental circulation intact (fetal resuscitation [ FR]) or after delivery (neonatal resuscitation [NR]). After the initial 15 minutes, lambs received surfactant and were maintained with either ventilatory support (FR-VS and NR-VS) or placental support (FR-PS) for 2 hours, 45 minutes. A control group received no resuscitation and was maintained with placental support. Samples of bronchoalveolar lavage fluid, lung, and liver were analyzed.

Measurements and main results: Inflammatory cells and protein in bronchoalveolar lavage fluid, heat shock protein-70 immunostaining, IL-1beta, IL-6, IL-8, monocyte chemotactic protein-1, serum amyloid A (SAA)-3, Toll-like receptor (TLR)-2, and TLR4 mRNA in the lungs were increased in the FR-PS group compared with control animals. There were further elevations in neutrophils, IL-6, and IL-8 mRNA in the FR-VS and NR-VS groups compared with FR-PS. SAA3, TLR2, and TLR4 mRNA increased in the liver in all resuscitation groups relative to control animals.

Conclusions: Ventilation for 15 minutes with a Vt of 15 ml/kg initiates an injurious process in the preterm lung and a hepatic acute-phase response. Subsequent ventilatory support causes further increases in some injury indicators.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Bronchoalveolar Lavage Fluid / chemistry*
  • Chemokine CCL2 / metabolism
  • Disease Models, Animal
  • Female
  • HSP70 Heat-Shock Proteins / metabolism
  • Immunohistochemistry
  • Interleukins / metabolism
  • Liver / metabolism
  • Lung / metabolism*
  • Lung Diseases / embryology
  • Lung Diseases / etiology*
  • Lung Diseases / metabolism
  • Pregnancy
  • RNA, Messenger / analysis
  • Respiration, Artificial / adverse effects*
  • Resuscitation / methods
  • Serum Amyloid A Protein / metabolism
  • Severity of Illness Index
  • Sheep
  • Tidal Volume*
  • Toll-Like Receptor 2 / metabolism
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism


  • Biomarkers
  • Chemokine CCL2
  • HSP70 Heat-Shock Proteins
  • Interleukins
  • RNA, Messenger
  • Serum Amyloid A Protein
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4