title: Early biomarkers and potential mediators of ventilation-induced lung injury in very preterm lambs.
abstract: BACKGROUND
  Bronchopulmonary dysplasia (BPD) is closely associated with ventilator-induced lung injury (VILI) in very preterm infants. The greatest risk of VILI may be in the immediate period after birth, when the lungs are surfactant deficient, still partially filled with liquid and not uniformly aerated. However, there have been very few studies that have examined this immediate post-birth period and identified the initial injury-related pathways that are activated. We aimed to determine if the early response genes; connective tissue growth factor (CTGF), cysteine rich-61 (CYR61) and early growth response 1 (EGR1), were rapidly induced by VILI in preterm lambs and whether ventilation with different tidal volumes caused different inflammatory cytokine and early response gene expression.
  
  
  METHODS
  To identify early markers of VILI, preterm lambs (132 d gestational age; GA, term approximately 147 d) were resuscitated with an injurious ventilation strategy (V(T) 20 mL/kg for 15 min) then gently ventilated (5 mL/kg) for 15, 30, 60 or 120 min (n = 4 in each). To determine if early response genes and inflammatory cytokines were differentially regulated by different ventilation strategies, separate groups of preterm lambs (125 d GA; n = 5 in each) were ventilated from birth with a V(T) of 5 (VG5) or 10 mL/kg (VG10) for 135 minutes. Lung gene expression levels were compared to levels prior to ventilation in age-matched control fetuses.
  
  
  RESULTS
  CTGF, CYR61 and EGR1 lung mRNA levels were increased approximately 25, 50 and 120-fold respectively (p < 0.05), within 30 minutes of injurious ventilation. VG5 and VG10 caused significant increases in CTGF, CYR61, EGR1, IL1- , IL-6 and IL-8 mRNA levels compared to control levels. CTGF, CYR61, IL-6 and IL-8 expression levels were higher in VG10 than VG5 lambs; although only the IL-6 and CYR61 mRNA levels reached significance.
  
  
  CONCLUSIONS
  CTGF, CYR61 and EGR1 may be novel early markers of lung injury and mechanical ventilation from birth using relatively low tidal volumes may be less injurious than using higher tidal volumes.
authors.affiliation: Department of Physiology, Monash University, Victoria, Australia. megan.wallace@med.monash.edu.au
authors.forename: Megan J
authors.initials: MJ
authors.lastname: Wallace
authors.forename: Megan E
authors.initials: ME
authors.lastname: Probyn
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Zahra
authors.forename: Kelly
authors.initials: K
authors.lastname: Crossley
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Cole
authors.forename: Peter G
authors.initials: PG
authors.lastname: Davis
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Morley
authors.forename: Stuart B
authors.initials: SB
authors.lastname: Hooper
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D055513:Connective Tissue Growth Factor / Q000235:genetics; D055515:Cysteine-Rich Protein 61 / Q000235:genetics; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1 / Q000235:genetics; D005819:Genetic Markers; D005865:Gestational Age; D007378:Interleukins / Q000235:genetics; D008168:Lung / Q000378:metabolism* / Q000503:physiopathology; D047928:Premature Birth; D012333:RNA, Messenger / Q000378:metabolism; D012121:Respiration, Artificial / Q000009:adverse effects* / Q000379:methods; D012756:Sheep; D013990:Tidal Volume; D013997:Time Factors; D015854:Up-Regulation; D055397:Ventilator-Induced Lung Injury / Q000209:etiology / Q000235:genetics* / Q000517:prevention & control
chemical_list: D055515:Cysteine-Rich Protein 61; D051766:Early Growth Response Protein 1; D005819:Genetic Markers; D007378:Interleukins; D012333:RNA, Messenger; D055513:Connective Tissue Growth Factor