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Early biomarkers and potential mediators of ventilation-induced lung injury in very preterm lambs.

Wallace MJ, Probyn ME, Zahra VA, Crossley K, Cole TJ, Davis PG, Morley CJ, Hooper SB - Respir. Res. (2009)

Bottom Line: Bronchopulmonary dysplasia (BPD) is closely associated with ventilator-induced lung injury (VILI) in very preterm infants.VG5 and VG10 caused significant increases in CTGF, CYR61, EGR1, IL1- , IL-6 and IL-8 mRNA levels compared to control levels.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Physiology, Monash University, Victoria, Australia. megan.wallace@med.monash.edu.au

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.

Conclusion: 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.

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Histological evidence of lung injury in lambs ventilated with VG5 and VG10 ventilation strategies. Representative haematoxylin and eosin stained lung tissue sections in preterm lambs mechanically ventilated from birth at 125 d of gestation with a tidal volume of 10 mL/kg (A) or 5 mL/kg (B) and unventilated control fetuses (C). Hyaline membranes are shown with arrows and detached epithelial cells are shown with arrowheads.
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Figure 6: Histological evidence of lung injury in lambs ventilated with VG5 and VG10 ventilation strategies. Representative haematoxylin and eosin stained lung tissue sections in preterm lambs mechanically ventilated from birth at 125 d of gestation with a tidal volume of 10 mL/kg (A) or 5 mL/kg (B) and unventilated control fetuses (C). Hyaline membranes are shown with arrows and detached epithelial cells are shown with arrowheads.

Mentions: The blood gas and ventilation parameters for these studies have been presented in detail previously [28]. The co-efficient of variation of the delivered VT was 6.5 ± 0.3%. The PIP and Paw delivered to VG10 lambs was significantly higher (p < 0.05) than the PIP and Paw delivered to VG5 lambs throughout the 15 minute resuscitation and 2 h ventilation period (Fig 5). PaCO2 values were significantly lower (p < 0.05) in the VG10 group than the VG5 group throughout the 15 minute resuscitation period and 2 h ventilation period. pHa values were significantly higher (p < 0.05) in lambs ventilated at 10 mL/kg compared with lambs ventilated at 5 mL/kg during the resuscitation period but were not different from the 5 mL/kg lambs during the 2 hour ventilation period. The SaO2 and AaDO2 were similar in both groups (Fig 5). Two of the VG10 lambs developed pneumothoraces and the experiments were terminated (just prior to the planned end of the ventilation period). Subpleural air leaks were also observed in three of the VG10 lambs. None of the VG5 lambs developed pneumothoraces and only one developed a subpleural air leak. At least three H&E stained tissue sections from three different regions of the lung from each lamb were closely examined under the light microscope for evidence of lung injury. All lung tissue sections from lambs ventilated with 10 mL/kg showed substantial and consistent evidence of hyaline membranes, cellular debris and epithelial cell detachment in the bronchioles and terminal airspaces of the lungs (Fig 6). In contrast, there was substantial variation within and between the lungs of the lambs ventilated with 5 mL/kg. Hyaline membranes in VG5 lambs were rare and minor in comparison to VG10 lambs and while epithelial cell detachment was a common finding (Fig 6) in all VG5 lambs, there was substantial regional variation. Hyaline membranes and epithelial cell detachment were not observed in lungs from control fetuses.


Early biomarkers and potential mediators of ventilation-induced lung injury in very preterm lambs.

Wallace MJ, Probyn ME, Zahra VA, Crossley K, Cole TJ, Davis PG, Morley CJ, Hooper SB - Respir. Res. (2009)

Histological evidence of lung injury in lambs ventilated with VG5 and VG10 ventilation strategies. Representative haematoxylin and eosin stained lung tissue sections in preterm lambs mechanically ventilated from birth at 125 d of gestation with a tidal volume of 10 mL/kg (A) or 5 mL/kg (B) and unventilated control fetuses (C). Hyaline membranes are shown with arrows and detached epithelial cells are shown with arrowheads.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2662809&req=5

Figure 6: Histological evidence of lung injury in lambs ventilated with VG5 and VG10 ventilation strategies. Representative haematoxylin and eosin stained lung tissue sections in preterm lambs mechanically ventilated from birth at 125 d of gestation with a tidal volume of 10 mL/kg (A) or 5 mL/kg (B) and unventilated control fetuses (C). Hyaline membranes are shown with arrows and detached epithelial cells are shown with arrowheads.
Mentions: The blood gas and ventilation parameters for these studies have been presented in detail previously [28]. The co-efficient of variation of the delivered VT was 6.5 ± 0.3%. The PIP and Paw delivered to VG10 lambs was significantly higher (p < 0.05) than the PIP and Paw delivered to VG5 lambs throughout the 15 minute resuscitation and 2 h ventilation period (Fig 5). PaCO2 values were significantly lower (p < 0.05) in the VG10 group than the VG5 group throughout the 15 minute resuscitation period and 2 h ventilation period. pHa values were significantly higher (p < 0.05) in lambs ventilated at 10 mL/kg compared with lambs ventilated at 5 mL/kg during the resuscitation period but were not different from the 5 mL/kg lambs during the 2 hour ventilation period. The SaO2 and AaDO2 were similar in both groups (Fig 5). Two of the VG10 lambs developed pneumothoraces and the experiments were terminated (just prior to the planned end of the ventilation period). Subpleural air leaks were also observed in three of the VG10 lambs. None of the VG5 lambs developed pneumothoraces and only one developed a subpleural air leak. At least three H&E stained tissue sections from three different regions of the lung from each lamb were closely examined under the light microscope for evidence of lung injury. All lung tissue sections from lambs ventilated with 10 mL/kg showed substantial and consistent evidence of hyaline membranes, cellular debris and epithelial cell detachment in the bronchioles and terminal airspaces of the lungs (Fig 6). In contrast, there was substantial variation within and between the lungs of the lambs ventilated with 5 mL/kg. Hyaline membranes in VG5 lambs were rare and minor in comparison to VG10 lambs and while epithelial cell detachment was a common finding (Fig 6) in all VG5 lambs, there was substantial regional variation. Hyaline membranes and epithelial cell detachment were not observed in lungs from control fetuses.

Bottom Line: Bronchopulmonary dysplasia (BPD) is closely associated with ventilator-induced lung injury (VILI) in very preterm infants.VG5 and VG10 caused significant increases in CTGF, CYR61, EGR1, IL1- , IL-6 and IL-8 mRNA levels compared to control levels.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Physiology, Monash University, Victoria, Australia. megan.wallace@med.monash.edu.au

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.

Conclusion: 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.

Show MeSH
Related in: MedlinePlus