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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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Related in: MedlinePlus

Interleukin-1β, -6 and -8, EGR1, CYR61 and CTGF mRNA levels in control fetuses and following VG5 and VG10 ventilation strategies. IL-1β, IL-6 and IL-8 (A) and EGR1, CYR61 and CTGF (B) mRNA levels in unventilated age-matched control fetuses and in preterm lambs mechanically ventilated from birth at 125 days of gestation with either 5 (VG5) or 10 (VG10) mL/kg. The values are mean ± SEM and expressed as a fold-change relative to the mean levels in unventilated control fetuses. The asterisks (*) represents values significantly greater (p < 0.001) than values before ventilation measured in age-matched control fetuses. The hash (#) represents values significantly greater than those in the VG5 lambs (p < 0.05).
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Figure 7: Interleukin-1β, -6 and -8, EGR1, CYR61 and CTGF mRNA levels in control fetuses and following VG5 and VG10 ventilation strategies. IL-1β, IL-6 and IL-8 (A) and EGR1, CYR61 and CTGF (B) mRNA levels in unventilated age-matched control fetuses and in preterm lambs mechanically ventilated from birth at 125 days of gestation with either 5 (VG5) or 10 (VG10) mL/kg. The values are mean ± SEM and expressed as a fold-change relative to the mean levels in unventilated control fetuses. The asterisks (*) represents values significantly greater (p < 0.001) than values before ventilation measured in age-matched control fetuses. The hash (#) represents values significantly greater than those in the VG5 lambs (p < 0.05).

Mentions: The mRNA levels for IL-1β, IL-6 and IL-8 in lung tissue were significantly increased in both groups of ventilated lambs, compared to the levels prior to ventilation measured in age-matched control fetuses (p < 0.001; Fig 7). The increase in IL-1β mRNA levels was similar in VG5 (35.1 ± 12.0 fold) and VG10 (31.5 ± 9.9 fold) lambs and were greater than control levels (1.0 ± 0.3; p < 0.001). However, the increase in IL-6 was significantly greater in VG10 (116.9 ± 44.6 fold) lambs compared to VG5 lambs (28.9 ± 4.8 fold, p < 0.05), both of which were significantly higher than the levels before ventilation in control fetuses (1.0 ± 0.3; p < 0.001). The increase in IL-8 mRNA levels was also greater in the VG10 lambs (92.2 ± 52.4 fold) than in the VG5 lambs (32.8 ± 8.7 fold) and both groups were significantly higher than control levels (1.0 ± 0.4; p < 0.001), however, due to the large degree of variation between lambs the differences between the two ventilated groups were not statistically significant.


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)

Interleukin-1β, -6 and -8, EGR1, CYR61 and CTGF mRNA levels in control fetuses and following VG5 and VG10 ventilation strategies. IL-1β, IL-6 and IL-8 (A) and EGR1, CYR61 and CTGF (B) mRNA levels in unventilated age-matched control fetuses and in preterm lambs mechanically ventilated from birth at 125 days of gestation with either 5 (VG5) or 10 (VG10) mL/kg. The values are mean ± SEM and expressed as a fold-change relative to the mean levels in unventilated control fetuses. The asterisks (*) represents values significantly greater (p < 0.001) than values before ventilation measured in age-matched control fetuses. The hash (#) represents values significantly greater than those in the VG5 lambs (p < 0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Interleukin-1β, -6 and -8, EGR1, CYR61 and CTGF mRNA levels in control fetuses and following VG5 and VG10 ventilation strategies. IL-1β, IL-6 and IL-8 (A) and EGR1, CYR61 and CTGF (B) mRNA levels in unventilated age-matched control fetuses and in preterm lambs mechanically ventilated from birth at 125 days of gestation with either 5 (VG5) or 10 (VG10) mL/kg. The values are mean ± SEM and expressed as a fold-change relative to the mean levels in unventilated control fetuses. The asterisks (*) represents values significantly greater (p < 0.001) than values before ventilation measured in age-matched control fetuses. The hash (#) represents values significantly greater than those in the VG5 lambs (p < 0.05).
Mentions: The mRNA levels for IL-1β, IL-6 and IL-8 in lung tissue were significantly increased in both groups of ventilated lambs, compared to the levels prior to ventilation measured in age-matched control fetuses (p < 0.001; Fig 7). The increase in IL-1β mRNA levels was similar in VG5 (35.1 ± 12.0 fold) and VG10 (31.5 ± 9.9 fold) lambs and were greater than control levels (1.0 ± 0.3; p < 0.001). However, the increase in IL-6 was significantly greater in VG10 (116.9 ± 44.6 fold) lambs compared to VG5 lambs (28.9 ± 4.8 fold, p < 0.05), both of which were significantly higher than the levels before ventilation in control fetuses (1.0 ± 0.3; p < 0.001). The increase in IL-8 mRNA levels was also greater in the VG10 lambs (92.2 ± 52.4 fold) than in the VG5 lambs (32.8 ± 8.7 fold) and both groups were significantly higher than control levels (1.0 ± 0.4; p < 0.001), however, due to the large degree of variation between lambs the differences between the two ventilated groups were not statistically significant.

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