Abstract
BackgroundBronchopulmonary 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.MethodsTo identify early markers of VILI, preterm lambs (132 d gestational age; GA, term ~147 d) were resuscitated with an injurious ventilation strategy (VT 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 VT 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.ResultsCTGF, CYR61 and EGR1 lung mRNA levels were increased ~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-β, 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.ConclusionCTGF, 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.
Highlights
The lungs of very preterm infants have an immature distal airway structure, with a thick air/blood barrier and a small surface area for gas-exchange
The early response genes connective tissue growth factor (CTGF), cysteine-rich 61 (CYR61) and early growth response factor 1 (EGR1) are known to promote cell proliferation [20,21] and we have recently shown that they are rapidly activated in response to a fetal lung growth stimulus [22]
We have recently demonstrated that ventilator-induced lung injury (VILI) in the immature lung induces a rapid increase in distal lung cell proliferation [19] which is consistent with the fibroblast proliferation seen in infants with Bronchopulmonary dysplasia (BPD) [1] We have identified a number of early response genes (CTGF, early growth response 1 (EGR1) and cysteine rich-61 (CYR61)) that regulate cell proliferation and are thought to play a role in normal lung develop
Summary
The lungs of very preterm infants have an immature distal airway structure, with a thick air/blood barrier and a small surface area for gas-exchange. VILI promotes the recruitment of inflammatory cells such as neutrophils and macrophages and induces many pro-inflammatory cytokines, transcription factors and growth factors leading to abnormal lung development [8,9] These factors include interleukin (IL)-1β, IL-6, IL-8, IL-10, tumour necrosis factor (TNF)-α, transforming growth factor (TGF)-β1, nuclear factor (NF)-κB and interferon-γ [8,10,11,12,13]. Identifying the initial injury pathways is critical as the greatest risk of injury may be during the period immediately after birth when the lungs are partially liquid-filled, are surfactant deficient and are not uniformly aerated [16,17,18]. 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
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