Wallace Megan J, Probyn Megan E, Zahra Valerie A, Crossley Kelly, Cole Timothy J, Davis Peter G, Morley Colin J, Hooper Stuart B
Department of Physiology, Monash University, Victoria, Australia.
Respir Res. 2009 Mar 10;10(1):19. doi: 10.1186/1465-9921-10-19.
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.
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.
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.
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.
支气管肺发育不良（BPD）与极早产儿的呼吸机诱导性肺损伤（VILI）密切相关。VILI的最大风险可能在出生后的即刻，此时肺部缺乏表面活性物质，仍部分充满液体且通气不均匀。然而，很少有研究考察过这个出生后的即刻时期并确定被激活的初始损伤相关途径。我们旨在确定早期反应基因；结缔组织生长因子（CTGF）、富含半胱氨酸的61（CYR61）和早期生长反应1（EGR1）是否在早产羔羊中被VILI快速诱导，以及不同潮气量通气是否会导致不同的炎性细胞因子和早期反应基因表达。
为了确定VILI的早期标志物，早产羔羊（胎龄132天；GA，足月约147天）采用有害通气策略复苏（潮气量20 mL/kg，持续15分钟），然后轻柔通气（5 mL/kg）15、30、60或120分钟（每组n = 4）。为了确定不同通气策略是否对早期反应基因和炎性细胞因子有不同调节作用，将不同组的早产羔羊（胎龄125天；每组n = 5）从出生开始分别用5（VG5）或10 mL/kg（VG10）的潮气量通气135分钟。将肺基因表达水平与年龄匹配的对照胎儿通气前的水平进行比较。
在有害通气后30分钟内，CTGF、CYR61和EGR1的肺mRNA水平分别增加了约25、50和120倍（p < 0.05）。与对照水平相比，VG5和VG10导致CTGF、CYR61、EGR1、IL1 - 、IL - 6和IL - 8的mRNA水平显著增加。VG10羔羊中CTGF、CYR61、IL - 6和IL - 8的表达水平高于VG5羔羊；尽管只有IL - 6和CYR61的mRNA水平达到显著差异。
CTGF、CYR61和EGR1可能是肺损伤的新型早期标志物，出生后使用相对低潮气量进行机械通气可能比使用高潮气量的损伤性更小。
