Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan.
PLoS One. 2011;6(9):e24692. doi: 10.1371/journal.pone.0024692. Epub 2011 Sep 9.
Diaphragmatic dysfunction found in the patients with acute lung injury required prolonged mechanical ventilation. Mechanical ventilation can induce production of inflammatory cytokines and excess deposition of extracellular matrix proteins via up-regulation of transforming growth factor (TGF)-β1. Lumican is known to participate in TGF-β1 signaling during wound healing. The mechanisms regulating interactions between mechanical ventilation and diaphragmatic injury are unclear. We hypothesized that diaphragmatic damage by short duration of mechanical stretch caused up-regulation of lumican that modulated TGF-β1 signaling.
Male C57BL/6 mice, either wild-type or lumican-null, aged 3 months, weighing between 25 and 30 g, were exposed to normal tidal volume (10 ml/kg) or high tidal volume (30 ml/kg) mechanical ventilation with room air for 2 to 8 hours. Nonventilated mice served as control groups.
High tidal volume mechanical ventilation induced interfibrillar disassembly of diaphragmatic collagen fiber, lumican activation, type I and III procollagen, fibronectin, and α-smooth muscle actin (α-SMA) mRNA, production of free radical and TGF-β1 protein, and positive staining of lumican in diaphragmatic fiber. Mechanical ventilation of lumican deficient mice attenuated diaphragmatic injury, type I and III procollagen, fibronectin, and α-SMA mRNA, and production of free radical and TGF-β1 protein. No significant diaphragmatic injury was found in mice subjected to normal tidal volume mechanical ventilation.
Our data showed that high tidal volume mechanical ventilation induced TGF-β1 production, TGF-β1-inducible genes, e.g., collagen, and diaphragmatic dysfunction through activation of the lumican.
急性肺损伤患者存在膈肌功能障碍,需要长时间机械通气。机械通气可通过上调转化生长因子-β1(TGF-β1)诱导炎症细胞因子的产生和细胞外基质蛋白的过度沉积。已知赖氨酰氧化酶样蛋白 2(lumican)在伤口愈合过程中参与 TGF-β1 信号转导。调节机械通气与膈肌损伤之间相互作用的机制尚不清楚。我们假设短时间机械拉伸引起的膈肌损伤会导致 lumican 的上调,从而调节 TGF-β1 信号转导。
3 月龄雄性 C57BL/6 小鼠,野生型或 lumican 敲除型,体重 25 至 30 克,分别接受常频潮气量(10ml/kg)或大潮气量(30ml/kg)机械通气(空气)2 至 8 小时。未通气的小鼠作为对照组。
大潮气量机械通气导致膈肌胶原纤维的纤维间解体、lumican 激活、I 型和 III 型前胶原、纤维连接蛋白和α-平滑肌肌动蛋白(α-SMA)mRNA 的产生、自由基和 TGF-β1 蛋白的产生以及膈肌纤维中 lumican 的阳性染色。lumican 缺失型小鼠的机械通气减弱了膈肌损伤、I 型和 III 型前胶原、纤维连接蛋白和 α-SMA mRNA 的产生以及自由基和 TGF-β1 蛋白的产生。未发现接受常频潮气量机械通气的小鼠出现明显的膈肌损伤。
我们的数据表明,大潮气量机械通气通过激活 lumican 诱导 TGF-β1 产生、TGF-β1 诱导基因(如胶原)和膈肌功能障碍。