Department of Pediatrics, Stanford University, Stanford, California 94305-5162, USA.
Am J Physiol Lung Cell Mol Physiol. 2012 Aug 1;303(3):L215-27. doi: 10.1152/ajplung.00405.2011. Epub 2012 Jun 8.
Mechanical ventilation (MV) with O(2)-rich gas (MV-O(2)) offers life-saving treatment for newborn infants with respiratory failure, but it also can promote lung injury, which in neonates translates to defective alveolar formation and disordered lung elastin, a key determinant of lung growth and repair. Prior studies in preterm sheep and neonatal mice showed that MV-O(2) stimulated lung elastase activity, causing degradation and remodeling of matrix elastin. These changes yielded an inflammatory response, with TGF-β activation, scattered elastic fibers, and increased apoptosis, culminating in defective alveolar septation and arrested lung growth. To see whether sustained inhibition of elastase activity would prevent these adverse pulmonary effects of MV-O(2), we did studies comparing wild-type (WT) and mutant neonatal mice genetically modified to express in their vascular endothelium the human serine elastase inhibitor elafin (Eexp). Five-day-old WT and Eexp mice received MV with 40% O(2) (MV-O(2)) for 24-36 h. WT and Eexp controls breathed 40% O(2) without MV. MV-O(2) increased lung elastase and MMP-9 activity, resulting in elastin degradation (urine desmosine doubled), TGF-β activation (pSmad-2 increased 6-fold), apoptosis (cleaved-caspase-3 increased 10-fold), and inflammation (NF-κB activation, influx of neutrophils and monocytes) in lungs of WT vs. unventilated controls. These changes were blocked or blunted during MV-O(2) of Eexp mice. Scattered lung elastin and emphysematous alveoli observed in WT mice after 36 h of MV-O(2) were attenuated in Eexp mice. Both WT and Eexp mice showed defective VEGF signaling (decreased lung VEGF-R2 protein) and loss of pulmonary microvessels after lengthy MV-O(2), suggesting that elafin's beneficial effects during MV-O(2) derived primarily from preserving matrix elastin and suppressing lung inflammation, thereby enabling alveolar formation during MV-O(2). These results suggest that degradation and remodeling of lung elastin can contribute to defective lung growth in response to MV-O(2) and might be targeted therapeutically to prevent ventilator-induced neonatal lung injury.
机械通气（MV）用富氧气体（MV-O2）为呼吸衰竭的新生儿提供救生治疗，但它也可能促进肺损伤，这在新生儿中表现为肺泡形成缺陷和肺弹力蛋白紊乱，肺生长和修复的关键决定因素。先前在早产绵羊和新生小鼠中的研究表明，MV-O2 刺激肺弹性酶活性，导致基质弹力蛋白的降解和重塑。这些变化产生了炎症反应，伴随着 TGF-β的激活、散在的弹性纤维和增加的细胞凋亡，最终导致肺泡分隔缺陷和肺生长停滞。为了观察持续抑制弹性酶活性是否会预防 MV-O2 的这些不良肺效应，我们比较了野生型（WT）和经基因修饰在其血管内皮中表达人丝氨酸弹性蛋白酶抑制剂 Elafin（Eexp）的新生突变型小鼠的研究。5 天大的 WT 和 Eexp 小鼠接受 40%O2（MV-O2）的 MV 治疗 24-36 小时。WT 和 Eexp 对照在没有 MV 的情况下呼吸 40%O2。MV-O2 增加了肺弹性酶和 MMP-9 的活性，导致弹性蛋白降解（尿脱氧素二倍增加）、TGF-β激活（pSmad-2 增加 6 倍）、细胞凋亡（cleaved-caspase-3 增加 10 倍）和炎症（NF-κB 激活、中性粒细胞和单核细胞的流入）在 WT 与未通气对照的肺中。这些变化在 Eexp 小鼠的 MV-O2 期间被阻断或减弱。在 36 小时的 MV-O2 后，在 WT 小鼠中观察到散在的肺弹力蛋白和肺气肿肺泡，在 Eexp 小鼠中减弱。在长时间的 MV-O2 后，WT 和 Eexp 小鼠均显示出 VEGF 信号转导受损（肺 VEGF-R2 蛋白减少）和肺微血管丢失，表明 Elafin 在 MV-O2 期间的有益作用主要来自于维持基质弹力蛋白和抑制肺炎症，从而在 MV-O2 期间实现肺泡形成。这些结果表明，肺弹力蛋白的降解和重塑可能导致对 MV-O2 的肺生长缺陷，并可能成为治疗呼吸机诱导的新生儿肺损伤的治疗靶点。
