Hilgendorff Anne, Parai Kakoli, Ertsey Robert, Navarro Edwin, Jain Noopur, Carandang Francis, Peterson Joanna, Mokres Lucia, Milla Carlos, Preuss Stefanie, Alcazar Miguel Alejandre, Khan Suleman, Masumi Juliet, Ferreira-Tojais Nancy, Mujahid Sana, Starcher Barry, Rabinovitch Marlene, Bland Richard
Department of Pediatrics, Stanford University, Stanford, California; Comprehensive Pneumology Center, Ludwig-Maximilian University, Munich, Germany; and.
Department of Pediatrics, Stanford University, Stanford, California;
Am J Physiol Lung Cell Mol Physiol. 2015 Mar 1;308(5):L464-78. doi: 10.1152/ajplung.00278.2014. Epub 2014 Dec 24.
Elastin plays a pivotal role in lung development. We therefore queried if elastin haploinsufficient newborn mice (Eln(+/-)) would exhibit abnormal lung structure and function related to modified extracellular matrix (ECM) composition. Because mechanical ventilation (MV) has been linked to dysregulated elastic fiber formation in the newborn lung, we also asked if elastin haploinsufficiency would accentuate lung growth arrest seen after prolonged MV of neonatal mice. We studied 5-day-old wild-type (Eln(+/+)) and Eln(+/-) littermates at baseline and after MV with air for 8-24 h. Lungs of unventilated Eln(+/-) mice contained ∼50% less elastin and ∼100% more collagen-1 and lysyl oxidase compared with Eln(+/+) pups. Eln(+/-) lungs contained fewer capillaries than Eln(+/+) lungs, without discernible differences in alveolar structure. In response to MV, lung tropoelastin and elastase activity increased in Eln(+/+) neonates, whereas tropoelastin decreased and elastase activity was unchanged in Eln(+/-) mice. Fibrillin-1 protein increased in lungs of both groups during MV, more in Eln(+/-) than in Eln(+/+) pups. In both groups, MV caused capillary loss, with larger and fewer alveoli compared with unventilated controls. Respiratory system elastance, which was less in unventilated Eln(+/-) compared with Eln(+/+) mice, was similar in both groups after MV. These results suggest that elastin haploinsufficiency adversely impacts pulmonary angiogenesis and that MV dysregulates elastic fiber integrity, with further loss of lung capillaries, lung growth arrest, and impaired respiratory function in both Eln(+/+) and Eln(+/-) mice. Paucity of lung capillaries in Eln(+/-) newborns might help explain subsequent development of pulmonary hypertension previously reported in adult Eln(+/-) mice.
弹性蛋白在肺发育中起关键作用。因此，我们探究了弹性蛋白单倍体不足的新生小鼠（Eln(+/-)）是否会表现出与细胞外基质（ECM）组成改变相关的肺结构和功能异常。由于机械通气（MV）与新生肺中弹性纤维形成失调有关，我们还询问弹性蛋白单倍体不足是否会加剧新生小鼠长时间MV后出现的肺生长停滞。我们研究了5日龄的野生型（Eln(+/+)）和Eln(+/-)同窝小鼠，分别在基线时以及用空气进行MV 8 - 24小时后进行观察。与Eln(+/+)幼崽相比，未通气的Eln(+/-)小鼠肺中弹性蛋白含量减少约50%，胶原蛋白-1和赖氨酰氧化酶含量增加约100%。Eln(+/-)肺中的毛细血管比Eln(+/+)肺中的少，肺泡结构无明显差异。对MV的反应中，Eln(+/+)新生儿肺中的原弹性蛋白和弹性蛋白酶活性增加，而Eln(+/-)小鼠中原弹性蛋白减少且弹性蛋白酶活性未改变。MV期间两组小鼠肺中的原纤蛋白-1蛋白均增加，Eln(+/-)小鼠增加得比Eln(+/+)幼崽更多。两组中，MV均导致毛细血管减少，与未通气对照组相比，肺泡更大且数量更少。未通气的Eln(+/-)小鼠的呼吸系统弹性比Eln(+/+)小鼠小，MV后两组相似。这些结果表明，弹性蛋白单倍体不足对肺血管生成有不利影响，MV会使弹性纤维完整性失调，导致Eln(+/+)和Eln(+/-)小鼠肺毛细血管进一步减少、肺生长停滞和呼吸功能受损。Eln(+/-)新生小鼠肺毛细血管稀少可能有助于解释先前在成年Eln(+/-)小鼠中报道的肺动脉高压的后续发展。
