Franco-Montoya Marie-Laure, Bourbon Jacques R, Durrmeyer Xavier, Lorotte Stéphanie, Jarreau Pierre-Henri, Delacourt Christophe
Institut National de la Santé et de la Recherche Médicale, Unité 955, Faculté de Médecine, Université Paris-Val-de-Marne, Centre Hospitalier Intercommunal, Créteil, France.
Am J Physiol Lung Cell Mol Physiol. 2009 Nov;297(5):L965-76. doi: 10.1152/ajplung.00136.2009. Epub 2009 Aug 21.
Acute lung injury and compromised alveolar development characterize bronchopulmonary dysplasia (BPD) of the premature neonate. High levels of keratinocyte growth factor (KGF), a cell-cell mediator with pleiotrophic lung effects, are associated with low BPD risk. KGF decreases mortality in hyperoxia-exposed newborn rodents, a classic model of injury-induced impaired alveolarization, although the pulmonary mechanisms of this protection are poorly defined. These were explored through in vitro and in vivo approaches in the rat. Hyperoxia decreased by 30% the rate of wound closure of a monolayer of fetal alveolar epithelial cells, due to cell death, which was overcome by recombinant human KGF (100 ng/ml). In rat pups exposed to >95% O2 from birth, increased viability induced by intraperitoneal injection of KGF (2 microg/g body wt) every other day was associated with prevention of neutrophil influx in bronchoalveolar lavage (BAL), prevention of decreases in whole lung DNA content and cell proliferation rate, partial prevention of apoptosis increase, and a markedly increased proportion of surfactant protein B-immunoreactive cells in lung parenchyma. Increased lung antioxidant capacity is likely to be due in part to enhanced CAAT/enhancer binding protein alpha expression. By contrast, KGF neither corrected changes induced by hyperoxia in parameters of lung morphometry that clearly indicated impaired alveolarization nor had any significant effect on tissue or BAL surfactant phospholipids. These findings evidence KGF alveolar epithelial cell protection, enhancing effects on alveolar repair capacity, and anti-inflammatory effects in the injured neonatal lung that may account, at least in part, for its ability to reduce mortality. They argue in favor of a therapeutic potential of KGF in the injured neonatal lung.
急性肺损伤和肺泡发育受损是早产儿支气管肺发育不良（BPD）的特征。角质形成细胞生长因子（KGF）水平升高与低BPD风险相关，KGF是一种具有多效性肺效应的细胞间介质。KGF可降低暴露于高氧环境的新生啮齿动物的死亡率，高氧环境是损伤诱导的肺泡化受损的经典模型，尽管这种保护的肺机制尚不清楚。通过大鼠的体外和体内实验对此进行了探索。高氧使胎儿肺泡上皮细胞单层的伤口闭合率降低了30%，这是由于细胞死亡所致，而重组人KGF（100 ng/ml）可克服这一现象。在出生后暴露于>95%氧气的大鼠幼崽中，每隔一天腹腔注射KGF（2 μg/g体重）所诱导的存活率提高与预防支气管肺泡灌洗（BAL）中的中性粒细胞流入、预防全肺DNA含量和细胞增殖率降低、部分预防细胞凋亡增加以及肺实质中表面活性蛋白B免疫反应性细胞比例显著增加有关。肺抗氧化能力的提高可能部分归因于CAAT/增强子结合蛋白α表达的增强。相比之下，KGF既没有纠正高氧引起的明显表明肺泡化受损的肺形态学参数变化，也对组织或BAL表面活性物质磷脂没有任何显著影响。这些发现证明了KGF对肺泡上皮细胞的保护作用、对肺泡修复能力的增强作用以及在受损新生肺中的抗炎作用，这些作用可能至少部分解释了其降低死亡率的能力。它们支持KGF在受损新生肺中的治疗潜力。
