Krishnan Ramesh, Arrindell Esmond L, Frank Caminita, Jie Zhang, Buddington Randal K
Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, United States.
Baptist Women's Hospital, Memphis, TN, United States.
Front Pediatr. 2021 Sep 28;9:722497. doi: 10.3389/fped.2021.722497. eCollection 2021.
Bronchopulmonary dysplasia (BPD) is a devastating disease of prematurity that is associated with mechanical ventilation and hyperoxia. We used preterm pigs delivered at gestational day 102 as a translational model for 26-28-week infants to test the hypothesis administering recombinant human keratinocyte growth factor (rhKGF) at initiation of mechanical ventilation will stimulate type II cell proliferation and surfactant production, mitigate ventilator induced lung injury, and reduce epithelial to mesenchymal transition considered as a precursor to BPD. Newborn preterm pigs were intubated and randomized to receive intratracheal rhKGF (20 μg/kg; = 6) or saline (0.5 ml 0.9% saline; control; = 6) before initiating 24 h of ventilation followed by extubation to nasal oxygen for 12 h before euthanasia and collection of lungs for histopathology and immunohistochemistry to assess expression of surfactant protein B and markers of epithelial to mesenchymal transition. rhKGF pigs required less oxygen during mechanical ventilation, had higher tidal volumes at similar peak pressures indicative of improved lung compliance, and survival was higher after extubation (83% vs. 16%). rhKGF increased surfactant protein B expression ( < 0.05) and reduced TGF-1β ( < 0.05), that inhibits surfactant production and is a prominent marker for epithelial to mesenchymal transition. Our findings suggest intratracheal administration of rhKGF at initiation of mechanical ventilation enhances surfactant production, reduces ventilator induced lung injury, and attenuates epithelial-mesenchymal transition while improving pulmonary functions. rhKGF is a potential therapeutic strategy to mitigate pulmonary responses of preterm infants that require mechanical ventilation and thereby reduce the incidence and severity of bronchopulmonary dysplasia.
支气管肺发育不良（BPD）是一种与机械通气和高氧血症相关的严重早产儿疾病。我们使用妊娠第102天出生的早产猪作为26 - 28周龄婴儿的转化模型，以检验在机械通气开始时给予重组人角质形成细胞生长因子（rhKGF）将刺激II型细胞增殖和表面活性剂产生、减轻呼吸机诱导的肺损伤并减少被认为是BPD先兆的上皮 - 间充质转化这一假设。新生早产猪插管后随机分为两组，在开始24小时通气前接受气管内注射rhKGF（20μg/kg；n = 6）或生理盐水（0.5ml 0.9%生理盐水；对照组；n = 6），然后拔管至鼻导管吸氧12小时，之后安乐死并收集肺组织进行组织病理学和免疫组织化学检查，以评估表面活性蛋白B的表达和上皮 - 间充质转化的标志物。接受rhKGF治疗的猪在机械通气期间需要的氧气较少，在相似的峰值压力下潮气量更高，表明肺顺应性改善，拔管后的存活率更高（83%对16%）。rhKGF增加了表面活性蛋白B的表达（P < 0.05）并降低了TGF - 1β（P < 0.05），TGF - 1β抑制表面活性剂产生且是上皮 - 间充质转化的显著标志物。我们的研究结果表明，在机械通气开始时气管内给予rhKGF可增强表面活性剂产生、减少呼吸机诱导的肺损伤、减轻上皮 - 间充质转化，同时改善肺功能。rhKGF是一种潜在的治疗策略，可减轻需要机械通气的早产儿的肺部反应，从而降低支气管肺发育不良的发生率和严重程度。
