背景:支气管肺发育不良(BPD)是一种主要影响早产儿的慢性肺部疾病。氧疗,BPD的常用治疗方法,通常会导致高氧引起的肺损伤,特别是靶向肺泡上皮细胞(AECs)。至关重要的是,破坏的肺上皮-成纤维细胞相互作用显著有助于BPD的发病机制。先前关于白细胞介素-11(IL-11)在肺部疾病中的研究产生了矛盾的结果。最近的研究,然而,强调IL-11是纤维化的关键调节因子,基质炎症,和上皮功能障碍。尽管如此,IL-11在BPD中的具体作用仍未得到充分研究。我们对正常和高氧暴露的鼠肺组织的转录组分析显示IL-11RNA的表达增加。本研究旨在探讨IL-11在调节BPD中AECs与成纤维细胞之间的相互作用中的作用。
方法:通过将C57BL/6J新生小鼠暴露于高氧下,在体内对BPD进行建模。用苏木精-伊红染色评估肺组织的组织病理学变化,而肺纤维化使用Masson染色和免疫组织化学(IHC)进行评估。探讨IL-11在导致BPD的肺损伤中的作用,通过在暴露于高氧的小鼠中腹膜内施用IL-11RαFc来降低IL-11水平。此外,收集经受95%氧的MLE-12细胞并与小鼠肺成纤维细胞(MPF)共培养以测量α-SMA和胶原I表达水平。使用酶联免疫吸附测定(ELISA)定量上清液中的IL-11水平。
结果:IHC和Masson染色均显示抑制IL-11的表达减轻了高氧诱导的新生小鼠肺纤维化,同时降低肺组织中纤维化标志物α-SMA和I型胶原的表达。体外分析显示用高氧处理的MLE-12细胞的上清液中IL-11水平显著增加。在MLE-12细胞中沉默IL-11表达降低了与高氧处理的MLE-12细胞的上清液共培养的MPF中的α-SMA和胶原蛋白I浓度。此外,ERK抑制剂降低了与高氧处理的MLE-12细胞的上清液共培养的MPF中的α-SMA和胶原蛋白I水平。临床研究发现,BPD婴儿的气管抽吸物(TA)中IL-11水平升高。
结论:这项研究表明,高氧诱导肺上皮分泌IL-11。此外,来自肺上皮的IL-11通过ERK信号通路作为肌成纤维细胞分化的关键介质,强调其在BPD治疗中的潜在治疗价值。
BACKGROUND: Bronchopulmonary dysplasia (BPD) is a chronic lung disorder predominantly affecting preterm infants. Oxygen therapy, a common treatment for BPD, often leads to
hyperoxia-induced pulmonary damage, particularly targeting alveolar epithelial cells (AECs). Crucially, disrupted lung epithelium-fibroblast interactions significantly contribute to BPD\'s pathogenesis. Previous studies on interleukin-11 (IL-11) in lung diseases have yielded conflicting results. Recent research, however, highlights IL-11 as a key regulator of fibrosis, stromal inflammation, and epithelial dysfunction. Despite this, the specific role of IL-11 in BPD remains underexplored. Our transcriptome analysis of normal and
hyperoxia-exposed murine lung tissues revealed an increased expression of IL-11 RNA. This study aimed to investigate IL-11\'s role in modulating the disrupted interactions between AECs and fibroblasts in BPD.
METHODS: BPD was modeled in vivo by exposing C57BL/6J neonatal mice to
hyperoxia. Histopathological changes in lung tissue were evaluated with hematoxylin-eosin staining, while lung fibrosis was assessed using Masson staining and immunohistochemistry (IHC). To investigate IL-11\'s role in pulmonary injury contributing to BPD, IL-11 levels were reduced through intraperitoneal administration of IL-11RαFc in hyperoxia-exposed mice. Additionally, MLE-12 cells subjected to 95% oxygen were collected and co-cultured with mouse pulmonary fibroblasts (MPFs) to measure α-SMA and Collagen I expression levels. IL-11 levels in the supernatants were quantified using an enzyme-linked immunosorbent assay (ELISA).
RESULTS: Both IHC and Masson staining revealed that inhibiting IL-11 expression alleviated pulmonary fibrosis in neonatal mice induced by
hyperoxia, along with reducing the expression of fibrosis markers α-SMA and collagen I in lung tissue. In vitro analysis showed a significant increase in IL-11 levels in the supernatant of MLE-12 cells treated with hyperoxia. Silencing IL-11 expression in MLE-12 cells reduced α-SMA and collagen I concentrations in MPFs co-cultured with the supernatant of hyperoxia-treated MLE-12 cells. Additionally, ERK inhibitors decreased α-SMA and collagen I levels in MPFs co-cultured with the supernatant of hyperoxia-treated MLE-12 cells. Clinical studies found increased IL-11 levels in tracheal aspirates (TA) of infants with BPD.
CONCLUSIONS: This research reveals that
hyperoxia induces IL-11 secretion in lung epithelium. Additionally, IL-11 derived from lung epithelium emerged as a crucial mediator in myofibroblast differentiation via the ERK signaling pathway, highlighting its potential therapeutic value in BPD treatment.