2 型固有淋巴细胞衍生的双调蛋白调节支气管肺发育不良小鼠模型中 II 型肺泡上皮细胞转分化。

Type 2 innate lymphoid cell-derived amphiregulin regulates type II alveolar epithelial cell transdifferentiation in a mouse model of bronchopulmonary dysplasia.

机构信息

Department of Pediatrics, Affiliated Hospital of Jiangsu University, Zhenjiang, China.

出版信息

Int Immunopharmacol. 2023 Sep;122:110672. doi: 10.1016/j.intimp.2023.110672. Epub 2023 Jul 20.

DOI:10.1016/j.intimp.2023.110672

Abstract

Bronchopulmonary dysplasia (BPD) is a common complication in preterm infants characterized by alveolar growth arrest. Interleukin (IL)-33 and type 2 innate lymphoid cell (ILC2) affect type II alveolar epithelial cell (AECII) differentiation in BPD mice and may cause increased lung epithelial-mesenchymal transition (EMT). Amphiregulin (AREG) can be produced by ILC2 and is associated with tissue repair. However, the action mechanism of AREG produced by ILC2 to alveolar development in BPD is unclear. In this study, we aimed to demonstrate the role and mechanism of AREG in influencing AECII transdifferentiation in the lung tissue of BPD mice. The effects of ILC2-derived AREG on AECII transdifferentiation were verified in vivo and in vitro, and the role of IL-33 on ILC2-derived AREG in AECII transdifferentiation in BPD mice and a preliminary investigation of the role of AREG's receptor-epidermal growth factor receptor (EGFR) on AECII transdifferentiation. The results showed that neonatal mice developed severe lung injury after hyperoxia, and IL-33 induced AREG production via ILC2 affected normal AECII differentiation and promoted EMT. In addition, the blockade of EGFR was found to alleviate the impaired AECII differentiation under hyperoxia in an in vitro study. In summary, our study demonstrates that AREG secreted by ILC2 affects AECII transdifferentiation in BPD mice, which provides a new idea for the clinical treatment of BPD.

摘要

支气管肺发育不良（BPD）是一种常见的早产儿并发症，其特征是肺泡生长停滞。白细胞介素（IL）-33 和 2 型固有淋巴细胞（ILC2）影响 BPD 小鼠 II 型肺泡上皮细胞（AECII）的分化，并可能导致肺上皮-间充质转化（EMT）增加。双调蛋白（AREG）可由 ILC2 产生，并与组织修复有关。然而，ILC2 产生的 AREG 对 BPD 中肺泡发育的作用机制尚不清楚。在本研究中，我们旨在阐明 AREG 在影响 BPD 小鼠肺组织 AECII 转分化中的作用和机制。体内和体外验证了 ILC2 衍生的 AREG 对 AECII 转分化的影响，并初步探讨了 IL-33 对 BPD 小鼠 ILC2 衍生的 AREG 在 AECII 转分化中的作用及其受体表皮生长因子受体（EGFR）在 AECII 转分化中的作用。结果表明，新生小鼠在高氧环境下发生严重的肺损伤，IL-33 通过 ILC2 诱导 AREG 的产生，影响正常的 AECII 分化，并促进 EMT。此外，在体外研究中发现，阻断 EGFR 可减轻高氧条件下 AECII 分化受损。综上所述，本研究表明，ILC2 分泌的 AREG 影响 BPD 小鼠的 AECII 转分化，为 BPD 的临床治疗提供了新思路。