Yanagihara Toyoshi, Zhou Quan, Tsubouchi Kazuya, Revill Spencer, Ayoub Anmar, Gholiof Mahsa, Chong Sy Giin, Dvorkin-Gheva Anna, Ask Kjetil, Shi Wei, Kolb Martin Rj
Firestone Institute for Respiratory Health, Research Institute at St Joseph's Healthcare, Department of Medicine, McMaster University, Hamilton, ON, Canada; Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Firestone Institute for Respiratory Health, Research Institute at St Joseph's Healthcare, Department of Medicine, McMaster University, Hamilton, ON, Canada.
Biochem Biophys Res Commun. 2023 May 14;656:53-62. doi: 10.1016/j.bbrc.2023.03.020. Epub 2023 Mar 16.
Type 1 alveolar epithelial cells (AT1s) and type 2 alveolar epithelial cells (AT2s) regulate the structural integrity and function of alveoli. AT1s mediate gas exchange, whereas AT2s serve multiple functions, including surfactant secretion and alveolar repair through proliferation and differentiation into AT1s as progenitors. However, mechanisms regulating AT2 proliferation and differentiation remain unclear. Here we demonstrate that Gremlin, an intrinsic inhibitor of bone morphogenetic protein (BMP), induces AT2 proliferation and differentiation. Transient overexpression of Gremlin in rat lungs by adenovirus vector delivery suppressed BMP signaling, induced proliferation of AT2s and the production of Bmp2, which in turn led to the recovery of BMP signaling and induced AT2 differentiation into AT1s. Bleomycin-induced lung injury upregulated Gremlin and showed a similar time course of biomarker expression comparable to the adenovirus model. TGF-β and IL-1β induced Gremlin expression in fibroblasts. Taken together, our findings implicate that Gremlin expression during lung injury leads to precisely timed inhibition of BMP signaling and activates AT2s, leading to alveolar repair.
1型肺泡上皮细胞（AT1s）和2型肺泡上皮细胞（AT2s）调节肺泡的结构完整性和功能。AT1s介导气体交换，而AT2s具有多种功能，包括表面活性剂分泌以及通过增殖和分化为祖细胞AT1s来进行肺泡修复。然而，调节AT2增殖和分化的机制仍不清楚。在此，我们证明骨形态发生蛋白（BMP）的内在抑制剂Gremlin可诱导AT2增殖和分化。通过腺病毒载体递送在大鼠肺中短暂过表达Gremlin可抑制BMP信号传导，诱导AT2s增殖和Bmp2的产生，这反过来又导致BMP信号传导的恢复并诱导AT2分化为AT1s。博来霉素诱导的肺损伤上调了Gremlin，并显示出与腺病毒模型相当的生物标志物表达时间进程。转化生长因子-β（TGF-β）和白细胞介素-1β（IL-1β）诱导成纤维细胞中Gremlin的表达。综上所述，我们的研究结果表明，肺损伤期间Gremlin的表达导致BMP信号传导的精确适时抑制并激活AT2s，从而导致肺泡修复。
