Macrophage-derived IL-6 trans-signaling as a novel target in the pathogenesis of bronchopulmonary dysplasia (RNA-seq-P14-HYXvsNOX)

Rationale: Premature infants exposed to oxygen are at risk for bronchopulmonary dysplasia (BPD), which is characterized by lung growth arrest. Inflammation is important, but the mechanisms remain elusive. Here, we investigated inflammatory pathways and therapeutic targets in severe clinical and experimental BPD.

Methods and Results: First, transcriptomic analysis with in-silico cellular deconvolution identified a lung-intrinsic M1-like-driven cytokine pattern in newborn mice after hyperoxia. These findings were confirmed by gene expression of macrophage-regulating chemokines (Ccl2, Ccl7, Cxcl5) and markers (Il6, Il17A, Mmp12). Second, hyperoxia-activated IL-6/STAT3 signaling was measured in vivo and related to loss of alveolar epithelial type II cells (ATII) as well as increased mesenchymal marker. Il6 null mice exhibited preserved ATII survival, reduced myofibroblasts and improved elastic fiber assembly, thus enabling lung growth and protecting lung function. Pharmacological inhibit...

研究背景： 暴露于氧疗环境的早产儿罹患支气管肺发育不良（bronchopulmonary dysplasia, BPD）的风险显著升高，该病以肺生长停滞为核心病理特征。炎症反应在疾病进程中发挥关键作用，但其具体分子机制仍未明确。本研究针对重症临床及实验性BPD，对其炎症通路与潜在治疗靶点展开了系统探究。
研究方法与结果： 首先，通过计算机模拟细胞解卷积的转录组学分析，在高氧暴露后的新生小鼠体内鉴定出一种肺内源性M1样极化驱动的细胞因子表达谱。上述结论通过调控巨噬细胞的趋化因子（Ccl2、Ccl7、Cxcl5）及相关标志物（Il6、Il17A、Mmp12）的基因表达水平得到验证。其次，本研究在活体小鼠中检测到高氧激活的IL-6/STAT3信号通路，且该通路的激活与II型肺泡上皮细胞（alveolar epithelial type II cells, ATII）存活率下降及间充质标志物表达上调显著相关。IL6基因敲除小鼠可维持ATII存活、减少肌成纤维细胞生成并改善弹性纤维组装，进而促进肺组织生长并保护肺功能。药物抑制……