Bronchopulmonary dysplasia (BPD) is characterized by shortened secondary septa and fewer, larger alveoli. Elastin deposition to the distal tips of the secondary septa is critical for elongation of the secondary septa. Alveolar myofibroblasts, which are thought to migrate to the septal tips during alveolarization, are mainly responsible for elastin production and deposition. Antenatal exposure to inflammation induces abnormal elastin deposition, thereby increasing the risk of developing BPD. Here, we found that lipopolysaccharide (LPS) significantly increased the expression of transforming growth factor-α (TGF-α) in an LPS-induced rat model of BPD and in LPS-treated human pulmonary epithelial cells (BEAS-2B). In addition, experiments suggested that LPS upregulated TGF-α expression via toll-like receptor 4 (TLR4)/tumor necrosis factor α-converting enzyme (TACE) signaling. Increased TGF-α levels via its receptor epidermal growth factor receptor (EGFR)-induced lysyl oxidase (LOX) overactivation and cell division cycle 42 (Cdc42) activity inhibition of myofibroblasts. Similarly, LOX overactivation and inhibition of Cdc42 activity were observed in the lungs of LPS-exposed pups. LOX overactivation led to abnormal elastin deposition, and inhibition of Cdc42 activity disturbed the directional migration of myofibroblasts and disrupted elastin localization. Most importantly, the EGFR inhibitor erlotinib partially rescued LOX overactivation and Cdc42 activity inhibition, and improved elastin deposition and alveolar development in antenatal LPS-treated rats. Taken together, our data suggest that TGF-α/EGFR signaling is critically involved in the regulation of elastin deposition and represents a novel therapeutic target.

中文翻译：

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TGF-α/EGFR 信号传导促进脂多糖诱导的异常弹性蛋白沉积和肺泡简化

支气管肺发育不良 (BPD) 的特征是次级间隔缩短和肺泡变少且变大。弹性蛋白沉积到二级隔膜的远端对于二级隔膜的伸长至关重要。肺泡肌成纤维细胞被认为在肺泡化过程中迁移到隔膜尖端，主要负责弹性蛋白的产生和沉积。产前接触炎症会导致弹性蛋白沉积异常，从而增加患 BPD 的风险。在这里，我们发现脂多糖（LPS）显着增加了 LPS 诱导的 BPD 大鼠模型和 LPS 处理的人肺上皮细胞（BEAS-2B）中转化生长因子-α（TGF-α）的表达。此外，实验表明，LPS 通过 Toll 样受体 4 (TLR4)/肿瘤坏死因子 α 转换酶 (TACE) 信号传导上调 TGF-α 表达。通过其受体表皮生长因子受体 (EGFR) 诱导的赖氨酰氧化酶 (LOX) 过度激活和肌成纤维细胞的细胞分裂周期 42 (Cdc42) 活性抑制来增加 TGF-α 水平。同样，在暴露于 LPS 的幼崽的肺部也观察到了 LOX 过度激活和 Cdc42 活性抑制。 LOX 过度激活导致弹性蛋白沉积异常，而 Cdc42 活性的抑制会扰乱肌成纤维细胞的定向迁移并破坏弹性蛋白定位。最重要的是，EGFR 抑制剂厄洛替尼部分缓解了 LOX 过度激活和 Cdc42 活性抑制，并改善了产前 LPS 治疗大鼠的弹性蛋白沉积和肺泡发育。综上所述，我们的数据表明 TGF-α/EGFR 信号传导在弹性蛋白沉积的调节中至关重要，并且代表了一个新的治疗靶点。