Medical Science Research Center, Ansan Hospital, Korea University College of Medicine, Ansan-si, Gyeonggi, Republic of Korea.
Department of Radiology, Ansan Hospital, Korea University College of Medicine, Ansan-si, Gyeonggi, Republic of Korea.
BMC Pharmacol Toxicol. 2022 Mar 30;23(1):19. doi: 10.1186/s40360-022-00559-5.
Lung injury elicited by respiratory exposure to humidifier disinfectants (HDs) is known as HD-associated lung injury (HDLI). Current elucidation of the molecular mechanisms related to HDLI is mostly restricted to fibrotic and inflammatory lung diseases. In our previous report, we found that lung tumors were caused by intratracheal instillation of polyhexamethylene guanidine phosphate (PHMG-p) in a rat model. However, the lung cancer-related genetic changes concomitant with the development of these lung tumors have not yet been fully defined. We aimed to discover the effect of long-term exposure of PHMG-p on normal human lung alveolar cells.
We investigated whether PHMG-p could increase distorted homeostasis of oncogenes and tumor-suppressor genes, with long-term and low-dose treatment, in human pulmonary alveolar epithelial cells (HPAEpiCs). Total RNA sequencing was performed with cells continuously treated with PHMG-p and harvested after 35 days.
After PHMG-p treatment, genes with transcriptional expression changes of more than 2.0-fold or less than 0.5-fold were identified. Within 10 days of exposure, 2 protein-coding and 5 non-coding genes were selected, whereas in the group treated for 27-35 days, 24 protein-coding and 5 non-coding genes were identified. Furthermore, in the long-term treatment group, 11 of the 15 upregulated genes and 9 of the 14 downregulated genes were reported as oncogenes and tumor suppressor genes in lung cancer, respectively. We also found that 10 genes of the selected 24 protein-coding genes were clinically significant in lung adenocarcinoma patients.
Our findings demonstrate that long-term exposure of human pulmonary normal alveolar cells to low-dose PHMG-p caused genetic changes, mainly in lung cancer-associated genes, in a time-dependent manner.
通过呼吸暴露于加湿器消毒剂（HDs）引起的肺损伤被称为 HD 相关的肺损伤（HDLI）。目前，与 HDLI 相关的分子机制的阐明大多仅限于纤维化和炎症性肺病。在我们之前的报告中，我们发现聚六亚甲基胍磷酸盐（PHMG-p）经气管内滴注可在大鼠模型中引起肺肿瘤。然而，与这些肺肿瘤发展相关的肺癌相关遗传变化尚未完全定义。我们旨在发现 PHMG-p 对正常人类肺肺泡细胞的长期暴露的影响。
我们研究了 PHMG-p 是否可以通过长期和低剂量处理增加人类肺泡上皮细胞（HPAEpiCs）中致癌基因和肿瘤抑制基因的扭曲的动态平衡。用 PHMG-p 连续处理细胞并在 35 天后收获细胞，进行总 RNA 测序。
在 PHMG-p 处理后，确定了转录表达变化超过 2.0 倍或小于 0.5 倍的基因。暴露 10 天内，选择了 2 个编码蛋白和 5 个非编码基因，而在处理 27-35 天的组中，选择了 24 个编码蛋白和 5 个非编码基因。此外，在长期治疗组中，上调基因中有 11 个和下调基因中有 9 个分别被报道为肺癌中的致癌基因和肿瘤抑制基因。我们还发现，在选择的 24 个编码蛋白基因中，有 10 个基因在肺腺癌患者中具有临床意义。
我们的研究结果表明，人类肺正常肺泡细胞长期暴露于低剂量 PHMG-p 会导致遗传变化，主要是肺癌相关基因，具有时间依赖性。
