Fernandez Jenna A, Han Qiyuan, Rajczewski Andrew T, Kono Thomas, Weirath Nicholas A, Lee Alexander S, Rahim Abdur, Tretyakova Natalia Y
Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.
Department of Biochemistry, Biophysics, and Molecular Biology, University of Minnesota, Minneapolis, MN 55455, USA.
Int J Mol Sci. 2025 May 14;26(10):4692. doi: 10.3390/ijms26104692.
Chronic inflammation plays a central role in the pathogenesis of lung diseases including asthma, long COVID, chronic obstructive pulmonary disease (COPD), and lung cancer. Lipopolysaccharide (LPS) is a potent inflammatory agent produced by Gram-negative bacteria and also found in cigarette smoke. Our earlier study revealed that the intranasal exposure of A/J mice to LPS for 7 days altered gene expression levels in alveolar Type II epithelial cells (AECIIs), which serve as precursors to lung adenocarcinoma and are also preferentially targeted by SARS-CoV-2. In the present work, we employed a comprehensive multi-omics approach to characterize changes in DNA methylation/hydroxymethylation, gene expression, and global protein abundances in the AECIIs of A/J mice following the sub-chronic exposure to LPS and after a 4-week recovery period. Exposure to LPS led to hypermethylation at regulatory elements within the genome such as enhancer regions and expression changes in genes known to play a role in lung cancer tumorigenesis. Changes in protein abundance were consistent with an inflammatory phenotype and also included tumor suppressor proteins. Integration of the multi-omics data resulted in a model where LPS-driven inflammation in AECIIs triggers epigenetic changes that, along with genetic mutations, may contribute to lung cancer development.
慢性炎症在包括哮喘、长期新冠、慢性阻塞性肺疾病（COPD）和肺癌在内的肺部疾病发病机制中起核心作用。脂多糖（LPS）是革兰氏阴性菌产生的一种强效炎症因子，也存在于香烟烟雾中。我们早期的研究表明，将A/J小鼠经鼻暴露于LPS 7天会改变肺泡II型上皮细胞（AECIIs）中的基因表达水平，AECIIs是肺腺癌的前体，也是SARS-CoV-2的优先靶向细胞。在本研究中，我们采用了全面的多组学方法来表征A/J小鼠的AECIIs在亚慢性暴露于LPS后以及4周恢复期后的DNA甲基化/羟甲基化、基因表达和整体蛋白质丰度的变化。暴露于LPS导致基因组内调控元件（如增强子区域）的高甲基化以及已知在肺癌肿瘤发生中起作用的基因的表达变化。蛋白质丰度的变化与炎症表型一致，还包括肿瘤抑制蛋白。多组学数据的整合产生了一个模型，其中AECIIs中LPS驱动的炎症触发表观遗传变化，这些变化与基因突变一起可能导致肺癌的发展。
