Multi-omics Analysis of the Epigenetic Effects of Inflammation in Murine Type II Pneumocytes

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 intranasal exposure of A/J mice to LPS for 7 days altered gene expression levels in alveolar type II epithelial cells (AECII), 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 AECII of A/J mice following sub-chronic exposure to LPS and after 4-week recovery period. Exposure to LPS led to hypermethylation at regulatory elements within the genome such as enhancer regions and led to expression changes in genes known to play a role in lung cancer tumorigenesis. Changes in protein abundance were consistent with an inflammatory phenotype but also included tumor suppressor proteins. Integration of the multi-omics data resulted in a model where LPS-driven inflammation in AECII triggers epigenetic changes that, along with genetic mutations, contribute to lung cancer development.