Cigarette Smoke with Poly I:C Challenges as an exacerbation model of acute lung inflammation

<bold>Rationale:</bold> Historically, cigarette smoke mouse models have shown poor correlation with human chronic obstructive pulmonary disease (COPD). Exacerbations have been shown to be associated with lung function decline but are often a component absent in mouse models. We aim to evaluate a model combining poly I:C challenges as an exacerbator in the context of cigarette smoke. <bold>Aim:</bold> We sought to determine transcriptional differences and similarities of acute smoke exposure with and without poly I:C challenges to determine if poly I:C challenges mimic aspects of a viral exacerbation. Furthermore, we evaluated whether the model approximates human disease based on gene enrichment. <bold>Methods:</bold> Mice were exposed to cigarette smoke, poly I:C, or both. Lungs were processed for Luminex protein analysis and bulk RNAseq. Gene signature overlaps were compared with published datasets of human lung COPD. <bold>Results:</bold> We identified a set of differentially expressed genes associated with smoke, poly I:C, or the combination. The smoke alone signature was less prominent, compared to the poly I:C signature; however, both were consistently observed in the combination signature. Pathway enrichment revealed downregulation of immune pathways, including eosinophil and monocyte pathways in all models and upregulation of interferon signaling in the poly I:C model. Interestingly, unbiased global transcriptome analysis identified common gene signatures shared between mice exposed to cigarette smoke plus poly I:C and sputum from COPD patients. <bold>Conclusion:</bold> We characterized a mouse model of cigarette smoke and exacerbations and found that there are features and gene signatures shared with human disease.