Per3 deficiency aggravates cigarettes-smoking induced emphysema in mice

<bold>Background:</bold> Peripheral circadian clock dysregulation was found in patients with chronic obstructive pulmonary disease (COPD). Per3, the core gene of circadian clock, showed increased expression following cigarettes smoke (CS) exposure in lung tissue of mice before. However, the role of Per3 in COPD pathogenesis remains unclear. <bold>Methods:</bold> Per3 knockout (Per3^−/−) and wild type (WT) mice were scarified after 12-week nose-only exposure to CS. Lung function test was performed. Inflammatory cytokines in bronchoalveolar lavage fluid (BALF) were measured. Transcriptome sequencing (RNA-Seq) on lung tissues was performed, followed by protein quantification by western blot (WB). <bold>Results:</bold> After CS exposure, Per3^−/− mice have higher functional residual capacity /body weight (FRC/BW), total lung capacity /body weight (TLC/BW) and mean linear intercept (MLI) compared to WT mice, indicating aggravated emphysema in CS-treated Per3^−/− mice. Additionally, IL-1β, IL-6 and TNF-α levels in BALF are elevated in CS-treated Per3^−/− mice. However, no difference is observed in BALF neutrophils ratio or counts. RNA-Seq analysis reveals 717 upregulated and 690 downregulated differential expressed genes, which are enriched in pathways of protein processing, MAPK and IL-17 signaling etc. Given that heat shock protein 70 (Hsp70) is previously associated with COPD disease severity and smoking status and participates in above pathways, we further validate by WB that Hsp70 is upregulated in lung tissue of CS-treated Per3^−/− mice. <bold>Conclusion:</bold> Our study reveals that Per3 deficiency aggravates emphysema induced by CS, with upregulated Hsp70 potentially functioning as a downstream effector. The underlying mechanism should be elucidated in future study.