Inhibition of Circadian Rhythm Gene per1 Promotes Macrophage Infiltration in e-Cigarette Aerosol-Induced Pulmonary Fibrosis in Mice

Abstract

Although electronic cigarettes (e-cigarettes) are a substitute for traditional cigarettes, increasing studies indicate that e-cigarettes are unsafe. Here, we first analyzed the constituents of e-cigarette liquid (e-liquid) and e-liquid vaping-produced aerosols (e-aerosols) by gas chromatography quadrupole time-of-flight mass spectrometry (GC/Q-TOF MS) and inductively coupled plasma-MS (ICP-MS), and our result indicated that the components of e-aerosols differed from those of e-liquid. However, there is insufficient evidence on the toxicity of e-aerosols; therefore, an animal study was conducted accordingly. Mice were exposed to e-aerosols for 30, 60, or 90 days within a whole-body exposure chamber equipped with an air quality monitor. Compared with the control, weakened lung function and fiber deposition in murine lungs were observed following e-cigarette exposure. Microcomputed tomography (Micro-CT) images suggested fibrosis-like lesions in the lungs. Mechanistically, the expression of the core circadian rhythm gene, per1, was significantly inhibited by e-aerosols, which is negatively correlated with interleukin-6 (IL6) expression and resulted in continuous IL6⁺ macrophage infiltration in the lungs during both daytime and night. Eventually, the knockout of il6 expression could completely resist e-aerosol-induced pulmonary fibrosis in mice. Our results raise concerns regarding the role of circadian rhythm in regulating pulmonary fibrosis and the potential damages of e-cigarette consumption.