Abstract
Daily oscillations of pulmonary function depend on the rhythmic activity of the circadian timing system. Environmental tobacco/cigarette smoke (CS) disrupts circadian clock leading to enhanced inflammatory responses. Infection with influenza A virus (IAV) increases hospitalization rates and death in susceptible individuals, including patients with Chronic Obstructive Pulmonary Disease (COPD). We hypothesized that molecular clock disruption is enhanced by IAV infection, altering cellular and lung function, leading to severity in airway disease phenotypes. C57BL/6J mice exposed to chronic CS, BMAL1 knockout (KO) mice and wild-type littermates were infected with IAV. Following infection, we measured diurnal rhythms of clock gene expression in the lung, locomotor activity, pulmonary function, inflammatory, pro-fibrotic and emphysematous responses. Chronic CS exposure combined with IAV infection altered the timing of clock gene expression and reduced locomotor activity in parallel with increased lung inflammation, disrupted rhythms of pulmonary function, and emphysema. BMAL1 KO mice infected with IAV showed pronounced detriments in behavior and survival, and increased lung inflammatory and pro-fibrotic responses. This suggests that remodeling of lung clock function following IAV infection alters clock-dependent gene expression and normal rhythms of lung function, enhanced emphysematous and injurious responses. This may have implications for the pathobiology of respiratory virus-induced airway disease severity and exacerbations.
Highlights
Oscillations of pulmonary function depend on the rhythmic activity of the circadian timing system
The body weight of mice in both influenza A virus (IAV)-infected groups dropped significantly on days 1–3 post-infection, with a slightly more dramatic decline in the CS1Virus group (Fig. 1a). This suggests that chronic cigarette smoke (CS)-exposed mice exhibited greater mortality following IAV infection
We found that chronic air and CS-exposed mice infected with IAV showed significant reduction in body weight compared to corresponding controls at the end of chronic exposure or day 9 post-infection (Supplementary Fig. 2b)
Summary
Oscillations of pulmonary function depend on the rhythmic activity of the circadian timing system. BMAL1 KO mice infected with IAV showed pronounced detriments in behavior and survival, and increased lung inflammatory and pro-fibrotic responses This suggests that remodeling of lung clock function following IAV infection alters clock-dependent gene expression and normal rhythms of lung function, enhanced emphysematous and injurious responses. An early morning surge in lung function and pronounced troughs in forced vital capacity (FVC), FEV1 and peak expiratory flow (PEF) during the night are common in patients with COPD exacerbations, including chronic smokers[23,24] This could be due to cigarette smoke (CS)-mediated alterations in circadian clock proteins, levels of steroid hormones, surfactants in the lungs, mucus retention/secretion accompanied by increased inflammatory responses and a decline in normal rhythms of lung function[15,25,26,27]. To more directly assess the role of the timing system in response to infection, we measured activity, body weight, mortality, inflammation and emphysematous responses in the lungs of BMAL1 knockout mice and WT littermates following IAV infection
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