Influenza A virus-dependent remodeling of pulmonary clock function in a mouse model of COPD.
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.
Department of Environmental Medicine Lung Biology and Disease Program, University of Rochester Medical Center, Rochester, NY, USA.
Isaac K
IK
Sundar
Department of Environmental Medicine Lung Biology and Disease Program, University of Rochester Medical Center, Rochester, NY, USA.
Tanveer
T
Ahmad
Department of Environmental Medicine Lung Biology and Disease Program, University of Rochester Medical Center, Rochester, NY, USA.
Hongwei
H
Yao
Department of Environmental Medicine Lung Biology and Disease Program, University of Rochester Medical Center, Rochester, NY, USA.
Jae-woong
JW
Hwang
Department of Environmental Medicine Lung Biology and Disease Program, University of Rochester Medical Center, Rochester, NY, USA.
Janice
J
Gerloff
Department of Environmental Medicine Lung Biology and Disease Program, University of Rochester Medical Center, Rochester, NY, USA.
B Paige
BP
Lawrence
Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Rochester Medical Center, Rochester, NY, USA.
Michael T
MT
Sellix
Department of Environmental Medicine Lung Biology and Disease Program, University of Rochester Medical Center, Rochester, NY, USA.
Irfan
I
Rahman
D056930:ARNTL Transcription Factors / Q000172:deficiency / Q000235:genetics; D000818:Animals; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D057906:Circadian Clocks / Q000235:genetics*; D002940:Circadian Rhythm / Q000235:genetics*; D004195:Disease Models, Animal; D004646:Emphysema / Q000209:etiology / Q000235:genetics* / Q000401:mortality / Q000821:virology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D009980:Influenza A virus / Q000472:pathogenicity / Q000502:physiology*; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000821:virology; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology / Q000235:genetics* / Q000401:mortality / Q000821:virology; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000235:genetics* / Q000401:mortality / Q000821:virology; D012129:Respiratory Function Tests; D012906:Smoke / Q000009:adverse effects; D016019:Survival Analysis
D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D012906:Smoke; D056926:CLOCK Proteins; C538944:Clock protein, mouse