Study reveals mechanism by which a circadian clock molecule leads to lung fibrosis NatureComms
, numerous reports including this study demonstrate the fundamental role of Rev-erbα in lung injury, and Rev-erbα agonists can prevent lung inflammation and injury induced by CS or IAV infection. A detailed study of the anti-fibrotic properties of different Rev-erbα agonists is needed to identify a proper agonist with suitable pharmaceutical characteristics for in vivo study, and even clinical trials.
Overall, Rev-erbα abundance was decreased in fibrotic progression, and naturally reduced Rev-erbα exacerbated the fibrogenesis. Rev-erbα deficiency exaggerated the fibrotic responses and lung injury induced by IAV infection, and Rev-erbα was involved in the activation of collagen stabilization via lysyl oxidase during the fibrotic progression caused by IAV. Treatment with Rev-erbα agonist can prevent the induction of collagen-lysyl oxidase interactions and stabilization.
. Lung sections were prepared from the FFPE blocks with 5 μm thickness using a microtome. The sections are used for immunohistological chemistry staining.Rev-erbα global heterozygous mice were purchased from Jackson laboratory , and adult C57BL/6 wild-type were bred in the vivarium at the University of Rochester Medical Center. Before treatment, mice were transferred to the inhalation core facility and allowed 1 week acclimatization period.
. The mice were sacrificed 14 days post-dosing, and the lungs were snap-frozen for further analysis. For IAV dosing, mice were anesthetized with isoflurane, and a total amount of 10. A total of 3 female mice were housed individually ad libitum food and water were supplied in a special cage with a running wheel connected to an automatic counter. Mice were accommodated in the wheel running cage for 1 week, and counters were adjusted during this week.
. Mice were sacrificed at 15 days p.i., and whole blood was collected through the posterior vena cava vein. Serum was separated from whole blood by centrifugation . The IAV-specific IgG2a and IgA antibodies in serum were determined using ELISA via serial dilution as described in our previous publicationPrimary human lung fibroblast and small airway epithelial cells were purchased from Lonza.
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