title: Mitotic asynchrony induces transforming growth factor-β1 secretion from airway epithelium.
abstract: We recently proposed that mitotic asynchrony in repairing tissue may underlie chronic inflammation and fibrosis, where immune cell infiltration is secondary to proinflammatory cross-talk among asynchronously repairing adjacent tissues. Building on our previous finding that mitotic asynchrony is associated with proinflammatory/fibrotic cytokine secretion (e.g., transforming growth factor [TGF]-β1), here we provide evidence supporting cause-and-effect. Under normal conditions, primary airway epithelial basal cell populations undergo mitosis synchronously and do not secrete proinflammatory or profibrotic cytokines. However, when pairs of nonasthmatic cultures were mitotically synchronized at 12 hours off-set and then combined, the mixed cell populations secreted elevated levels of TGF-β1. This shows that mitotic asynchrony is not only associated with but is also causative of TGF-β1 secretion. The secreted cytokines and other mediators from asthmatic cells were not the cause of asynchronous regeneration; synchronously mitotic nonasthmatic epithelia exposed to conditioned media from asthmatic cells did not show changes in mitotic synchrony. We also tested if resynchronization of regenerating asthmatic airway epithelia reduces TGF-β1 secretion and found that pulse-dosed dexamethasone, simvastatin, and aphidicolin were all effective. We therefore propose a new model for chronic inflammatory and fibrotic conditions where an underlying factor is mitotic asynchrony.
authors.affiliation: 1 Division of Emergency Medicine, and.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Alcala
authors.forename: Angela S
authors.initials: AS
authors.lastname: Benton
authors.forename: Alan M
authors.initials: AM
authors.lastname: Watson
authors.forename: Suraiya
authors.initials: S
authors.lastname: Kureshi
authors.forename: Erica M K
authors.initials: EM
authors.lastname: Reeves
authors.forename: Jesse
authors.initials: J
authors.lastname: Damsker
authors.forename: Zuyi
authors.initials: Z
authors.lastname: Wang
authors.forename: Kanneboyina
authors.initials: K
authors.lastname: Nagaraju
authors.forename: Julia
authors.initials: J
authors.lastname: Anderson
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Williams
authors.forename: Amber J Y
authors.initials: AJ
authors.lastname: Lee
authors.forename: Kathleen
authors.initials: K
authors.lastname: Hayes
authors.forename: Mary C
authors.initials: MC
authors.lastname: Rose
authors.forename: Eric P
authors.initials: EP
authors.lastname: Hoffman
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Freishtat
mesh_terms: D016590:Aphidicolin / Q000008:administration & dosage; D001249:Asthma / Q000378:metabolism*; D001980:Bronchi / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000737:chemistry; D003907:Dexamethasone / Q000008:administration & dosage; D004847:Epithelial Cells / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D007249:Inflammation; D008938:Mitosis; D020545:Respiratory Mucosa / Q000378:metabolism; D019821:Simvastatin / Q000008:administration & dosage; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D017077:Culture Media, Conditioned; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D016590:Aphidicolin; D003907:Dexamethasone; D019821:Simvastatin
keywords: asthma; fibrosis; mitosis; transforming growth factor-β1