Regenerative Asynchrony as a Driver in Airway Remodeling
Open AccessAsthma is a heterogeneous lung syndrome that has traditionally been characterized as a disease of chronic inflammation. In addition to inflammation, structural changes in the airway, also known as remodeling, is a key feature of asthma. Remodeling includes thickening of the basement membrane, mucus hypersecretion, smooth muscle proliferation and fibrosis. These collectively are not reversible and contribute to a decline in lung function. The current paradigm indicates that inflammation leads to remodeling in asthma. Glucocorticoids have been a mainstay in the treatment of asthma because they reduce airway inflammation. According to the current paradigm, reduction of inflammation should reduce airway remodeling and lung function decline; however, glucocorticoids have not been efficacious in preventing downstream airway remodeling. This necessitates a paradigm shift, wherein inflammation is not the primary inducer of remodeling. The airway epithelium plays a central role in asthma pathogenesis because it is the first defense against external insults. Timely repair and injury resolution after epithelial insult is important for maintaining and restoring homeostasis. Epithelial regeneration normally occurs in response to incidental injury, then the injury resolves – the wound closes, progenitors differentiate and cytokines associated with repair return to baseline. A key feature of asthmatic epithelium is repeated airway injury that does not fully resolve – wound closure is slow, the asthmatic epithelium is less differentiated and cytokine production in response to injury is increased and sustained. During repeat injury resolution may fail, in part, because neighboring cells are receiving inappropriate temporal regeneration signals from each other. These inappropriate cues are termed regenerative asynchrony. Temporally appropriate signals during regeneration are termed regenerative synchrony. Mitotic behaviors play a significant role in how regeneration is carried out. In non-asthmatic epithelium, regeneration after injury is mitotically synchronous. The majority of the airway cells contributing to injury repair are in the same phase of the cell cycle. Asthmatic airway epithelial cells exhibit mitotic asynchrony, a specific type of regenerative asynchrony, wherein the cells are more evenly distributed in the cell cycle. This asynchrony leads to the production of TGF-β1, a key mediator of fibroproliferation in asthma. We proposed that regenerative asynchrony, specifically mitotic asynchrony, in repairing tissue may underlie chronic inflammation and fibrosis, where immune cell infiltration is secondary to pro-inflammatory cross-talk among asynchronously repairing adjacent tissues. Cumulative analysis shows mitotic synchrony is the homeostatic state in airway epithelial progenitor populations. Poorly-synchronized mitosis (as in asthma) induces TGF-β1 secretion and a pro-inflammatory/pro-fibrotic airway. These findings establish a rationale for targeting progenitor cell mitotic behavior rather than immune-mediated inflammation in fibrotic disease.
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