Disruption of ß-catenin/CBP signaling inhibits human airway epithelial-mesenchymal transition and repair.

The epithelium of asthmatics is characterized by reduced expression of E-cadherin and increased expression of the basal cell markers ck-5 and p63 that is indicative of a relatively undifferentiated repairing epithelium. This phenotype correlates with increased proliferation, compromised wound healing and an enhanced capacity to undergo epithelial-mesenchymal transition (EMT). The transcription factor ß-catenin plays a vital role in epithelial cell differentiation and regeneration, depending on the co-factor recruited. Transcriptional programs driven by the ß-catenin/CBP axis are critical for maintaining an undifferentiated and proliferative state, whereas the ß-catenin/p300 axis is associated with cell differentiation. We hypothesized that disrupting the ß-catenin/CBP signaling axis would promote epithelial differentiation and inhibit EMT. We treated monolayer cultures of human airway epithelial cells with TGFß1 in the presence or absence of the selective small molecule ICG-001 to inhibit ß-catenin/CBP signaling. We used western blots to assess expression of an EMT signature, CBP, p300, ß-catenin, fibronectin and ITGß1 and scratch wound assays to assess epithelial cell migration. Snai-1 and -2 expressions were determined using q-PCR. Exposure to TGFß1 induced EMT, characterized by reduced E-cadherin expression with increased expression of α-smooth muscle actin and EDA-fibronectin. Either co-treatment or therapeutic administration of ICG-001 completely inhibited TGFß1-induced EMT. ICG-001 also reduced the expression of ck-5 and -19 independent of TGFß1. Exposure to ICG-001 significantly inhibited epithelial cell proliferation and migration, coincident with a down regulation of ITGß1 and fibronectin expression. These data support our hypothesis that modulating the ß-catenin/CBP signaling axis plays a key role in epithelial plasticity and function.

The airway epithelium in asthma: developmental issues that scar the airways for life?

While allergies are very common, affecting ∼40% of the population in most Western countries, only a proportion of allergic people develop asthma. This highlights the importance of tissue and cell specific mechanisms that contribute to the disease. As the interface between the inhaled environment and the internal environment of the lung, the epithelium normally possesses numerous mechanisms to maintain an effective protective barrier. However, the inability of the airway epithelium of asthmatics to effectively defend the lung against normally innocuous inhaled agents strongly suggests that asthma must involve defects in the epithelial barrier rather than being primarily an allergic disease. Evidence is accumulating that in asthma, the epithelium does not go through normal stages of development and differentiation and as a consequence, remain somewhat "immature". This in turn leads to a chronic cycle of dysregulated damage and repair which ultimately impacts on the airways function by increasing inflammation, but also by initiating processes that ultimately lead to changes to the structure and function of the airway.