Dexamethasone can stimulate G1-S phase transition in human airway fibroblasts in asthma

Abstract

Corticosteroids are the first line of therapy for asthma. Whether they alter the progression of airway remodelling in asthma is, as yet, unknown.To determine whether corticosteroids could alter the fibroblast cell cycle the current authors studied the effect of dexamethasone on cultured airway fibroblasts obtained from nine mild-tomoderate, steroid-naïve asthmatics (forced expiratory volume in one second 78¡4% predicted), and seven normal controls. Fibroblasts were cultured from endobronchial biopsies obtained via bronchoscopy. Cells were exposed to dexamethasone (10 -9 -10 -7 M) and studied at 72 h to determine differences in progression through the cell cycle.In asthmatic fibroblasts, dexamethasone, at concentrations of 10 -8M and 10 -7 M, nearly doubled the number of cells in the S phase (17.8¡3.0% and 18.4¡3.1%, respectively) compared with untreated fibroblasts (10.3¡1.4%). There was no significant effect in normal control fibroblasts. Dexamethasone induced hyperphosphorylation of the tumour suppressor, retinoblastoma (RB) in asthmatic fibroblasts; fibroblasts from normal controls had significantly less hyperphosphorylation of RB. No difference in protein expression of the CCAAT/enhancer binding protein a between the two groups was detected. This study suggests that dexamethasone can stimulate G1-S phase cell cycle transition in human airway fibroblasts obtained from asthmatics. Whether this leads to enhanced airway remodelling in some individuals remains to be determined.

Specificity of basement membrane thickening in severe asthma

“…6,24,25 On the other hand, some in vitro studies suggested that steroids could increase extracellular matrix deposition. 26 Nonetheless, whereas the patients with the most severe asthma had the highest RBM thicknesses, in the current study we noted, like Minshall et al 27 in a previous study, a negative correlation between RBM thickness and FEV 1 when considering the 2 asthma groups. In a variable and heterogeneous condition such as severe asthma, a single parameter such as FEV 1 did not account for the complexity of the disease.…”

Asthma therapy and airway remodeling

“…69,70 However, studies using fibroblasts from patients with asthma show that dexamethasone can increase fibroblast proliferation and stimulate G1-S phase transition. 71,72 This is an important observation, suggesting that corticosteroids may also promote elements of airway remodeling in asthma. FP displays anti-inflammatory effects on human lung fibroblasts during their myofibroblastic differentiation.…”

Mast Cell Fibroblastoid Differentiation Mediated by Airway Smooth Muscle in Asthma

“…Sequential 2-mm sections were cut from glycomethacrylate-embedded bronchial biopsies and stained using mAbs against a-smooth muscle actin (a-SMA; Dako, Ely, U.K.), mast cell tryptase (Dako), the fibroblast marker Thy-1 (Ab1) (Calbiochem, San Diego, CA) (20) (7,13,15). The whole biopsy was assessed, and a minimum area of 0.1 mm 2 was considered assessable, as described previously (7).…”