The roles of transforming growth factor-β1 and vascular endothelial growth factor in the tracheal granulation formation

Background: Acquired tracheal stenosis is common in patients with a long-term tracheostomy and granulation is one of the most commonly observed lesions in benign airway stenosis. The aim of this study was to investigate the mechanisms of tracheal granulation formation and find the potential therapeutic targets to prevent the granulation formation. Results: In granulation tissue obtained from patients during interventional bronchoscopy for the relief of airway obstruction, increased expression of transforming growth factor (TGF)-beta(1) and vascular endothelial growth factor (VEGF), as well as increased numbers of fibroblasts, was found by immunohistochemical staining. TGF-beta(1) expression was detected in both the epithelial and submucosal layers. The highest levels of VEGF and vimentin expression occurred in the submucosal layers. In comparison with the control, significantly increased numbers of small vessels were observed in the submucosal layers of the granulation tissue. In vitro, TGF-beta(1) stimulated production of VEGF by cultured fibroblasts at both the mRNA and protein level. VEGF siRNA treatment resulted in a significant decrease of TGF-beta(1)-induced VEGF production. SIS3, a selective Smad3 inhibitor, and UO126 both inhibited p44/42 MAP kinase phosphorylation and attenuated subsequent VEGF production by fibroblasts. A low concentration of erythromycin (1 mu g/ml), but not dexamethasone (100 mu M), inhibited TGF-beta(1)-induced VEGF production. Conclusion: This study provides important information that facilitates an understanding, at least in part, of the mechanisms of granulation formation. Targeting these mediators and cells may help to prevent the formation of granulation tissue in long-term tracheostomy or prolonged endotracheal intubation patients. (C) 2010 Elsevier Ltd. All rights reserved.