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)-β₁ and vascular endothelial growth factor (VEGF), as well as increased numbers of fibroblasts, was found by immunohistochemical staining. TGF-β₁ 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-β₁ stimulated production of VEGF by cultured fibroblasts at both the mRNA and protein level. VEGF siRNA treatment resulted in a significant decrease of TGF-β₁-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 μg/ml), but not dexamethasone (100 μM), inhibited TGF-β₁-induced VEGF production.


CONCLUSIONS
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.
Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang-Ming University, Taipei, Taiwan.
Yu-Chin
YC
Lee
Ming-Hui
MH
Hung
Lung-Yu
LY
Liu
Kuo-Ting
KT
Chang
Tec-Ying
TY
Chou
Yi-Chung
YC
Wang
Yu-Chung
YC
Wu
Chun-Liang
CL
Lai
Cheng-Chien
CC
Tsai
Kang-Cheng
KC
Su
Diahn-Warng
DW
Perng
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006097:Granulation Tissue / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D051900:Smad3 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D014132:Trachea / Q000473:pathology*; D053773:Transforming Growth Factor beta1 / Q000032:analysis / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000502:physiology*; D014746:Vimentin / Q000032:analysis / Q000502:physiology
C497790:SMAD3 protein, human; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D014746:Vimentin; D048049:Extracellular Signal-Regulated MAP Kinases