Subglottic stenosis (SGS) is characterized by the obliteration of the tracheal lumen due to excessive deposition of connective tissue. We hypothesize that tracheal injury triggers the early production of transforming growth factor-β1 (TGF-β1), a factor implicated in fibroproliferative disorders. In turn, TGF-β1 stimulates the transformation of tracheal fibroblasts into myofibroblasts with increased matrix production and scar contraction that might be influential in laying the foundation for the development of SGS. Consistent with this hypothesis, histologic analysis of tracheas from humans with SGS and from rats with experimental tracheal injury revealed increased α–smooth muscle actin—positive cells as compared to control tracheas, suggesting increased myofibroblast differentiation. Rat tracheal fibroblasts exposed to TGF-β1 or gastric juice in vitro showed increased expression of α–smooth muscle actin, alterations in the expression of matrix molecules, and increased contraction of collagen gels. These findings suggest that gastric juice or other agents of tracheal injury promote tissue remodeling through the stimulation of the differentiation of fibroblasts into myofibroblasts.
MaronianNCAzadehHWaughPHillelA. Association of laryngopharyngeal reflux disease and subglottic stenosis. Ann Otol Rhinol Laryngol2001; 110: 606–12.
2.
DedoHHCattenMD. Idiopathic progressive subglottic stenosis: Findings and treatment in 52 patients. Ann Otol Rhinol Laryngol2001; 110: 305–11.
3.
DuynsteeMLde KrijgerRRMonnierPVerwoerdCDVerwoerd-VerhoefHL. Subglottic stenosis after endolaryngeal intubation in infants and children: Result of wound healing processes. Int J Pediatr Otorhinolaryngol2002; 62: 1–9.
HartnickCJHartleyBELacyPD. Topical mitomycin application after laryngotracheal reconstruction: A randomized, double-blind, placebo-controlled trial. Arch Otolaryngol Head Neck Surg2001; 127: 1260–4.
6.
CorreaAJReinischLSandersDL. Inhibition of subglottic stenosis with mitomycin-C in the canine model. Ann Otol Rhinol Laryngol1999; 108: 1053–60.
7.
DillardDGGalAARoman-RodriguezJWhiteSJacobsIN. Transforming growth factor and neutralizing antibodies in subglottic stenosis. Ann Otol Rhinol Laryngol2001; 110: 393–400.
8.
GoumenosDSTsamandasACOldroydS. Transforming growth factor-β(1) and myofibroblasts: A potential pathway towards renal scarring in human glomerular disease. Nephron2001; 87: 240–8.
9.
XuGBochaton-PiallatMLAndreuttiDLowRBGabbianiGNeuvilleP. Regulation of alpha-smooth muscle actin and CRBP-1 expression by retinoic acid and TGF-beta in cultured fibroblasts. J Cell Physiol2001; 187: 315–25.
10.
SchuppanDKodaMBauerMHahnEG. Fibrosis of liver, pancreas and intestine: Common mechanisms and clear targets?. Acta Gastroenterol Belg2000; 63: 366–70.
11.
MorishimaYNomuraAUchidaY. Triggering the induction of myofibroblast and fibrogenesis by airway epithelial shedding. Am J Respir Cell Mol Biol2001; 24: 1–11.
12.
BorderWARuoslahtiE. Transforming growth factor-beta in disease: The dark side of tissue repair. J Clin Invest1992; 90: 1–7.
13.
PhanSH. The myofibroblast in pulmonary fibrosis. Chest2002; 122(suppl 6): 286S–289S.
14.
RomanJSchuylerWMcDonaldJARoserS. Heparin inhibits lung branching morphogenesis: Potential role of smooth muscle cells in cleft formation. Am J Med Sci1998; 316: 368–78.
15.
PerezRLRomanJRoserS. Cytokine message and protein expression during lung granuloma formation and resolution induced by the mycobacterial cord factor trehalose-6,6ℙ-dimycolate. J Interferon Cytokine Res2000; 20: 795–804.
16.
Rivera-MarreroCASchuylerWRoserSRitzenthalerJRNewburnSARomanJ. M. tuberculosis induction of matrix metalloproteinase–9: The role of mannose and receptor-mediated mechanisms. Am J Physiol Lung Cell Mol Physiol2002; 282: L546–L555.
17.
RomanJLaChanceRMBroekelmannTJ. The fibronectin receptor is organized by extracellular matrix fibronectin: Implications for oncogenic transformation and for cell recognition of fibronectin matrices. J Cell Biol1989; 108: 2529–43.
18.
BolesBRitzenthalerJRBirkenmeierTRomanJ. Phorbol ester-induced U-937 differentiation: Effects on integrin alpha(5) gene transcription. Am J Physiol Lung Cell Mol Physiol2000; 278: L703–L712.
19.
FanJMHuangXRNgYY. Interleukin-1 induces tubular epithelial-myofibroblast transdifferentiation through a transforming growth factor-β1-dependent mechanism in vitro. Am J Kidney Dis2001; 37: 820–31.
20.
DoharJEKleinECBetschJLHebdaPA. Fetal airway wound repair: A new frontier. Arch Otolaryngol Head Neck Surg1998; 124: 25–9.
21.
BusseWEliasJSheppardDBanks-SchlegelS. Airway remodeling and repair. Am J Respir Crit Care Med1999; 160: 1035–42.
22.
DoharJEKleinECBetschJLHebdaPA. Acquired subglottic stenosis — Depth and not extent of the insult is key. Int J Pediatr Otorhinolaryngol1998; 46: 159–70.
23.
RoySGNozakiYPhanSH. Regulation of alpha-smooth muscle actin gene expression in myofibroblast differentiation from rat lung fibroblasts. Int J Biochem Cell Biol2001; 33: 723–34.
24.
RomanJ. Extracellular matrices in lung injury and repair. In: SchwarzMKingT, eds. Interstitial lung disease. 3rd ed. London, England: BC Decker, 1998: 207–27.
25.
HockingD. Fibronectin matrix deposition and cell contractility: Implications for airway remodeling in asthma. Chest2002; 122(suppl 6): 275S–278S.
WalnerDLSternYGerberMERudolphCBaldwinCYCottonRT. Gastroesophageal reflux in patients with subglottic stenosis. Arch Otolaryngol Head Neck Surg1998; 124: 551–5.
28.
NostrantTT. Gastroesophageal reflux and laryngitis: A skeptic's view. Am J Med2000; 108(suppl 4A): 149S–152S.
29.
YellonRFSzeremetaWGrandisJRDiguisseppePDickmanPS. Role of subglottic injury, gastric juice, and peptide growth factors in a porcine model. Int Anesthesiol Clin1997; 35: 115–25.
30.
KhalilN. Post translational activation of latent transforming growth factor beta (L-TGF-beta): Clinical implications. Histol Histopathol2001; 16: 541–51.
