Background/Purpose: Acquired tracheal stenosis (ATS) is an unusual disease secondary to inflammatory diseases or to prolonged mechanical trauma. Tracheal mucosa undergoes inflammation and granulation tissue formation with subsequent narrowing of the tracheal lumen. The aim of this study was to analyse the potential role of TGF-β pro-fibrotic pathway in the development of tracheal stenosis.

Methods: Human tissues were obtained by excision of tracheobronchial granulation tissues from patients with benign airway stenosis (n=7) and healthy controls (n=9). We developed a model of tracheal stenosis in adult NZ rabbits, where after a previous incomplete transverse incision the trachea, a circumferential thermal injury to the mucosa with electrocautery was made. To assess the involvement and potential as therapeutic target of pro-fibrotic factor TGF-β1 in this model, rabbits were postoperatively treated with either a peri-tracheal collagen sponge containing a peptide antagonist of TGF-β1 p17 (2mg/ml) or control vehicle. Animals were sacrificed and tracheas excised at 4 weeks for histomorphometric and immunohistochemical (IHC) analysis. Collagen accumulation was analyzed by Masson’s trichrome staining and expression of TGF-β pathway surrogate markers (α-SMA myofibroblasts, CTGF and p-Smad2/3) by immunohistochemistry. Quantitative data were compared by Mann-Whitney U-test and correlation analysis by Spearman’s rank test. p-value less than 0.05 was considered significant.

Results:  Histological examination of human and rabbit stenotic tracheas showed an extensive submucosal fibrotic, collagen stained area, as well as inflammatory cell infiltration and epithelial hyperplasia. We observed a significant increase in the density of α-SMA⁺ myofibroblasts and CTGF⁺ cells in both cases compared to control tracheas. In human stenotic tracheal tissues, this was accompanied by increased nuclear p-Smad2/3 expression compared to healthy tissues. In rabbit stenotic lesions, p17 treatment significantly reduced the fibrotic thickness (p=0.0006) and the densities of α-SMA⁺ myofibroblasts and CTGF⁺ cells per mm² (p=0.0084 and p=0.001 respectively). However, we did not observe a significant increase in the luminal stenotic area in p17 compared to saline-treated group. Correlation between the tracheal luminal area and collagen thickness was non-significant (r=0.29, p=0.17).

Conclusion:  Tracheal stenosis is characterized by an important fibrotic component and by the activation of the TGF-β pro-fibrotic pathway. The animal model reproduces similar features and therefore, it provides a valid preclinical model. Local treatment with TGF-β1 antagonist demonstrates its ability to reduce the fibrotic but not the stenotic component, suggesting that fibrosis is only a partial contributor to the reduction of the tracheal lumen in ATS

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/human-and-experimental-tracheal-stenosis-is-characterized-by-a-tgf-%ce%b2-dependent-fibrotic-component/