Novel insights into the role of hypoxia-inducible factor-1 in the pathogenesis of human post-intubation tracheal stenosis

Hypoxia is an important mechanism involved in dermal scar formation. Post-intubation tracheal stenosis (PTS) has similar pathological characteristics and formation mechanisms to skin hypertrophic scars. Hypoxia-inducible factor-1 alpha (HIF-1 alpha) is a nuclear transcription factor that facilitates the adaptation of human cells to compromised oxygen tension under hypoxic conditions. The aim of this study was to investigate whether hypoxia and HIF-1 alpha were involved in PTS. In the first part of our study, we observed the effects of tracheal mucosal pressure exerted by the endotracheal tube cuff and duration of intubation on tracheal stenosis using prospective methods. In the second part of our study, 24 patients were divided into three groups, according to the characteristics observed using bronchoscopy: granulation phase group, proliferative phase group and mature phase group. Tissues showing dysplasia were obtained using bronchoscopy forceps, and western blotting was performed to detect the protein expression of HIF-1 alpha and its target genes, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and transforming growth factor (TGF)-beta. In experiment one, we observed that the tracheal mucosal pressure exerted by the endotracheal tube cuff in the PTS group was significantly higher compared with that in the group without PTS, and the duration of intubation was longer compared with that in the group without PTS (P<0.05). In experiment two, we observed that the expression of HIF-1 alpha was highest in the granulation phase, showed a decrease in the proliferative phase and in the mature phase was significantly reduced compared with the other two phases. The results were similar for VEGF and bFGF. TGF-beta protein expression was highest in the proliferative phase, significantly reduced in the mature phase and the same trends were observed for collagen type I and III, and alpha-smooth muscle actin. HIF-1 alpha is involved in the pathogenesis of PTS and may be a potential key regulator in the initiation and facilitation of this process.