Objective To investigate the association between mucosal fibroblast activity and subglottic stenosis (SGS) development. Design Animals were assigned to either cricothyroidotomy and CO2 laser injury, or cricothyroidotomy and silver nitrate (AgNO3) injury groups. Airways were excised for histologic analysis and the establishment of primary fibroblast cultures. Surgical excision of established SGS followed by recovery was used to analyze SGS recurrence in this animal model. Subjects New Zealand white rabbits. Interventions The subglottis was approached via cricothyroidotomy and subjected to either CO2 laser or AgNO3 injury prior to closure. The SGS lesions were excised between 8 and 10 weeks and used to establish explants for fibroblast culture. The animals underwent recovery for an additional 14 days to follow recurrence of SGS. After 14 days all the animals were euthanized and subglottic tissue was harvested for histological evaluation. Rates of migration and contraction of SGS and normal airway fibroblasts were assayed using established in vitro methods under basal conditions and with prostaglandin (PG) E2 treatment. Results 1) Mucosal injury resulted in acute fibroplasia and chronic SGS. 2) Surgical excision of mature SGS at 8 weeks resulted in rapid recurrence of stenosis. 3) SGS derived fibroblasts were relatively refractory to the effects of PGE2 on migration and contraction. Conclusion SGS represents a fibrotic airway repair process, involving fibroblasts that produce recurrent, excessive scar formation. We suggest that SGS development and recurrence may be partially dictated by altered fibroblast responsiveness to anti-fibroplastic signals during mucosal repair.

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Objectives/Hypothesis-To characterize the activation of cyclooxygenase (COX)-2/ prostaglandin (PG) E2 signaling during airway mucosal repair and its subsequent role during the wound healing process.Study Design-Prospective animal study.Methods-The subglottis was approached via cricothyroidotomy. Sham airways were closed, and wounded airways were subjected to laser injury and closed. Subglottic tissue was harvested at 12 hours, 24 hours, 48 hours, and 72 hours postinjury. Secretions were collected preoperatively and at time of sacrifice. Inflammatory gene expression was analyzed using quantitative reverse transcriptase polymerase chain reaction. Subglottic/tracheal explants were exposed to exogenous IL-1β in the presence or absence of COX inhibitors. Explant-produced PGE2 levels were assayed using enzyme linked immunoassays. Human airway fibroblast migration and collagen contraction were assayed in the presence or absence of prostaglandin E2.Results-Laser injury triggers a rapid, dose-dependent increase in mucosal IL-1β and COX-2 gene expression, with an anatomical distribution proportional to the distance from the site of injury. Gene up-regulation correlates with dose-dependent increases in PGE2 mucosal secretion levels. Ex vivo analysis indicates IL-1β is responsible for the activation of the COX-2/PGE2 pathway. Prostaglandin E2 differentially inhibits airway fibroblast migration and contraction in a specific, dose-dependent manner.Conclusions-PGE2 is activated during mucosal inflammation and acts to decrease fibroplastic activity in the mucosal wound bed. During subglottic stenosis (SGS) development, the levels of PGE2 generated in response to injury may be insufficient to blunt the intrinsically fibroplastic phenotype of SGS fibroblasts, resulting in excessive scarring.

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