Subglottic Stenosis Examined as a Fibrotic Response to Airway Injury Characterized by Altered Mucosal Fibroblast Activity

Abstract

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.

Plasmin Overcomes Resistance to Prostaglandin E2 in Fibrotic Lung Fibroblasts by Reorganizing Protein Kinase A Signaling

“…Second, lung fibroblast lines obtained from the majority of IPF patients (10) as well as from mice with bleomycin-induced pulmonary fibrosis (11) are resistant to the normal collagen-inhibiting action of PGE 2 . Fibroblast resistance to PGE 2 is also observed in other fibrotic diseases (12,13), motivating efforts to restore the anti-fibrotic efficacy of deficient PGE 2 as a therapeutic approach in such disorders.…”

Inhibitory Effect of Mitomycin C on Proliferation of Primary Cultured Fibroblasts from Human Airway Granulation Tissues

“…Fibroblasts are the key component of granulation tissue, and they play a critical role in the development of granulation and scar formation. Abnormal fibroblasts are resistant to apoptosis signals and are an originator of excessive extracellular matrices [1,3]. MMC displays antimetabolite and antiproliferative properties by inhibiting cell DNA synthesis or suppressing RNA and protein synthesis [4,9], and has been shown to be a strong inhibitor of fibroblast proliferation in wound-healing processes when applied topically [10].…”

“…The underlying mechanism of BTS is an aberrant mucosal wound-healing response that leads to excessive fibroplasia [1]. Although a variety of interventional bronchoscopic techniques have recently been developed to provide immediate relief from airway obstruction, they may cause secondary damage to the airway structures, resulting in excessive granulation tissue and scar formation during the wound-healing procedure, and ultimately restenosis.…”

<i>In vitro</i> pharmacokinetics of sirolimus-coated stent for tracheal stenosis

“…Unfortunately, intratracheal stent can damage the airway mucosa, and cause excessive proliferation of fibrous tissue. These lead to stent restenosis, which seriously affects the clinical efficacy of stent implantation [3]. In recent years, clinically-applied drug-eluting stent (DES) has been used in a wide range of patients with cardiopathy, gastroenteropathy or urologic diseases [4,5].…”