Inhalation of Carboxymethyl Chitosan Alleviates Posttraumatic Tracheal Fibrosis.

OBJECTIVES: The present study was performed to determine whether the inhalation of carboxymethyl (CM)-chitosan can alleviate tracheal fibrosis in a rabbit model. METHODS: We designed a rabbit model of tracheal stenosis involving electrocoagulation with a spherical electrode. Twenty New Zealand white rabbits were randomly divided into experimental and control groups (10 animals each). Tracheal damage was successfully established by electrocoagulation in all animals. The experimental group was given CM-chitosan (inhalation for 28 days), while the control group inhaled saline. The effects of CM-chitosan inhalation on tracheal fibrosis were analyzed. Laryngoscopy was performed to evaluate and grade tracheal granulation, while tracheal fibrosis was evaluated by histological examination. The effects of CM-chitosan inhalation on the tracheal mucosa were examined by scanning electron microscopy (SEM), and hydroxyproline content in tracheal scar tissue was determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: Laryngoscopy showed that the tracheal cross-sectional area was smaller in the experimental than control group. The amounts of loose connective tissue and damaged cartilage, as well as the severity of collagen and fibrosis, decreased following inhalation of CM-chitosan. According to the ELISA, the experimental group had low levels of hydroxyproline in the tracheal scar tissue. CONCLUSION: The findings presented here showed that inhalation of CM-chitosan mitigated posttraumatic tracheal fibrosis in a rabbit model, thus suggesting a potential new treatment for tracheal stenosis.

Down-regulation of miR-21-5p by pirfenidone to inhibit fibroblast proliferation in the treatment of acquired tracheal stenosis.

OBJECTIVE: Treatment options for acquired tracheal stenosis (ATS) are limited due to a series of pathophysiological changes including inflammation and cell proliferation. Micro ribonucleic acid-21-5p (miR-21-5p) may promote the excessive proliferation of fibroblasts. However, various types of fibrosis can be prevented with pirfenidone (PFD). Currently, the effect of PFD on miR-21-5p and its biological function has not been clarified. In this study, PFD was evaluated as a potential treatment for ATS by inducing fibroblast proliferation in lipopolysaccharide (LPS)-induced fibroblasts by targeting miR-21-5p. METHODS: For 48 h, 1 g/ml LPS was used to generate fibroblasts in vitro, followed by the separation of cells into four groups: control, PFD, mimic, and mimic + PFD. The Cell Counting Kit-8 (CCK-8) technique was adopted to measure the proliferation of fibroblasts. Real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot (WB) were used to measure the relative expressions of tumor necrosis factor-α (TNF-α), transforming growth factor-ß1 (TGF-ß1), drosophila mothers against decapentaplegic 7 (Smad7) and collagen type I alpha 1(COL1A1) messenger RNA (mRNA) and proteins, respectively. RESULTS: (1) At 0, 24, 48, and 72 h, fibroblast growth was assessed using the CCK-8 method. Compared with the control group, the mimic group showed the highest fibroblast viability, and the PFD group showed the lowest fibroblast viability. However, fibroblast viability increased in the mimic + PFD group but decreased in the mimic one. (2) RT-qPCR and WB showed that the mimic group exhibited a significant up-regulation in the relative expressions of TNF-α, TGF-ß1, and COL1A1 mRNA and proteins but a down-regulation in the relative expression of Smad7 mRNA and protein compared with the control one. In the PFD group, the results were the opposite. Nevertheless, the relative expressions of TNF-α, TGF-ß1, and COL1A1 mRNA and proteins were increased, whereas that of Smad7 mRNA was decreased in the mimic + PFD group. The change was less in the mimic group. CONCLUSION: PFD may have a preventive and curative effect on ATS by inhibiting fibroblast proliferation and the fibrotic process and possibly through down-regulating miR-21-5p and up-regulating Smad7 and its mediated fibrotic and inflammatory responses.

Use of Mitomycin-C in Laryngotracheal Stenosis: A Focused Clinical Review.

BACKGROUND: Therapeutic options for managing laryngotracheal stenosis (LTS) are limited. Endoscopy is a minimally invasive approach to treating LTS, but carries a high risk of stenosis recurrence. Mitomycin C (MMC) is often used as an adjunct therapy to delay the time to symptomatic recurrence of LTS. This review synthesizes the current literature on the topic of MMC as an adjunct treatment strategy for LTS. METHODS: A focused literature search was carried out from PubMed on June 12, 2022 using the terms "mitomycin c AND stenosis" in all fields with no date limitations. Evidence-based recommendations relevant to the clinical application of MMC as an adjunct therapy for LTS were formulated. Three questions were addressed: 1) efficacy of MMC, 2) single versus multiple application(s) of MMC, and 3) safety of MMC. The evidence rating and recommendation strength were guided by the GRADE system. RESULTS: Twenty-nine studies were reviewed. The efficacy of MMC as an adjunct therapy for LTS varied across studies. Randomized controlled trials have not shown an outcome difference with MMC use, although methodologic flaws including underpowering were noted. A meta-analysis of observational studies with a comparator arm found the unadjusted probability of remaining symptom-free for > 1 year is greater with versus without MMC application (73% vs. 35%). Single versus multiple application(s) of MMC resulted in similar restenosis rates at long-term follow-up. Complications related to MMC use are rarely reported using conventional doses (0.4 mg/mL). Overall, the quality of evidence was low and the recommendation for intervention was weak. CONCLUSION: The role for MMC as an adjunct therapy in LTS is uncertain. While safe in its application, the efficacy of MMC in reducing stenosis recurrence remains a matter of debate. Large, prospective studies are needed to inform future recommendations.

Sirolimus-eluting airway stent reduces profibrotic Th17 cells and inhibits laryngotracheal stenosis.

Laryngotracheal stenosis (LTS) is pathologic fibrotic narrowing of the larynx and trachea characterized by hypermetabolic fibroblasts and CD4+ T cell-mediated inflammation. However, the role of CD4+ T cells in promoting LTS fibrosis is unknown. The mTOR signaling pathways have been shown to regulate the T cell phenotype. Here we investigated the influence of mTOR signaling in CD4+ T cells on LTS pathogenesis. In this study, human LTS specimens revealed a higher population of CD4+ T cells expressing the activated isoform of mTOR. In a murine LTS model, targeting mTOR with systemic sirolimus and a sirolimus-eluting airway stent reduced fibrosis and Th17 cells. Selective deletion of mTOR in CD4+ cells reduced Th17 cells and attenuated fibrosis, demonstrating CD4+ T cells' pathologic role in LTS. Multispectral immunofluorescence of human LTS revealed increased Th17 cells. In vitro, Th17 cells increased collagen-1 production by LTS fibroblasts, which was prevented with sirolimus pretreatment of Th17 cells. Collectively, mTOR signaling drove pathologic CD4+ T cell phenotypes in LTS, and targeting mTOR with sirolimus was effective at treating LTS through inhibition of profibrotic Th17 cells. Finally, sirolimus may be delivered locally with a drug-eluting stent, transforming clinical therapy for LTS.

IL-11 drives the phenotypic transformation of tracheal epithelial cells and fibroblasts to enhance abnormal repair after tracheal injury.

Tracheal stenosis (TS) is a multifactorial and heterogeneous disease that can easily lead to respiratory failure and even death. Interleukin-11 (IL-11) has recently received increased attention as a fibrogenic factor, but its function in TS is uncertain. This study aimed to investigate the role of IL-11 in TS regulation based on clinical samples from patients with TS and a rat model of TS produced by nylon brush scraping. Using lentiviral vectors expressing shRNA (lentivirus-shRNA) targeting the IL-11 receptor (IL-11Rα), we lowered IL-11Rα levels in the rat trachea. Histological and immunostaining methods were used to evaluate the effects of IL-11Rα knockdown on tracheal injury, molecular phenotype, and fibrosis in TS rats. We show that IL-11 was significantly elevated in circulating serum and granulation tissue in patients with TS. In vitro, TGFß1 dose-dependently stimulated IL-11 secretion from human tracheal epithelial cells (Beas-2b) and primary rat tracheal fibroblasts (PRTF). IL-11 transformed the epithelial cell phenotype to the mesenchymal cell phenotype by activating the ß-catenin pathway. Furthermore, IL-11 activated the atypical ERK signaling pathway, stimulated fibroblasts proliferation, and transformed fibroblasts into alpha-smooth muscle actin (α-SMA) positive myofibroblasts. IL-11-neutralizing antibodies (IL-11NAb) or ERK inhibitors (U0126) inhibited IL-11 activity and downregulated fibrotic responses involving TGFß/SMAD signaling. In vivo, IL-11Rα knockdown rats showed unobstructed tracheal lumen, relatively intact epithelial structure, and significantly reduced granulation tissue proliferation and collagen fiber deposition. Our findings confirm that IL-11 may be a target for future drug prevention and treatment of tracheal stenosis.

Comparison of Inhaled Drug Delivery in Patients With One- and Two-level Laryngotracheal Stenosis.

OBJECTIVES/HYPOTHESIS: Laryngotracheal stenosis (LTS) is a functionally devastating condition with high respiratory morbidity and mortality. This preliminary study investigates airflow dynamics and stenotic drug delivery in patients with one- and two-level LTS. STUDY DESIGN: A Computational Modeling Restropective Cohort Study. METHODS: Computed tomography scans from seven LTS patients, five with one-level (three subglottic, two tracheal), and two with two-level (glottis + trachea, glottis + subglottis) were used to reconstruct patient-specific three-dimensional upper airway models. Airflow and orally inhaled drug particle transport were simulated using computational fluid dynamics modeling. Drug particle transport was simulated for 1-20 µm particles released into the mouth at velocities of 0 m/s, 1 m/s, 3 m/s, and 10 m/s for metered dose inhaler (MDI) and 0 m/s for dry powder inhaler (DPI) simulations. Airflow resistance and stenotic drug deposition in the patients' airway models were compared. RESULTS: Overall, there was increased airflow resistance at stenotic sites in subjects with two-level versus one-level stenosis (0.136 Pa s/ml vs. 0.069 Pa s/ml averages). Subjects with two-level stenosis had greater particle deposition at sites of stenosis compared to subjects with one-level stenosis (average deposition 2.31% vs. 0.96%). One-level stenosis subjects, as well as one two-level stenosis subject, had the greatest deposition using MDI with a spacer (0 m/s): 2.59% and 4.34%, respectively. The second two-level stenosis subject had the greatest deposition using DPI (3.45%). Maximum deposition across all stenotic subtypes except one-level tracheal stenosis was achieved with particle sizes of 6-10 µm. CONCLUSIONS: Our results suggest that patients with two-level LTS may experience a more constricted laryngotracheal airflow profile compared to patients with one-level LTS, which may enhance overall stenotic drug deposition. LEVEL OF EVIDENCE: NA Laryngoscope, 133:366-374, 2023.

Infliximab therapy of relapsing tracheal stenosis in a pediatric patient with granulomatosis with polyangiitis: a case report.

BACKGROUND: Granulomatosis with polyangiitis is a granulomatous, necrotizing small-vessel vasculitis affecting both children and adults. However, subglottic tracheal stenosis appears more frequently in the pediatric cohort. To date, granulomatosis with polyangiitis is often treated with steroids, cyclophosphamide, azathioprine, or rituximab, but tumor-necrosis-factor-α-antagonistic drugs are increasingly gaining significance in treatment of refractory cases. CASE PRESENTATION: We report the case of a 15-year-old Caucasian male diagnosed with proteinase-3-positive granulomatosis with polyangiitis with acute shortness of breath. X-ray and magnet resonance imaging showed extensive subglottic narrowing. Forced expiratory volume in 1 s was reduced to 50% of age norm, with massively increased effective airway resistance. The patient initially responded very well to high-dose steroids and maintenance therapy with azathioprine. He was subsequently treated with four doses of rituximab, and levels of proteinase 3 antibodies normalized. After 6 months of clinical remission, the patient presented again with acute respiratory symptoms. Again, he was treated with high-dose steroids, but showed poor clinical response this time. Therefore, we decided to commence a tumor-necrosis-factor-α-antagonistic treatment with infliximab, under which our patient achieved clinical remission and normalization of lung function parameters. CONCLUSIONS: The use of tumor-necrosis-factor-α-antagonistic agents might be a promising alternative for the treatment of refractory tracheal stenosis in pediatric patients with granulomatosis with polyangiitis.

Rapid and durable response to fifth-line lorlatinib plus olaparib in an ALK -rearranged, BRCA2-mutated metastatic lung adenocarcinoma patient with critical tracheal stenosis: a case report.

Treatment options for heavily treated anaplastic lymphona kinase (ALK )-positive nonsmall cell lung cancer (NSCLC) patients, who typically bear-resistant mechanisms to ALK tyrosine kinase inhibitors (TKIs), are usually limited to chemotherapy, which elicits limited clinical benefit and may incur severe toxicity. It is clinically relevant to explore other revenues for these patients. poly (ADP-ribose) polymerase (PARP) inhibitors, such as olaparib are currently approved to treat BReast CAncer gene 1/2 ( BRCA1/2 )-mutated patients in a few tumor types. There have been a trial and two case reports of an olaparib-containing regimen in treating epidermal growth factor receptor (EGFR)-positive or driver-negative NSCLC. We report a case of a 27-year-old female nonsmoker diagnosed with ALK -rearranged metastatic lung adenocarcinoma. She was treated with alectinib and acquired ALK p.I1171N and p.V1180L mutations. Germline BRCA2 p.F2801fs was also identified. After sequential lines of ceritinib and chemotherapy, lorlatinib was chosen as the fourth-line therapy and maintained control for 6 months. Shortly after progression, the patient was admitted to the ICU due to critically severe stenosis caused by a tracheal mass and soon relieved by embolization and stenting. Afterward lorlatinib plus olaparib was started and elicited a rapid response within 1 month. The progression-free survival was 6 months as of the latest follow-up, with the best response of partial response. To the best of our knowledge, this case is the first to provide clinical evidence of antitumor activity of olaparib plus ALK TKI in ALK -positive, g BRCA -mutated metastatic NSCLC. Together with previous reports in EGFR -positive or driver-negative patients, our finding warrants further studies on PARP inhibition in BRCA1/2 -mutated NSCLC.

On the possibility of photodynamic inactivation of tracheobronchial tree pathogenic microbiota using methylene blue (in vitro study).

BACKGROUND: The treatment of patients after mechanical ventilation of lungs suffering from a multi-species infection of the tracheobronchial tree can be complicated.. The situation is aggravated in patients with post-intubation tracheal stenosis, where infection plays a leading pathogenetic role in damage to the tracheal wall. As a result of such a pathological process, cicatricial stenosis of the trachea of purulent-inflammatory infectious genesis or infected tracheal stenosis (ITS) may occur. METHODS: In this work, we studied the possibility of photodynamic inactivation of pathogenic microbiota typical for patients with ITS using methylene blue (MB) as a photosensitizer. RESULTS: 13 clinical isolates of 8 species of bacteria from 9 patients were susceptible to photodynamic inactivation with MB. 30 µM of MB at a light irradiation dose of 25 J/cm2 and incubation with MB for 15 min allows to completely inactivate bacteria found in the tracheobronchial secretions of patients with ITS. CONCLUSIONS: MB retains its optico-physical properties in the range of 3-30 µM and provides effective inactivation of isolated Gram-positive and Gram-negative bacteria, including multi- and pan-resistant to antibiotics.

Inhibition of extracellular signal-regulated kinase pathway suppresses tracheal stenosis in a novel mouse model.

Tracheal stenosis is a refractory and recurrent disease induced by excessive cell proliferation within the restricted tracheal space. We investigated the role of extracellular signal-regulated kinase (ERK), which mediates a broad range of intracellular signal transduction processes in tracheal stenosis and the therapeutic effect of the MEK inhibitor which is the upstream kinase of ERK. We histologically analyzed cauterized tracheas to evaluate stenosis using a tracheal stenosis mouse model. Using Western blot, we analyzed the phosphorylation rate of ERK1/2 after cauterization with or without MEK inhibitor. MEK inhibitor was intraperitoneally injected 30 min prior to cauterization (single treatment) or 30 min prior to and 24, 48, 72, and 96 hours after cauterization (daily treatment). We compared the stenosis of non-inhibitor treatment, single treatment, and daily treatment group. We successfully established a novel mouse model of tracheal stenosis. The cauterized trachea increased the rate of stenosis compared with the normal control trachea. The phosphorylation rate of ERK1 and ERK2 was significantly increased at 5 min after the cauterization compared with the normal controls. After 5 min, the rates decreased over time. The daily treatment group had suppressed stenosis compared with the non-inhibitor treatment group. p-ERK1/2 activation after cauterization could play an important role in the tracheal wound healing process. Consecutive inhibition of ERK phosphorylation is a potentially useful therapeutic strategy for tracheal stenosis.

Antifibrotic Role of Nintedanib in Tracheal Stenosis After a Tracheal Wound.

OBJECTIVES/HYPOTHESIS: Tracheal stenosis is an obstructive disease of the upper airway that commonly develops as a result of abnormal wound healing. We evaluated the anti-inflammatory and antifibrotic properties of nintedanib on tracheal stenosis both in vitro and in vivo. STUDY DESIGN: Prospective controlled animal study and in vitro comparative study of human cells. METHODS: An animal model of tracheal stenosis was induced via tracheal trauma. Postsurgical rats were orally administered with nintedanib (10 or 20 mg/kg/d) or saline (negative control) for 2 weeks, and tracheal specimens were harvested after 3 weeks. Degree of stenosis, collagen deposition, fibrotic surrogate markers expression, and T-lymphocytic infiltration were evaluated. Human fetal lung fibroblast-1 (HFL-1) cells were cultured to determine the effects of nintedanib on changes of cellular biological function induced by transforming growth factor-ß1 (TGF-ß1). RESULTS: Rat tracheal stenotic tissues exhibited thickened lamina propria with irregular epithelium, characterized by significantly increased collagen deposition and elevated TGF-ß1, collagen I, α-SMA and fibronectin expressions. Nintedanib markedly attenuated the tracheal stenotic lesions, reduced the collagen deposition and the expression of fibrotic marker proteins, and mitigated CD4+ T-lymphocyte infiltration. Additionally, cellular proliferation and migration were decreased dose-dependently in TGF-ß1-stimulated HFL-1 cells when treated with nintedanib. Furthermore, nintedanib inhibited TGF-ß1-induced HFL-1 differentiation and reduced the mRNA levels of the profibrotic genes. TGF-ß1-activated phosphorylation of the TGF-ß/Smad2/3 and ERK1/2 pathways were also blocked by nintedanib. CONCLUSION: Nintedanib effectively prevented tracheal stenosis in rats by inhibiting fibrosis and inflammation. The antifibrotic effect of nintedanib may be achieved by inhibiting fibroblasts' proliferation, migration and differentiation and suppressing the TGF-ß1/Smad2/3 and ERK1/2 signaling pathways. LEVEL OF EVIDENCE: NA Laryngoscope, 131:E2496-E2505, 2021.

Glutamine Inhibition Reduces Iatrogenic Laryngotracheal Stenosis.

OBJECTIVE/HYPOTHESIS: Glutamine inhibition has been demonstrated an antifibrotic effect in iatrogenic laryngotracheal stenosis (iLTS) scar fibroblasts in vitro. We hypothesize that broadly active glutamine antagonist, DON will reduce collagen formation and fibrosis-associated gene expression in iLTS mice. STUDY DESIGN: Prospective controlled animal study. METHODS: iLTS in mice were induced by chemomechanical injury of the trachea using a bleomycin-coated wire brush. PBS or DON (1.3 mg/kg) were administered by intraperitoneal injection (i.p.) every other day. Laryngotracheal complexes were harvested at days 7 and 14 after the initiation of DON treatment for the measurement of lamina propria thickness, trichrome stain, immunofluorescence staining of collagen 1, and fibrosis-associated gene expression. RESULTS: The study demonstrated that DON treatment reduced lamina propria thickness (P = .025) and collagen formation in trichrome stain and immunofluorescence staining of collagen 1. In addition, DON decreased fibrosis-associated gene expression in iLTS mice. At day 7, DON inhibited Col1a1 (P < .0001), Col3a1 (P = .0046), Col5a1 (P < .0001), and Tgfß (P = .023) expression. At day 14, DON reduced Co1a1 (P = .0076) and Tgfß (P = .023) expression. CONCLUSIONS: Broadly active glutamine antagonist, DON, significantly reduces fibrosis in iLTS mice. These results suggest that the concept of glutamine inhibition may be a therapeutic option to reduce fibrosis in the laryngotracheal stenosis. LEVEL OF EVIDENCE: N/A Laryngoscope, 131:E2125-E2130, 2021.

Orally Inhaled Drug Particle Transport in Computerized Models of Laryngotracheal Stenosis.

OBJECTIVE: Adjuvant management for laryngotracheal stenosis (LTS) may involve inhaled corticosteroids, but metered dose inhalers are designed for pulmonary drug delivery. Comprehensive analyses of drug particle deposition efficiency for orally inhaled corticosteroids in the stenosis of LTS subjects are lacking. STUDY DESIGN: Descriptive research. SETTING: Academic medical center. METHODS: Anatomically realistic 3-dimensional reconstructions of the upper airway were created from computed tomography images of 4 LTS subjects-2 subglottic stenosis and 2 tracheal stenosis subjects. Computational fluid dynamics modeling was used to simulate airflow and drug particle transport in each airway. Three inhalation pressures were simulated, 10 Pa, 25 Pa, and 40 Pa. Drug particle transport was simulated for 100 to 950 nanoparticles and 1 to 50 micron-particles. Particles were released into the airway to mimic varying inhaler conditions with and without a spacer chamber. RESULTS: Based on smallest to largest cross-sectional area ratio, the laryngotracheal stenotic segment shrunk by 57% and 47%, respectively, for subglottic stenosis models and by 53% for both tracheal stenosis models. Airflow resistance at the stenotic segment was lower in subglottic stenosis models than in tracheal stenosis models: 0.001 to 0.011 Pa.s/mL vs 0.024 to 0.082 Pa.s/mL. Drug depositions for micron-particles and nanoparticles at stenosis were 0.06% to 2.48% and 0.10% to 2.60% for subglottic stenosis and tracheal stenosis models, respectively. Particle sizes with highest stenotic deposition were 6 to 20 µm for subglottic stenosis models and 1 to 10 µm for tracheal stenosis models. CONCLUSION: This study suggests that at most, 2.60% of inhaled drug particles deposit at the stenosis. Particle size ranges with highest stenotic deposition may not represent typical sizes emitted by inhalers.

Fiberoptic Bronchoscopic Submucosal Injection of Mitomycin C for Recurrent Bening Tracheal Stenosis: A Case Series.

BACKGROUND: Benign tracheal stenosis has emerged as a therapeutic challenge for physicians involved in the care of survivors of critical care units. Although the traditional mainstay of open surgical reconstructive treatment is still considered the gold standard, endoscopic therapies such as laser re-canalization, balloon dilation, or stenting are commonly practiced in invasive bronchology. Recurrent obstructing granulomas pose a challenge for bronchoscopists. Mitomycin C (MyC) is a cytotoxic agent that is isolated from Streptomyces caespitosus and acts by inhibiting DNA and RNA synthesis through alkylation and cross-linkages. Topical MyC is commonly used in indirect laryngoscopies for the treatment of granulation tissue in the trachea by using saturated pledgets. OBJECTIVES: To describe fiberoptic bronchoscopic submucosal injection of MyC as a treatment for recurrent bening tracheal stenosis. METHODS: The authors report their successful experience with submucosal intralesional injection of MyC in the management of recurrent obstructing granulomas/stenosis using the flexible fiberoptic bronchoscope in a series of 10 patients between 2005 and 2019. RESULTS: The results suggest that intralesional injection of MyC using the flexible bronchoscope after the endoscopic treatment of the stenotic lesion may reduce the rate of subsequent formation of granulation tissue and scarring without side effects. CONCLUSIONS: The efficacy of MyC injection should be studied prospectively.

Design of a Biocompatible Drug-Eluting Tracheal Stent in Mice with Laryngotracheal Stenosis.

Laryngotracheal stenosis (LTS) is a pathologic narrowing of the subglottis and trachea leading to extrathoracic obstruction and significant shortness of breath. LTS results from mucosal injury from a foreign body in the trachea, leading to tissue damage and a local inflammatory response that goes awry, leading to the deposition of pathologic scar tissue. Treatment for LTS is surgical due to the lack of effective medical therapies. The purpose of this method is to construct a biocompatible stent that can be miniaturized to place into mice with LTS. We demonstrated that a PLLA-PCL (70% poly-L-lactide and 30% polycaprolactone) construct had optimal biomechanical strength, was biocompatible, practicable for an in vivo placement stent, and capable of eluting drug. This method provides a drug delivery system for testing various immunomodulatory agents to locally inhibit inflammation and reduce airway fibrosis. Manufacturing the stents takes 28-30 h and can be reproduced easily, allowing for experiments with large cohorts. Here we incorporated the drug rapamycin within the stent to test its effectiveness in reducing fibrosis and collagen deposition. Results revealed that PLLA-PCL tents showed reliable rapamycin release, were mechanically stable in physiological conditions, and were biocompatible, inducing little inflammatory response in the trachea. Further, the rapamycin-eluting PLLA-PCL stents reduced scar formation in the trachea in vivo.

Role of Erythromycin-Regulated Histone Deacetylase-2 in Benign Tracheal Stenosis.

Objective: This study aims to explore the role of erythromycin-regulated histone deacetylase-2 in benign tracheal stenosis. Methods: The rabbit model of tracheal stenosis was established. The rabbits were randomly divided into 8 groups. Histone deacetylase-2 (HDAC2) expression was detected by immunofluorescence. The expression of type I collagen and type III collagen was detected by immunohistochemical method. The expression of TGF-ß1, VEGF and IL-8 in serum and alveolar lavage fluid was detected by ELISA. The expression of HDAC2, TGF-ß1, VEGF and IL-8 in serum and alveolar lavage fluid was detected by ELISA. The expression of HDAC2, TGF. Results: In Erythromycin (ERY) group, ERY + Budesonide group, ERY + Vorinostat group and ERY + Budesonide + Vorinostat group, the degree of bronchial stenosis was alleviated, and the mucosal epithelium was still slightly proliferated. The effect of ERY combined with other drugs was more obvious. The HDAC2 protein expression increased significantly in ERY group, ERY + Budesonide group and ERY + Budesonide + Vorinostat group and decreased significantly in Vorinostat group, the expression of collagen I and III decreased significantly in ERY group, ERY + Budesonide group and ERY + Budesonide + Vorinostat group (P < 0.05). The TGF-ß1, VEGF and IL-8 in serum and alveolar lavage fluid was detected by ELISA. The expression of HDAC2, TGF-P < 0.05). The TGF. Conclusions: Erythromycin inhibited inflammation and excessive proliferation of granulation tissue after tracheobronchial mucosal injury by up-regulating the expression of HDAC2, it promoted wound healing and alleviated tracheobronchial stenosis. When combined with budesonide, penicillin and other glucocorticoids and antibiotics, it had a good synergistic effect. However, vorinostat could attenuate erythromycin's effect by down-regulating the expression of HDAC2. It may have good clinical application prospects in the treatment of tracheal stenosis.

A randomized controlled trial of adjuvant mitomycin-c in endoscopic surgery for laryngotracheal stenosis.

OBJECTIVES/HYPOTHESIS: Topical mitomycin-C (MMC) application is a commonly accepted adjuvant therapy in the surgical treatment for laryngotracheal stenosis (LTS). However, the efficacy of MMC has not been examined in a prospective, randomized clinical trial in humans. We aimed to examine the efficacy of MMC in the treatment of LTS patients as compared to a placebo-controlled group. STUDY DESIGN: Prospective, randomized, double-blind, placebo-controlled clinical trial. METHODS: Fifteen patients with LTS were enrolled in a 24-month trial and randomized into one of two groups: 1) endoscopic surgical treatment with topical application of MMC or 2) endoscopic surgical treatment with topical application of saline. Postoperatively, patients were evaluated at standardized intervals with a symptom questionnaire and spirometry. Subsequent surgery was performed as needed based on relapse of stenosis on exam and patient-reported symptom severity. RESULTS: The average interval between surgical treatments was 17.9 months in the placebo group and 17.4 months in the MMC group (P = .95). There was no difference in magnitude of peak inspiratory flow (PIF) improvement between groups. The average magnitude of PIF change was 1.3 L/sec and 1.1 L/sec for the placebo and MMC groups, respectively (P = .64). Similarly, there was no difference in magnitude of symptom improvement or duration of symptom improvement between the two groups. CONCLUSIONS: This prospective, randomized. double-blind. placebo-controlled trial suggests that the use of MMC as a topical adjuvant therapy has no additional benefit in the endoscopic surgical management of LTS. Further study is needed. LEVEL OF EVIDENCE: 1b Laryngoscope, 130:706-711, 2020.