The Wound Healing of Autologous Regenerative Factor on Recurrent Benign Airway Stenosis: A Canine Experimental and Pilot Study.

INTRODUCTION: Benign airway stenosis (BAS) is a severe pathologic condition. Complex stenosis has a high recurrence rate and requires repeated bronchoscopic interventions for achieving optimal control, leading to recurrent BAS (RBAS) due to intraluminal granulation. METHODS: This study explored the potential of autologous regenerative factor (ARF) for treating RBAS using a post-intubation tracheal stenosis canine model. Bronchoscopic follow-ups were conducted, and RNA-seq analysis of airway tissue was performed. A clinical study was also initiated involving 17 patients with recurrent airway stenosis. RESULTS: In the animal model, ARF demonstrated significant effectiveness in preventing further collapse of the injured airway, maintaining airway patency and promoting tissue regeneration. RNA-seq results showed differential gene expression, signifying alterations in cellular components and signaling pathways. The clinical study found that ARF treatment was well-tolerated by patients with no severe adverse events requiring hospitalization. ARF treatment yielded a high response rate, especially for post-intubation tracheal stenosis and idiopathic tracheal stenosis patients. CONCLUSION: The study concludes that ARF presents a promising, effective, and less-invasive method for treating RBAS. ARF has shown potential in prolonging the intermittent period and reducing treatment failure in patients with recurrent tracheal stenosis by facilitating tracheal mucosal wound repair and ameliorating tracheal fibrosis. This novel approach could significantly impact future clinical applications.

Autologous Airway Basal Cell Transplantation Alleviates Airway Epithelium Defect in Recurrent Benign Tracheal Stenosis.

BACKGROUND: Airway epithelium defects are a hallmark of recurrent benign tracheal stenosis (RBTS). Reconstructing an intact airway epithelium is of great importance in airway homeostasis and epithelial wound healing and has great potential for treating tracheal stenosis. METHODS: An experimental study was conducted in canines to explore the therapeutic effect of autologous basal cell transplantation in restoring airway homeostasis. First, airway mucosae from human patients with recurrent tracheal stenosis were analyzed by single-cell RNA sequencing. Canines were then randomly divided into tracheal stenosis, Stent, Stent + Cells, and Stent + Cells + Biogel groups. Autologous airway basal cells of canines in the Stent + Cells and Stent + Cells + Biogel groups were transplanted onto the stenotic airway after modeling. A biogel was coated on the airway prior to basal cell transplantation in the Stent + Cells + Biogel group. After bronchoscopic treatments, canines were followed up for 16 weeks. RESULTS: Single-cell RNA sequencing demonstrated packed airway basal cells and an absence of normal airway epithelial cells in patients with RBTS. Autologous airway basal cell transplantation, together with biogel coating, was successfully performed in the canine model. Follow-up observation indicated that survival time in the Stent + Cells + Biogel group was significantly prolonged, with a higher (100%) survival rate compared with the other groups. In terms of pathological and bronchoscopic findings, canines that received autologous basal cell transplantation showed a reduction in granulation hyperplasia as well as airway re-epithelialization with functionally mature epithelial cells. CONCLUSIONS: Autologous airway basal cell transplantation might serve as a novel regenerative therapy for airway re-epithelialization and inhibit recurrent granulation hyperplasia in benign tracheal stenosis.

Optimize Initial Freezing Time of Transbronchial Cryobiopsy for the Diagnosis of Interstitial Lung Disease: A Prospective Randomized Parallel Group Study.

BACKGROUND: Transbronchial cryobiopsy (TBCB) is increasingly being identified as a potential alternative for the diagnosis of interstitial lung disease (ILD). The specimen size of TBCB is positively related to the freezing time. However, the proper initial freezing time for the clinical application of TBCB in ILD remains unknown. METHODS: A prospective randomized parallel group study was employed to investigate ILD patients with unclear diagnosis, who were admitted to the First Affiliated Hospital of Guangzhou Medical University from May 2019 to October 2020 and required TBCB. All patients were randomly divided into 4 groups according to the different freezing times of TBCB: 3 s, 4 s, 5 s, and 6 s groups. All operations were performed under intravenous anesthesia with endotracheal intubation, 60-65 bar pressure of freezing gas source, and 1.9-mm cryoprobe. Compare differences among groups in specimen size, complications, pathological diagnosis efficiency, and multidisciplinary discussion (MDD) diagnostic efficiency. RESULTS: A total of 100 patients were recruited and randomly assigned into 4 groups (n = 25 each group). The specimen sizes of TBCB in ILD were positively correlated with the freezing time (r = 0.639, p < 0.05). None of the patients experienced Grade 3 severe bleeding. Pneumothorax occurred in 1 patient in the 4 s, 5 s, and 6 s groups, respectively. The diagnostic yield of MDD in the 3 s, 4 s, 5 s, and 6 s groups were 64%, 88%, 88%, and 96%, respectively (p < 0.05), but showing no significant differences among 4 s, 5 s, and 6 s groups. CONCLUSIONS: The specimen size and diagnostic efficiency of TBCB in ILD increased with a longer freezing time. When the freezing gas pressure is 60-65 bar, we recommended 4 s as the initial freezing time of TBCB, and this time is associated with high diagnostic efficiency and low incidence of complications.

Enhanced secretion of hepatocyte growth factor in human umbilical cord mesenchymal stem cells ameliorates pulmonary fibrosis induced by bleomycin in rats.

Umbilical cord mesenchymal stem cells (UCMSCs) are a reportedly promising choice in the treatment of irreversible pulmonary fibrosis and lethal interstitial lung disease with limited drug treatment options. In this study, we investigated the therapeutic efficacy of UCMSCs overexpressing hepatocyte growth factor (HGF), which is considered one of the main anti-fibrotic factors secreted by MSCs. Adenovirus vector carrying the HGF gene was transfected into UCMSCs to produce HGF-modified UCMSCs (HGF-UCMSCs). Transfection promoted the proliferation of UCMSCs and did not change the morphology, and differentiation ability, or biomarkers. Rats were injected with HGF-UCMSCs on days 7 and 11 after intratracheal administration of bleomycin (10 mg/kg). We performed an analysis of histopathology and lung function to evaluate the anti-fibrotic effect. The results showed that HGF-UCMSCs decreased the Ashcroft scores in hematoxylin and eosin-stained sections, the percentage positive area in Masson trichrome-stained sections, and the hydroxyproline level in lungs. Forced expiratory volume in the first 300 m/forced vital capacity was also improved by HGF-UCMSCs. To explore the possible therapeutic mechanism of HGF-UCMSCs, we detected inflammatory factors in the lungs and performed mRNA sequencing in UCMSCs and HGF-UCMSCs. The data indicated that inhibition of interleukin-17 in the lung may be related to the anti-fibrosis of HGF-UCMSCs, and overexpressed HGF probably played a primary role in the treatment. Collectively, our study findings suggested that the overexpression of HGF may improve the anti-fibrotic effect of UCMSCs through directly or indirectly interacting with interleukin-17-producing cells in fibrotic lungs.

Applied pressure of cooling gas: a neglected determinant for size of specimens in transbronchial cryobiopsy.

BACKGROUND: Transbronchial cryobiopsy (TBCB) is an option to surgical biopsy for the diagnosis in interstitial lung diseases. Several impact factors have received wide attention, including the freezing time, cryoprobe size, and contact pressure. However, the effect of the applied gas pressure on the specimen size has not been well elucidated. The purpose of this study is to investigate the effect of the applied gas pressure on the TBCB specimen size. METHODS: Cryoprobes with a diameter of 1.9 mm were used to perform TBCB on 4 beagle canines under general anesthesia. TBCB was performed with a total of 16 time-pressure combinations that were randomly combined with 4 freezing times (3, 4, 5, and 6 s) and 4 gas pressures (40, 50, 55, and 60 bar). For each combination, 8 biopsies were performed. The size and quality of specimens, as well as complications, were evaluated. RESULTS: A total of 128 TBCB specimens were obtained. With the same freezing time, the specimen sizes obtained by different applied gas pressures were significantly different (P<0.05) and positively correlated with the gas pressures (r: 0.797-0.867). With the same gas pressure, the size of the TBCB specimens was positively correlated with the freezing time (r: 0.503-0.752). In the 40-bar group, no tissues were obtained when the freezing times were 3-5 s. In the 50-bar and 55-bar groups, qualified specimens were obtained when the freezing times were 5 and 6 s. In the 60-bar group, qualified specimens were obtained when the freezing times were 3-6 s. CONCLUSIONS: The TBCB specimen size was positively correlated with the applied gas pressure. The applied gas pressure contributed to the sample size and quality. To obtain qualified specimens with a 1.9-mm cryoprobe during TBCB, the lowest limit of the normal working gas pressure range should be increased to greater than 50 bar.

The application of transbronchial cryobiopsy in interstitial lung disease: a prospective, multicenter, real-world study.

BACKGROUND: Transbronchial cryobiopsy (TBCB) has been widely used to diagnose interstitial lung disease (ILD). Existing reports on TBCB in ILD are mostly single-center prospective or retrospective studies but rarely multicenter prospective real-world studies. We explored the diagnostic efficiency and safety of TBCB in ILD in a real world setting. METHODS: A prospective, multicenter, real-world study was conducted to analyze the data of patients with unclarified ILD who underwent TBCB in 20 hospitals in China from October 2018 to October 2019. The results of the pathological and multidisciplinary discussion (MDD) diagnosis and complications related to TBCB were then analyzed. RESULTS: A total of 373 patients were enrolled in this study, including 194 males and 179 females, with an average age of 52.6±12.4 years. None of the patients had severe hemorrhaging, and the incidence of pneumothorax was 4.8%. The proportions of definitive, possible, and unclassified pathological diagnoses were 62.5%, 5.6%, and 31.9%, respectively. The overall diagnostic yield of MDD was 63.5%. There were 237 patients with a definitive diagnosis of MDD and 136 patients with an unclarified MDD diagnosis. The cooling gas pressure, freezing durations, number of specimens, maximum lengths of specimens, and specimen sizes varied significantly between the definitive and unclarified MDD diagnoses. CONCLUSIONS: In China, the application of TBCB in ILD is generally safe, and its diagnostic efficiency is acceptable. Using a 1.9-mm cryoprobe to collect five samples would achieve a better positive diagnostic rate for TBCB in ILD, without a significant increase in complication risk. TRIAL REGISTRATION: ClinicalTrials.gov; date of registration: 09/25/2018; registration number: NCT03704233; URL: clinicaltrials.gov.

Safety and efficacy of sufentanil combined with midazolam in bronchoscopy under conscious sedation: retrospective study of 11,158 cases.

BACKGROUND: The recommended conscious sedation for bronchoscopy is still lacking. The safety and efficacy of sufentanil combined with midazolam in bronchoscopy under conscious sedation is not well elucidated. METHODS: A retrospective analysis was conducted on patients who received bronchoscopy in the First Affiliated Hospital of Guangzhou Medical University from September 2013 to July 2017. Sufentanil and midazolam were administrated for conscious sedation. The drug dosage, sedating effect and adverse event were collected and analyzed. RESULTS: Totally, 7,089 males and 4,069 females aged 54±16 years (ranged from 4 to 94 years) were enrolled in this study. The dosage of sufentanil and midazolam were 5.25±1.28 mcg (2-13 mcg) and 2.03±0.51 mg (0.5-4.5 mg), respectively. Ninety-eight point six percent (10,998/11,158) of bronchoscopies were successfully completed, while 68.7% (7,670/11,158) procedures were performed with initial dose of 5 mcg sufentanil and 2 mg midazolam. Endobronchial biopsy, transbronchial lung biopsy (TBLB), transbronchial needle aspiration (TBNA), therapeutic procedure and asthma were predictors of giving incremental doses of sufentanil and midazolam (all OR >1, P<0.05), whereas, the age was associated with lower incidence of adding dose of sufentanil and midazolam (both OR <1, P<0.05). Patients with chronic obstructive lung disease (COPD) had lower incidence of adding dose of midazolam alone (OR =0.597, P=0.003). Whereas, female and pulmonary infection were predictors of adding dose of sufentanil alone (OR >1, P<0.05). The conscious sedation related adverse events were not observed. CONCLUSIONS: Sufentanil combined with midazolam was safe and effective for bronchoscopy under conscious sedation.