Lung Fibrosis Is Linked to Increased Endothelial Cell Activation and Dysfunctional Vascular Barrier Integrity.

Pulmonary fibrosis (PF) can be a fatal disease characterized by progressive lung scarring. It is still poorly understood how the pulmonary endothelium is involved in the disease pathogenesis. Differences of the pulmonary vasculature between patients and donors were analyzed using transmission electron microscopy, immunohistochemistry, and single-cell RNA sequencing. Vascular barrier resistance, endothelial-immune cell adhesion, and sensitivity to an inflammatory milieu were studied in vitro. Integrity and activation markers were measured by ELISA in human plasma. Transmission electron microscopy demonstrated abnormally swollen endothelial cells (ECs) in fibrotic lungs compared with donors. A more intense CD31 and von Willebrand Factor (vWF) and patchy vascular endothelial (VE)-Cadherin staining in fibrotic lungs supported the presence of a dysregulated endothelium. Integrity markers CD31, VE-Cadherin, Thrombomodulin, and VEGFR-2 (vascular endothelial growth factor receptor-2) and activation marker vWF gene expression was increased in different endothelial subpopulations (e.g., arterial, venous, general capillary, aerocytes) in PF. This was associated with a heightened sensitivity of fibrotic ECs to TNF-α or IFN-γ and elevated immune cell adhesion. The barrier strength was overall reduced in ECs from fibrotic lungs. vWF and IL-8 were increased in the plasma of patients, whereas VE-Cadherin, Thrombomodulin, and VEGFR-2 were decreased. VE-Cadherin staining was also patchy in biopsy tissue and was decreased in plasma samples of patients with PF 6 months after the initial diagnosis. Our data demonstrate highly abnormal ECs in PF. The vascular compartment is characterized by hyperactivation and increased immune cell adhesion, as well as dysfunctional endothelial barrier function. Reestablishing EC homeostasis and function might represent a new therapeutic option for fibrotic lung diseases.

A comprehensive map of proteoglycan expression and deposition in the pulmonary arterial wall in health and pulmonary hypertension.

Changes in the extracellular matrix of pulmonary arteries (PAs) are a key aspect of vascular remodeling in pulmonary hypertension (PH). Yet, our understanding of the alterations affecting the proteoglycan (PG) family remains limited. We sought to investigate the expression and spatial distribution of major vascular PGs in PAs from healthy individuals and various PH groups (chronic obstructive pulmonary disease: PH-COPD, pulmonary fibrosis: PH-PF, idiopathic: IPAH). PG regulation, deposition, and synthesis were notably heightened in IPAH, followed by PH-PF, with minor alterations in PH-COPD. Single-cell analysis unveiled cell-type and disease-specific PG regulation. Agrin expression, a basement membrane PG, was increased in IPAH, with PA endothelial cells (PAECs) identified as a major source. PA smooth muscle cells (PASMCs) mainly produced large-PGs, aggrecan and versican, and small-leucine-like proteoglycan (SLRP) biglycan, whereas the major PGs produced by adventitial fibroblasts were SLRP decorin and lumican. In IPAH and PF-PH, the neointima-forming PASMC population increased the expression of all investigated large-PGs and SLRPs, except fibroblast-predominant decorin (DCN). Expression of lumican, versican, and biglycan also positively correlated with collagen 1α1/1α2 expression in PASMCs in patients with IPAH and PH-PF. We demonstrated that transforming growth factor-beta (TGF-ß) regulates versican and biglycan expression, indicating their contribution to vessel fibrosis in IPAH and PF-PH. We furthermore show that certain circulating PG levels display a disease-dependent pattern, with increased decorin and lumican across all patient groups, while versican was elevated in PH-COPD and IPAH and biglycan reduced in IPAH. These findings suggest unique compartment-specific PG regulation in different forms of PH, indicating distinct pathological processes.NEW & NOTEWORTHY Idiopathic pulmonary arterial hypertension (IPAH) pulmonary arteries (PAs) displayed the greatest proteoglycan (PG) changes, with PH associated with pulmonary fibrosis (PH-PF) and PH associated with chronic obstructive pulmonary disease (PH-COPD) following. Agrin, an endothelial cell-specific PG, was solely upregulated in IPAH. Among all cells, neo-intima-forming smooth muscle cells (SMCs) displayed the most significant PG increase. Increased levels of circulating decorin, lumican, and versican, mainly derived from SMCs, and adventitial fibroblasts, may serve as systemic indicators of pulmonary remodeling, reflecting perivascular fibrosis and neointima formation.

[Paediatric Airway Surgery - Indications and Techniques]. / Pädiatrische Atemwegschirurgie: Indikationen und Techniken.

Even in specialised centres, surgical procedures on the airway are only rarely performed in paediatric patients. Moreover, knowledge of various specific anatomical characteristics, diseases and surgical techniques is a prerequisite to treat these patients. Most commonly, sequelae of long-term intubation or tracheostomy in multimorbid patients necessitate surgical repair. Moreover, congenital malformations of the airways might require surgical interventions. However, these are commonly associated with other organ malformations, which adds further complexity to the treatment concept. Thus, cooperation within an interdisciplinary team is absolutely necessary to treat these patients. However, good postoperative outcomes after paediatric airway surgery can be achieved in experienced centres with an appropriate infrastructure. Specifically, this means long-term tracheostomy-free survival with preserved laryngeal functions in most of the patients. This review provides a summary of common indications and surgical techniques in paediatric airway surgery.

Pädiatrische Atemwegschirurgie: Indikationen und Techniken.

Even in specialised centres, surgical procedures on the airway are only rarely performed in paediatric patients. Moreover, knowledge of various specific anatomical characteristics, diseases and surgical techniques is a prerequisite to treat these patients. Most commonly, sequelae of long-term intubation or tracheostomy in multimorbid patients necessitate surgical repair. Moreover, congenital malformations of the airways might require surgical interventions. However, these are commonly associated with other organ malformations, which adds further complexity to the treatment concept. Thus, cooperation within an interdisciplinary team is absolutely necessary to treat these patients. However, good postoperative outcomes after paediatric airway surgery can be achieved in experienced centres with an appropriate infrastructure. Specifically, this means long-term tracheostomy-free survival with preserved laryngeal functions in most of the patients. This review provides a summary of common indications and surgical techniques in paediatric airway surgery.

The impact of previous endoscopic treatments on functional outcome after cricotracheal resection.

OBJECTIVES: Treatment options for benign subglottic stenosis include endoscopic techniques or open surgery. Although endoscopic treatment is less invasive, a considerable proportion of patients develop recurrent stenosis. Endoscopic pretreatments do not exclude patients from a later surgical repair; however, the impact of previous endoscopic treatment attempts on functional outcome after open surgery is unknown. METHODS: All patients, who received a cricotracheal resection (CTR) between January 2017 and June 2023 at the Department of Thoracic Surgery, Medical University of Vienna, were included in this retrospective study. Patient characteristics, surgical variables and postoperative outcome including a detailed functional assessment were analysed. RESULTS: A total of 65 patients received a CTR during the study period, of which 40 were treatment naïve and 25 had a median of 2 (range 1-9) endoscopic pretreatments. Less-invasive voice-sparing CTR or standard CTR were more often possible in treatment-naïve patients. In contrary, pretreated patients regularly required extended procedures (P = 0.049). Three or more endoscopic treatments resulted in a significantly lower mean fundamental frequency (F0) after open repair (P = 0.048). In addition, a trend towards smaller mean sound pressure levels, a higher voice handicap index, higher impairments in RBH scores (roughness, breathing and hoarseness) and a higher dysphagia severity index was found in pretreated patients. The respiratory outcome after surgery was comparable between both groups. CONCLUSIONS: Multiple endoscopic pretreatments lead to worse voice quality after CTR. The impact of prior endoscopic treatment before surgical repair should be considered when discussing treatment options with patients suffering from subglottic stenosis.

A novel technique of voice-sparing cricotracheal resection.

Background: Cricotracheal resection (CTR) is considered the standard of care for patients suffering from idiopathic subglottic stenosis (iSGS). Although CTR results in permanent restoration of airway patency, it has a mild to moderate impact on voice quality. Here we propose modifications of the standard CTR technique to make it a voice-preserving procedure. Methods: Five women with iSGS underwent voice-sparing CTR between January 2022 and January 2023. In this procedure, through several technical adaptations, the function of the cricothyroid joint was preserved. Outcomes of these voice-sparing CTRs were compared to outcomes in patients who underwent standard CTR in our institution. All patients underwent full functional preoperative and postoperative workups, including spirometry, voice measurements, patient self-assessment, and fiberoptic endoscopic evaluation of swallowing. Results: All 5 patients in the study group suffered from iSGS with high-grade Myer-Cotton III° stenosis (100%); 1 patient had previously undergone endoscopic laser resection. Voice evaluation demonstrated a nearly unchanged fundamental pitch (mean preoperative, 191 ± 73.1 Hz; postoperative, 182 ± 64.2 Hz) and dynamic voice range (preoperative, 24.4 semitones; postoperative, 20.4 semitones). This was in contrast to the control group, in which significantly reduced voice quality was observed. Conclusions: In selected patients suffering from iSGS, excellent functional results can be obtained with voice-sparing CTR.

In-depth analysis of pre- and postoperative functional outcome parameters in patients receiving laryngotracheal surgery.

OBJECTIVES: Surgical treatment for airway stenosis necessitates personalized techniques based on the stenosis location and length, leading to favourable surgical outcomes. However, there is limited literature on functional outcomes following laryngotracheal surgery with an adequate number of patients. METHODS: We conducted a retrospective analysis of patients who underwent laryngotracheal surgery at the Department of Thoracic Surgery, Medical University of Vienna, from January 2017 to June 2021. The study included standardized functional assessments before and after surgery, encompassing spirometry, voice measurements, swallowing evaluation and subjective patient perception. RESULTS: The study comprised 45 patients with an average age of 51.9 ± 15.9 years, of whom 89% were female, with idiopathic being the most common aetiology (67%). Procedures included standard cricotracheal resection in 11%, cricotracheal resection with dorsal mucosal flap in 49%, cricotracheal resection with dorsal mucosal flap and lateral cricoplasty in 24% and single-stage laryngotracheal reconstruction in 16%. There were no in-hospital mortalities or restenosis cases during the mean follow-up period of 20.8 ± 13.2 months. Swallowing function remained intact in all patients. Voice evaluations showed a decrease in fundamental vocal pitch [203 (81-290) Hz vs 150 (73-364) Hz, P < 0.001] and dynamic voice range (23.5 ± 5.8 semitones vs 17.8 ± 6.7 semitones, P < 0.001). However, no differences in voice volume were observed (60.0 ± 4.1 dB vs 60.2 ± 4.8 dB, P = 0.788). The overall predicted voice profile changed from R0B0H0 to R1B0H1. CONCLUSIONS: Laryngotracheal surgery proves effective in fully restoring breathing capacity while preserving vocal function. Even in cases of high-grade and complex airway stenosis necessitating laryngotracheal reconstruction, favourable functional outcomes can be achieved.

The ESTS-AIR database-initial results of a multi-institutional database on airway surgery.

OBJECTIVES: Compared to lung resections, airway procedures are relatively rare in thoracic surgery. Despite this, a growing number of dedicated airway centres have formed throughout Europe. These centres are characterized by a close interdisciplinary collaboration and they often act as supra-regional referring centres. To date, most evidence of airway surgery comes from retrospective, single-centre analysis as there is a lack of large-scale, multi-institutional databases. METHODS: In 2018, an initiative was formed, which aimed to create an airway database within the framework of the ESTS database (ESTS-AIR). Five dedicated airway centres were asked to test the database in a pilot phase. A 1st descriptive analysis of ESTS-AIR was performed. RESULTS: A total of 415 cases were included in the analysis. For adults, the most common indication for airway surgery was post-tracheostomy stenosis and idiopathic subglottic stenosis; in children, most resections/reconstructions had to be performed for post-intubation stenosis. Malignant indications required significantly longer resections [36.0 (21.4-50.6) mm] when compared to benign indications [26.6 (9.4-43.8) mm]. Length of hospital stay was 11.0 (4.1-17.3) days (adults) and 13.4 (7.6-19.6) days (children). Overall, the rates of complications were low with wound infections being reported as the most common morbidity. CONCLUSIONS: This evaluation of the 1st cases in the ESTS-AIR database allowed a large-scale analysis of the practice of airway surgery in dedicated European airway centres. It provides proof for the functionality of ESTS-AIR and sets the basis for rolling out the AIR subsection to all centres participating in the ESTS database.

Voice-sparing cricotracheal resection.

The treatment of benign subglottic stenoses can be challenging. It requires an experienced multidisciplinary team. It is important to define the aetiology, severity and number/types of any pretreatments of the stenosis. Short-term symptom relief can be achieved with endoscopic techniques; however, this relief comes at the price of a high likelihood of restenosis, which often is more severe than the original stenosis. Successful long-term treatment of subglottic stenosis can be achieved by surgical resection in most cases.  Cricotracheal resection is the established standard technique to treat subglottic stenosis. In patients with advanced disease, it can be extended by a dorsal mucosectomy, a lateral cricoplasty or a partial anterior laryngeal split in order to remove the entire diseased area. In this video tutorial, we describe a modification of cricotracheal resection. In this technique for an extended resection, the cricoid arch is partially preserved. In addition to restoring sufficient airway width, this modification has the advantage that the cricothyroid joint remains intact. Therefore, the reduction in the pitch and volume of the voice associated with the standard resection techniques is avoided.

Cervical Repair of Iatrogenic Tracheobronchial Injury by Tracheal T-Incision.

BACKGROUND: Tracheobronchial injury is a rare but potentially life-threatening condition. Various surgical treatment options have been described for symptomatic patients with full-thickness injury. However, studies comprising a meaningful number of patients are sparse. METHODS: We retrospectively analyzed all patients who received surgical repair of tracheobronchial injury between January 1999 and May 2021 at the Department of Thoracic Surgery, Medical University of Vienna. Patient characteristics, surgical variables, postoperative morbidity, and mortality were retrieved and analyzed. RESULTS: Fifty patients with a median age of 68 years (range, 17-88) were included in the analysis. The etiologies of the iatrogenic tracheobronchial injuries were emergency intubation (48%), elective percutaneous dilatation tracheostomy (38%), or elective intubation (14%). The most common location of tracheobronchial injuries was distal third (28%) with a median length of 50 mm (range, 20-100 mm). The surgical approach was cervicotomy in 52%, thoracotomy in 38%, sternotomy in 2%, and combined approaches in 8% of cases. Moreover, intraoperative venovenous (n = 4) or venoarterial (n = 2) extracorporeal membrane oxygenation support was required in 12% of cases. Procedure-related mortality was 0%. However, as patients with tracheobronchial injury usually have severe comorbidities, the rate of patients discharged alive from the intensive care unit was only 66%. The median follow-up period of discharged patients was 5.5 months (range, 0.7-209). Airway stenosis or dehiscence was not observed in any patient. CONCLUSIONS: Surgical repair of tracheobronchial injuries can be performed safely with a low procedure-related morbidity. If possible, the less-invasive cervical access should be preferred for patients with tracheobronchial injury, even for injuries extending to the main bronchi.

Functional outcome after single-stage laryngotracheal reconstruction with rib cartilage grafting.

OBJECTIVE: Single-stage laryngotracheal reconstruction (SSLTR) provides a definite surgical treatment for patients with complex glotto-subglottic stenosis. To date, the influence of SSLTR on the functional outcome after surgery has not been analyzed. METHODS: A retrospective analysis of all patients receiving a SSLTR between November 2012 and October 2019 was performed. Preoperatively and 3 months postoperatively, patients received a full functional evaluation, including spirometry; voice measurements (eg, fundamental frequency; dynamic range, singing voice range, and perceptual voice evaluation using the Roughness-Breathiness-Hoarseness [RBH] score, and fiberoptic endoscopic evaluation of swallowing [FEES]). RESULTS: A total of 15 patients with a mean age of 45 ± 17 years underwent SSTLR. Two (13%) patients were men and 13 (87%) were women. The majority of patients (67%) had undergone previous surgical or endoscopic treatment attempts that had failed. At the 3-month follow-up visit, none of the patients had signs of penetration or aspiration in their swallowing examination. Voice measurements revealed a significantly lower fundamental voice frequency (201.0 Hz vs 155.5 Hz; P = .006), whereas voice range (19.1 semitones vs 14.9 semitones; P = .200) and dynamic range (52.5 dB vs 53.0 dB; P = .777) was hardly affected. The median RBH score changed from R1 B0 H1 to R2 B1 H2. In spirometry, breathing capacity increased significantly (peak expiratory flow, 44% vs 87% [P < .001] and mean expiratory flow at 75% of vital capacity, 48% vs 90% [P < .001]). During a median follow-up of 32.5 months (range, 7-88 months), none of the patients developed re-stenosis. CONCLUSIONS: For complex glotto-subglottic stenoses, durable long-term airway patency together with reasonable voice quality and normal deglutition can be achieved by SSLTR.

Laryngotracheal resection can be performed safely without a guardian Chin stitch-a single-centre experience including 165 consecutive patients.

OBJECTIVES: A tension-free anastomosis is crucial to minimize the risk of airway complications after laryngotracheal surgery. The 'guardian' chin stitch is placed to prevent hyperextension of the neck in the early postoperative period. This manoeuvre was introduced early in tracheal surgery and is now routinely performed by many airway surgeons. However, the evidence for or against is sparse. METHODS: We performed a retrospective analysis of all adult patients receiving a (laryngo-)tracheal resection at our department from October 2011 to December 2019. According to our institutional standard, none of the patients received a chin stitch. Instead, a head cradle was used to obtain anteflexion of the neck during the first 3 days and patients were instructed to avoid hyperextension of the neck during the hospital stay. The postoperative outcome and the rate of anastomotic complications were analysed. RESULTS: A total of 165 consecutive patients were included in this study. Median age at surgery was 53 years (18-80). Seventy-four patients received a tracheal resection, 24 a cricotracheal resection, 52 an extended cricotracheal resection including dorsal mucosectomy and 15 a single-stage laryngotracheal reconstruction. The median resection length was 25 mm (range 10-55 mm). One hundred and sixty-two out of 165 (98.2%) patients had an unremarkable postoperative course. One patient (0.6%) had partial anastomotic rupture after a traumatic reintubation, which required revision surgery and re-anastomosis. Two patients (1.2%) after previous radiation therapy (>60 Gy) developed a partial necrosis of the anastomosis, resulting in prolonged airleak and fistulation. At follow-up, bronchoscopy 3 months after surgery, 92.7% (127/137) of the patients had a proper anastomosis, 6.6% (9/137) had minor granuloma formations at the site of the anastomosis, which were all treated successfully by endoscopic removal. One patient received dilatation for restenosis (0.7%). CONCLUSIONS: After sufficient mobilization of the central airways, postoperative anteflexion of the neck supported by a head cradle is sufficient to prevent excessive anastomotic tension and dehiscence. Considering the risk for severe neurological complications associated with the chin stitch, the routine use of this manoeuvre in laryngotracheal surgery should not be recommended.

Established and innovative surgical techniques for the treatment of benign subglottic stenosis.

Surgical treatment of benign subglottic stenoses can be challenging. It requires the close cooperation of an experienced team that includes various specialist disciplines. The treatment success will be evaluated with an extensive documentation of voice quality, lung function and swallowing function. The stenosis has to be analyzed in terms of its etiology, severity and pretreatment. Endoscopic removal of the stenotic tissue often leads to good short-term results. However, the proportion of re-stenoses is very high, which are often even more severe. Long-term treatment success can often only be achieved by surgical resection. The surgical technique used must be strictly adapted to the individual stenosis. In principle, a distinction can be made between classic cricotracheal resections and those that receive an expanded operative component. Particularly in the case of high-grade side-to-side stenoses, complex reconstruction with cartilage graft may be necessary. It is important not just to restore the airway flow. Maintaining the vocal function is an equally important treatment goal. Experienced centers can achieve very satisfactory long-term results with regard to functional outcome and voice quality.

Functional evaluation before and after laryngo-tracheal resection.

Laryngotracheal resections have become a clinical routine in experienced airway centers and even extended glotto-subglottic resections and reconstructions can be performed with low complication rates and excellent long-term airway patency. However, reports on the functional outcome after laryngotracheal resections are sparse and there is no general agreement among airway surgeons, which functional evaluations should be performed before and after surgery. The following review provides an overview on basic assessment tools, which can be used to objectively report functional outcome after laryngotracheal surgery.

Laryngeal Mask as the Primary Airway Device During Laryngotracheal Surgery: Data From 108 Patients.

BACKGROUND: Airway management during repair of laryngotracheal stenosis is demanding, and there is currently no accepted standard of care. Recently an increasing number of airway centers have started to use a laryngeal mask until the airway is surgically exposed and cross-table ventilation can be initiated. However detailed data on this approach are missing in the literature. METHODS: Patients receiving laryngotracheal surgery from November 2011 until October 2018 were retrospectively included in this single-center study, except for patients who presented with a preexisting tracheostomy at time of surgery. Airway management uniformly consisted of laryngeal mask ventilation until cross-table ventilation was established. Clinical variables, perioperative complications, and airway complications were analyzed. RESULTS: One hundred eight patients (65 women, 43 men) receiving tracheal resection (n = 50), cricotracheal resection (n = 49), or single-stage laryngotracheal reconstruction (n = 9) were included in the analysis. Of the included patients 23 (21.3%) had malignant disease and 85 (78.7%) a benign pathology. In the subgroup of patients with subglottic disease 85.1% had high-grade stenosis (Myer-Cotton III°). Airway management with a laryngeal mask was successful in all except 1 patient (99.1%). Mean pulse oximetry and mean end-tidal CO2 during laryngeal mask ventilation was 98.7% ± 2.4% and 34.8 ± 7.6 mm Hg, respectively. At the end of surgery 95 patients (88%) were successfully weaned from the respirator using the laryngeal mask. CONCLUSIONS: The laryngeal mask as the primary airway device is feasible and safe in patients undergoing laryngotracheal surgery even in cases with high-grade stenosis.