Sebastian Fernandez-Bussy

Pleural mesothelial cell transformation into myofibroblasts and haptotactic migration in response to TGF-β1 in vitro

Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology characterized by the development of subpleural foci of myofibroblasts that contribute to the exuberant fibrosis noted in the pulmonary parenchyma. Pleural mesothelial cells (PMC) are metabolically dynamic cells that cover the lung and chest wall as a monolayer and are in intimate proximity to the underlying lung parenchyma. The precise role of PMC in the pathogenesis of pulmonary parenchymal fibrosis remains to be identified. Transforming growth factor (TGF)-beta1, a cytokine known for its capacity to induce proliferative and transformative changes in lung cells, is found in significantly higher quantities in the lungs of patients with IPF. High levels of TGF-beta1 in the subpleural milieu may play a key role in the transition of normal PMC to myofibroblasts. Here we demonstrate that PMC activated by TGF-beta1 undergo epithelial-mesenchymal transition (EMT) and respond with haptotactic migration to a gradient of TGF-beta1 and that the transition of PMC to myofibroblasts is dependent on smad-2 signaling. The EMT of PMC was marked by upregulation of alpha-smooth muscle actin (alpha-SMA), fibroblast specific protein-1 (FSP-1), and collagen type I expression. Cytokeratin-8 and E-cadherin expression decreased whereas vimentin remained unchanged over time in transforming PMC. Knockdown of smad-2 gene by silencing small interfering RNA significantly suppressed the transition of PMC to myofibroblasts and significantly inhibited the PMC haptotaxis. We conclude that PMC undergo EMT when exposed to TGF-beta1, involving smad-2 signaling, and PMC may be a possible source of myofibroblasts in IPF.

Parenchymal trafficking of pleural mesothelial cells in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is characterised by myofibroblast proliferation leading to architectural destruction. Neither the origin nor the continued proliferation of myofibroblasts is well understood. Explanted human IPF lungs were stained by immunohistochemistry for calretinin, a marker of pleural mesothelial cells (PMCs). Chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) lungs acted as controls. The number of PMCs per 100 nucleated cells and per photomicrograph was estimated along with the Ashcroft score of fibrosis. Mouse PMCs expressing green fluorescent protein (GFP) or labelled with nanoparticles were injected into the pleural space of mice given intranasal transforming growth factor (TGF)-&bgr;1. Mouse lungs were lavaged and examined for the presence of GFP, smooth muscle &agr;-actin (&agr;-SMA) and calretinin. Calretinin-positive PMCs were found throughout IPF lungs, but not in COPD or CF lungs. The number of PMCs correlated with the Ashcroft score. In mice, nanoparticle-laden PMCs were recoverable by bronchoalveolar lavage, depending on the TGF-&bgr;1 dose. Fluorescent staining showed &agr;-SMA expression in GFP-expressing PMCs, with co-localisation of GFP and &agr;-SMA. PMCs can traffic through the lung and show myofibroblast phenotypic markers. PMCs are present in IPF lungs, and their number correlates with IPF severity. Since IPF presumably begins subpleurally, PMCs could play a pathogenetic role via mesothelial–mesenchymal transition.

Prevalence of pulmonary hypertension in end-stage cystic fibrosis and correlation with survival

BACKGROUND Limited information is available about the prevalence of pulmonary hypertension diagnosed by right heart catheterization (RHC) in patients with cystic fibrosis being evaluated for lung transplantation. It is unclear whether there are factors that can predict the presence of pulmonary hypertension and whether the presence of pulmonary hypertension influences patient outcomes. METHODS The study included 57 unique and consecutive adult patients (33 women) with cystic fibrosis who underwent lung transplant evaluation at the University of Florida. RESULTS The average age at evaluation was 31.8 +/- 10 years. All patients were in New York Heart Association class III. The median (interquartile range) of mean pulmonary artery pressure (PAP) was 26 (24-30) mm Hg. Thirty-six patients (63.2%) had pulmonary hypertension (mean PAP >or= 25 mm Hg) and had a significantly higher degree of hypoxemia and oxygen requirements. Echocardiography evidenced limitations for the diagnosis of pulmonary hypertension. The 5-year mortality rate was similar in patients with or without pulmonary hypertension; however, it was higher in 7 patients identified by cluster analysis and in patients with a left ventricular ejection fraction < 55%. CONCLUSIONS More than half of our patients with cystic fibrosis and advanced lung disease have elevation of PAP, usually of mild degree. A lower left ventricular ejection fraction, but not the presence of pulmonary hypertension, was associated with worse outcomes.

Clinical Experience With a New Removable Tracheobronchial Stent in the Management of Airway Complications After Lung Transplantation

BACKGROUND Airway complications are among the most challenging problems after lung transplantation. This article describes the use of a new tracheobronchial stent that can be placed and removed easily by flexible bronchoscopy. METHODS A retrospective review was done of 24 consecutive patients requiring tracheobronchial stent placement after lung transplantation. A new self-expanding hybrid nitinol stent was used, and changes in airway diameter and spirometry were assessed. Stent related complications were recorded. RESULTS Between February 2007 and April 2008, 24 patients underwent stent placement, and 49 stents were placed for 36 anastomoses at risk. Indications included bronchial stenosis in 12, bronchomalacia in 12, bronchial stenosis plus bronchomalacia in 20, and partial bronchial dehiscence in 5. Adjunctive procedures included electrocautery in 1, balloon dilatation in 7, and electrocautery plus balloon dilatation in 4. The average degree of stenosis decreased from 80% to 20%. After stent placement, the average increase was 0.28 liters in forced vital capacity and 0.44 liters in forced expiratory volume in 1 second. Complications included granulation tissue formation in 10 stents, migration in 9, thick mucus formation in 2, and fracture in 3. CONCLUSION Airway complications in lung transplant patients were effectively palliated. Our complication rate with this new stent is comparable with other airway stents. This stent has the advantage of easy removability during flexible bronchoscopy if complications from the stent outweigh the benefits of palliation.

Tratamiento de complicaciones en la vía aérea postrasplante pulmonar

OBJECTIVE To describe our experience in airway complications following lung transplant and to suggest a management algorithm, using different tools from the Interventional Pulmonology armamentarium. METHOD Retrospective chart review of all airway complications following lung transplant from January 1999 to July 2007. RESULTS During that period 223 patients underwent lung transplantation, with a total of 345 anastomoses in the airway. Seventy anastomoses (20.23%) had complications requiring endoscopic treatment. The total number of endoscopic interventions were 631 in 52 patients. Thirty three patients had a combination of bronchial stenosis and bronchomalacia. Eighteen patients had bronchial stenosis only and 1 patient had dehiscence of the anastomosis. Balloon dilation was most commonly transiently effective and ultimately 47 patients required stent placement. The most common complication associated with the use of stent was granulation tissue formation, seen in 57.3% of patients. After stent placement, the forced expiratory volume in 1(st) second (FEV(1)) improved significantly. CONCLUSION Airway complications after lung transplant are frequent. Balloon dilation was effective only in a few patients with bronchial stenosis, although the majority ultimately needed a stent. Airway repermeabilization after stent placement improved FEV(1). Based on our experience, we propose a management algorithm for airway complications after lung transplant.

Treatment of Airway Complications Following Lung Transplantation

Abstract Objective To describe our experience in airway complications following lung transplantation and to suggest a management strategy using different interventional bronchoscopic techniques. Method Retrospective analysis of all airway complications following lung transplantation from January 1999 to July 2007. Results During this period, 223 patients underwent lung transplantation, with a total of 345 airway anastomoses. In 70 (20.23%), there were complications requiring endoscopic intervention. A total of 631 procedures were carried out in 52 patients. Thirty-three patients presented a combination of bronchial stenosis and bronchomalacia, 18 patients had bronchial stenosis alone and 1 patient presented dehiscence of the anastomosis. In most cases, pneumatic balloon dilatation was effective, although temporarily, and ultimately 47 patients required endobronchial stent placement. The most common complication associated with the use of stents was granulation tissue formation, seen in 57.3% of patients. After stent placement, forced expiratory volume in one second (FEV 1 ) improved significantly. Conclusion Airway complications after lung transplantation are frequent. Balloon dilatation was effective in only a few patients with bronchial stenosis, requiring stent placement in most. Airway permeabilization after endobronchial stent placement improved FEV 1 in these patients. Based on our experience, we propose a management strategy for airway complications after lung transplantation.

Concurrent Intrapleural Instillation of Tissue Plasminogen Activator and DNase for Pleural Infection. A Single-Center Experience

RATIONALE Treatment of pleural infection with instillation of intrapleural tissue plasminogen activator (tPA) and human recombinant DNase (DNase) has been proven to decrease the length of hospital stay, decrease surgical referral, and improve drainage. The optimal dosage, administration, timing, and frequency of the regimen remain unclear. It is unknown if the two drugs can be administered immediately one after the other (referred to as concurrent) instead of instilling them separately with a 1- to -2-hour interval in between. OBJECTIVES To assess the safety and efficacy of concurrent instillation of intrapleural tPA/DNase guided by radiographic and clinical response in patients with pleural infection. METHODS We conducted a retrospective cohort study. Consecutive patients with pleural infection who received concurrent tPA/DNase were included. The initiation and number of doses of tPA/DNase therapy were based on pleural fluid drainage, clinical response, and radiographic findings. MEASUREMENTS AND MAIN RESULTS Seventy-three patients received concurrent tPA/DNase therapy. Treatment was successful in 90.4% of them; 80.8% were effectively treated with fewer than six doses of therapy (median, 2; interquartile range [IQR], 1-3.5); and 71.2% received their first dose of tPA/DNase within 24 hours after chest tube insertion. The median hospital stay from the first dose of tPA/DNase to discharge was 7 days (IQR, 5-11 d). The volume of pleural fluid drained increased from a median of 295 ml (IQR, 97.5-520 ml) 24 hours before treatment to a median of 1,102 ml (IQR, 627-2,200 ml) 72 hours following therapy (P < 0.001). Nonfatal pleural bleeding occurred in 5.4%, 15.1% had chest pain, and 2.7% died as a result of pleural infection. CONCLUSIONS This cohort study shows that early administration of concurrent tPA/DNase in patients with pleural infection is relatively safe and effective. Given the high cost of therapy, it is feasible to guide therapy on the basis of clinical and radiographic response.

Tracheostomy Tube Placement: Early and Late Complications

Tracheostomy tube placement is a therapeutic procedure that has gained increased favor over the past decade. Upper airway obstructions, failure to liberate from the ventilator, and debilitating neurological conditions are only a few indications for tracheostomy tube placement. Tracheostomy tubes can be placed either surgically or percutaneously. A percutaneous approach offers fewer surgical site infections and postsurgical bleeding than a surgical approach. A surgical placement posses a lower risk of injury to the posterior tracheal wall and spontaneous decannulation is less common. Late complications of both approaches include stenosis, malacia, along with tracheoesophageal, tracheoinnominate, and tracheocutaneous fistulas. This review describes the indications and methods of placement of tracheostomy tubes along with early and late complications that may occur following placement.

External Fixation of Proximal Tracheal Airway Stents: A Modified Technique

Treatment of subglottic and proximal tracheal stenosis for nonsurgical candidates includes tracheostomy, Montgomery T tubes, and silicone stents. When used in lesions with concomitant malacia, silicone stents have a high incidence of migration. We describe a simple and effective technique of securing endoluminal stents using an Endo Close suturing device (Coviden, Boston, MA) and an external silicone button in 9 consecutive patients.

Tunneled Pleural Catheter Placement with and without Talc Poudrage for Treatment of Pleural Effusions Due to Congestive Heart Failure

RATIONALE There is a paucity of evidence regarding the role of tunneled pleural catheters in pleural effusions caused by congestive heart failure that is refractory to medical management. OBJECTIVES The aim of this study was to assess the feasibility of tunneled pleural catheter drainage for treatment of refractory pleural effusions associated with congestive heart failure, either when used alone or with concomitant talc pleurodesis performed during thoracoscopy. METHODS This was a retrospective cohort study. We identified patients with congestive heart failure and recurrent symptomatic pleural effusions who were treated between 2005 and 2015 by placement of a tunneled pleural catheter. Patients underwent either thoracoscopy followed by talc poudrage and pleural catheter placement (group 1) or catheter insertion alone (group 2). MEASUREMENTS AND MAIN RESULTS Forthy-three catheters were inserted in 36 patients, with 15 placed in group 1 and 28 in group 2. Successful pleurodesis was seen in 80% in group 1 and 25% in group 2. The median time of catheter placement was 11.5 days in group 1 and 66 days in group 2. There was a significant decrease in hospital admissions and pleural interventions after catheter placement compared with before insertion (P < 0.05). CONCLUSIONS This single-center, retrospective study demonstrated the feasibility of catheter placement used alone or with talc poudrage for the treatment of refractory pleural effusions associated with congestive heart failure. The addition of talc poudrage might increase the pleurodesis rate and reduce the days to catheter removal in highly selected patients. Prospective studies on a larger number of patients are warranted to verify the safety and efficacy of this intervention.