Exploring Insulin Production Following Alveolar Islet Transplantation (AIT).

Recent studies have demonstrated the feasibility of islet implantation into the alveoli. However, until today, there are no data on islet behavior and morphology at their transplant site. This study is the first to investigate islet distribution as well insulin production at the implant site. Using an ex vivo postmortem swine model, porcine pancreatic islets were isolated and aerosolized into the lung using an endoscopic spray-catheter. Lung tissue was explanted and bronchial airways were surgically isolated and connected to a perfusor. Correct implantation was confirmed via histology. The purpose of using this new lung perfusion model was to measure static as well as dynamic insulin excretions following glucose stimulation. Alveolar islet implantation was confirmed after aerosolization. Over 82% of islets were correctly implanted into the intra-alveolar space. The medium contact area to the alveolar surface was estimated at 60 +/- 3% of the total islet surface. The new constructed lung perfusion model was technically feasible. Following static glucose stimulation, insulin secretion was detected, and dynamic glucose stimulation revealed a biphasic insulin secretion capacity during perfusion. Our data indicate that islets secrete insulin following implantation into the alveoli and display an adapted response to dynamic changes in glucose. These preliminary results are encouraging and mark a first step toward endoscopically assisted islet implantation in the lung.

Combined intrapleural and intrabronchial injection of fibrin glue for closing alveolar pleural fistula: a case report.

BACKGROUND: The treatment of persistent air leak is a challenge. Herein, we reported the combined intrabronchial and intrapleural injection of fibrin glue using fiber bronchoscopy to seal off an alveolar pleura fistula developed following necrotizing pneumonia in high-risk patient. CASE PRESENTATION: A 74-year-old man was intubated in emergency for acute ischemic stroke. Percutaneous dilatational tracheostomy was then performed, and 15 days later patient returned to spontaneous breathing. However, he developed alveolar pleural fistula following necrotizing pneumonia with persistent air leaks. The intrabronchial and intrapleural injection of fibrin glue using fiber bronchoscopy sealed off the alveolar pleura fistula after that other endoscopic treatments as bronchial valve and intrabronchial fibrin glue application had failed. CONCLUSIONS: Our strategy is safe and easy to reproduce. It represents an additional method in the armamentarium of the physicians for the management of PAL when all standard strategies are unfeasible or fail.

Successful lung donation at the age of 6 weeks: Challenges and lessons learned.

A clinical case of successful procurement and transplantation of bilateral lungs from 6-week-old infant with sepsis secondary to bacterial meningitis is reported. Forty-one-day-old male infant (height 60 cm, weight 4 kg) died of cerebral edema secondary to Escherichia coli meningitis and bacteremia. Preretrieval assessment included the following: arterial gases; pO2 50.4 kPa (378 mm Hg), pCO2 4.9 kPa (37 mm Hg), on FiO2 100%, PEEP 5 cm H2 O. Fiberoptic bronchoscopy showed no secretions nor mucosal inflammation; CXR revealed clear lung fields and pleural spaces. Inspection revealed dense adhesions in pericardial cavity and purulent left hemithorax effusion (urgent Gram-stain came back as negative) but there was no consolidation in the lung. Good compliance of the lungs on inflation/deflation test was observed. The lungs were retrieved using the technique described. The recipient was a 4-month-old infant with alveolar capillary dysplasia and malaligned pulmonary veins. Implantation of the lungs was performed via bilateral thoracosternotomy on cardiopulmonary bypass, cooling to 30°C. Elective support with nitric oxide was used postoperatively. Two years after the transplantation, the recipient doing well with normal lung function. Lung procurement from a 6-week donor with infectious complications and prolonged ventilation is a challenging undertaking but can be successful and should be attempted whenever possible given the paucity of organs available for pediatric recipients.

Erythropoietin inhalation enhances adult canine alveolar-capillary formation following pneumonectomy.

Paracrine erythropoietin (EPO) signaling in the lung recruits endothelial progenitor cells, promotes cell maturation and angiogenesis, and is upregulated during canine postpneumonectomy (PNX) compensatory lung growth. To determine whether inhalational delivery of exogenous EPO augments endogenous post-PNX lung growth, adult canines underwent right PNX and received, via a permanent tracheal stoma, weekly nebulization of recombinant human EPO-containing nanoparticles or empty nanoparticles (control) for 16 wk. Lung function was assessed under anesthesia pre- and post-PNX. The remaining lobes were fixed for detailed morphometric analysis. Compared with control treatment, EPO delivery significantly increased serum EPO concentration without altering systemic hematocrit or hemoglobin concentration and abrogated post-PNX lipid oxidative stress damage. EPO delivery modestly increased post-PNX volume densities of the alveolar septum per unit of lung volume and type II epithelium and endothelium per unit of septal tissue volume in selected lobes. EPO delivery also augmented the post-PNX increase in alveolar double-capillary profiles, a marker of intussusceptive capillary formation, in all remaining lobes. EPO treatment did not significantly alter absolute resting lung volumes, lung and membrane diffusing capacities, alveolar-capillary blood volume, pulmonary blood flow, lung compliance, or extravascular alveolar tissue volumes or surface areas. Results established the feasibility of chronic inhalational delivery of growth-modifying biologics in a large animal model. Exogenous EPO selectively enhanced cytoprotection and alveolar angiogenesis in remaining lobes but not whole-lung extravascular tissue growth or resting function; the nonuniform response contributes to structure-function discrepancy, a major challenge for interventions aimed at amplifying the innate potential for compensatory lung growth.

Infants with Atypical Presentations of Alveolar Capillary Dysplasia with Misalignment of the Pulmonary Veins Who Underwent Bilateral Lung Transplantation.

OBJECTIVE: To describe disease course, histopathology, and outcomes for infants with atypical presentations of alveolar capillary dysplasia with misalignment of the pulmonary veins (ACDMPV) who underwent bilateral lung transplantation. STUDY DESIGN: We reviewed clinical history, diagnostic studies, explant histology, genetic sequence results, and post-transplant course for 6 infants with atypical ACDMPV who underwent bilateral lung transplantation at St. Louis Children's Hospital. We compared their histology with infants with classic ACDMPV and compared their outcomes with infants transplanted for other indications. RESULTS: In contrast with neonates with classic ACDPMV who present with severe hypoxemia and refractory pulmonary hypertension within hours of birth, none of the infants with atypical ACDMPV presented with progressive neonatal respiratory failure. Three infants had mild neonatal respiratory distress and received nasal cannula oxygen. Three other infants had no respiratory symptoms at birth and presented with hypoxemia and pulmonary hypertension at 2-3 months of age. Bilateral lung transplantation was performed at 4-20 months of age. Unlike in classic ACDMPV, histopathologic findings were not distributed uniformly and were not diffuse. Three subjects had apparent nonmosaic genetic defects involving FOXF1. Two infants had extrapulmonary anomalies (posterior urethral valves, inguinal hernia). Three transplanted children are alive at 5-16 years of age, similar to outcomes for infants transplanted for other indications. Lung explants from infants with atypical ACDMPV demonstrated diagnostic but nonuniform histopathologic findings. CONCLUSIONS: The 1- and 5-year survival rates for infants with atypical ACDMPV are similar to infants transplanted for other indications. Given the clinical and histopathologic spectra, ACDMPV should be considered in infants with hypoxemia and pulmonary hypertension, even beyond the newborn period.

Left-Sided Catamenial Pneumothorax with Thoracic Endometriosis and Bullae in the Alveolar Wall.

Catamenial pneumothorax (CP) is generally caused by intraperitoneal air leaking from the uterus into the thoracic cavity via a defect in the endometrial tissue of the diaphragm and is usually detected in the right thorax. We report a case of left-sided CP caused by endometriosis in the visceral pleura and with no abnormal findings in the diaphragm. A 33-year-old female patient presented at the end of a course of low-dose contraceptive pills for pelvic endometriosis, with spontaneous pneumothorax in the left chest. Chest CT revealed a bulla in the left upper lung lobe. The patient underwent partial resection of the lung. Immunohistochemistry confirmed the presence of endometrial stromal tissue in the visceral pleura and confirmed this as the cause of pneumothorax since there were no observable abnormalities in the diaphragm. This case suggests that immunohistochemical examination of patients with spontaneous pneumothorax can detect alternative endometrial lesions.

Breakdown of lung framework and an increase in pores of Kohn as initial events of emphysema and a cause of reduction in diffusing capacity.

PURPOSE: Pulmonary emphysema is the pathological prototype of chronic obstructive pulmonary disease and is also associated with other lung diseases. We considered that observation with different approaches may provide new insights for the pathogenesis of emphysema. PATIENTS AND METHODS: We reviewed tissue blocks of the lungs of 25 cases with/without emphysema and applied a three-dimensional observation method to the blocks. Based on the three-dimensional characteristics of the alveolar structure, we considered one face of the alveolar polyhedron as a structural unit of alveoli and called it a framework unit (FU). We categorized FUs based on their morphological characteristics and counted their number to evaluate the destructive changes in alveoli. We also evaluated the number and the area of pores of Kohn in FUs. We performed linear regression analysis to estimate the effect of these data on pulmonary function tests. RESULTS: In multivariable regression analysis, a decrease in the number of FUs without an alveolar wall led to a significant decrease in the diffusing capacity of the lung for carbon monoxide (DLCO) and DLCO per unit alveolar volume, and an increase in the area of pores of Kohn had a significant effect on an increase in residual capacity. CONCLUSION: A breakdown in the lung framework and an increase in pores of Kohn are associated with a decrease in DLCO and DLCO per unit alveolar volume with/without emphysema.

MAPK-Mediated YAP Activation Controls Mechanical-Tension-Induced Pulmonary Alveolar Regeneration.

The pulmonary alveolar epithelium undergoes extensive regeneration in response to lung injuries, including lung resection. In recent years, our understanding of cell lineage relationships in the pulmonary alveolar epithelium has improved significantly. However, the molecular and cellular mechanisms that regulate pneumonectomy (PNX)-induced alveolar regeneration remain largely unknown. In this study, we demonstrate that mechanical-tension-induced YAP activation in alveolar stem cells plays a major role in promoting post-PNX alveolar regeneration. Our results indicate that JNK and p38 MAPK signaling is critical for mediating actin-cytoskeleton-remodeling-induced nuclear YAP expression in alveolar stem cells. Moreover, we show that Cdc42-controlled actin remodeling is required for the activation of JNK, p38, and YAP in post-PNX lungs. Our findings together establish that the Cdc42/F-actin/MAPK/YAP signaling cascade is essential for promoting alveolar regeneration in response to mechanical tension in the lung.

Pleural gas analysis for the identification of alveolopleural fistulae.

PURPOSE OF REVIEW: The method for identification of alveolopleural fistulae (APF) by visual inspection of air bubbles in the chest drainage system has several limitations and suffers from poor accuracy. Here we discuss the use of a novel technique of pleural gas analysis in the identification and management of APF. RECENT FINDINGS: We found that pleural gas analysis has higher sensitivity and specificity than visual inspection in identifying APF. Additionally, we demonstrated that intrapleural gas milieu impacts lung healing and reduction of intrapleural carbon dioxide can promote resolution of APF. SUMMARY: Pleural gas analysis is a novel technique to identify and manage APF. Integration of gas analysis in chest drainage systems would provide a more objective method for managing chest tubes and providing a favorable pleural gas environment for lung healing.

In Vitro Lung Model Assessing the Efficacy of Surgical Sealants in Treating Alveolar Air Leaks.

PURPOSE: The lack of reliable testing methods limits the evidence-based practice of surgical sealants in treating alveolar air leak (AAL). We developed an in vitro lung model to evaluate sealants' efficacy and tested the widely used human thrombin-fibrinogen sponge, TachoSil as an example. MATERIALS AND METHODS: The caudal lobe of freshly excised swine lung (n = 10) was intubated and ventilated. A focal superficial parenchymal defect (40 × 25 mm) was created in the inflated lung. AAL was assessed with increasing inspired tidal volume (TVi). After sealant application, AAL was assessed in the same way until burst failure, defined as an AAL exceeding 20 mL. To evaluate the elasticity of the sealant, the length of defect was recorded in the inflated lung. RESULTS: Superficial parenchymal defects resulted in AAL increasing with ascending TVi. Multiple linear regression analysis revealed strong correlation between AAL and maximal inspiratory pressure, compliance and resistance. At TVi = 400, 500, and 600 mL, TachoSil achieved sealing in ten, eight, and seven tests, respectively. As TVi increased, superficial defects were still sealed in four, two, and two tests at TVi = 700, 800, and 900 mL, respectively. The burst pressure was 42 ± 5 cmH2O. Adhesive failures were found at the burst pressure in all tests. Concerning elasticity, TachoSil allowed an expansion of the covered lung defect of 7 ± 6 mm. CONCLUSIONS: TachoSil demonstrated a strong sealing efficiency and marked elasticity in treating AAL. These results are consistent to that of the previously published animal experiment, suggesting the reliability of the presented in vitro model.

In vitro comparison of two widely used surgical sealants for treating alveolar air leak.

BACKGROUND: Controversies surrounding the efficacy of sealants against alveolar air leak (AAL) are abundant in the literature. We sought to test the widely used sealants, TachoSil (Takeda Pharmaceutical Company Limited, Osaka, Japan) and BioGlue (CryoLife Europa Ltd., Surrey, United Kingdom) in an in vitro model. Materials and METHODS: After creation of a focal superficial defect (40 × 25 mm) in swine lungs (n=40), AAL was assessed with increasing inspired tidal volume (TVi). Upon sealant application in a randomized order, AAL was assessed in the same way until sealant burst. RESULTS: At TVi =400, 500, 600, and 700 mL, BioGlue achieved sealing in 19, 19, 16, and 14 tests, while TachoSil sealed in 19, 14, 4, and no test, respectively. The maximally tolerated pressure of BioGlue was higher than TachoSil (40.3 ± 3.0 vs. 36.0 ± 4.9 cm H2O, p=0.003). Cohesive and adhesive failures were found in 10 and 1 tests of BioGlue, respectively, while all burst failures of TachoSil were adhesive. Concerning elasticity, TachoSil allowed more expansion of the covered defect than BioGlue (6.3 ± 3.9 vs. 1.4 ± 1.0 mm, p<0.001). CONCLUSION: The tested sealants demonstrated high sealing efficacy. While BioGlue was superior in resisting higher ventilation pressure, TachoSil possessed better elasticity.

Existence, functional impairment, and lung repair potential of endothelial colony-forming cells in oxygen-induced arrested alveolar growth.

BACKGROUND: Bronchopulmonary dysplasia and emphysema are life-threatening diseases resulting from impaired alveolar development or alveolar destruction. Both conditions lack effective therapies. Angiogenic growth factors promote alveolar growth and contribute to alveolar maintenance. Endothelial colony-forming cells (ECFCs) represent a subset of circulating and resident endothelial cells capable of self-renewal and de novo vessel formation. We hypothesized that resident ECFCs exist in the developing lung, that they are impaired during arrested alveolar growth in experimental bronchopulmonary dysplasia, and that exogenous ECFCs restore disrupted alveolar growth. METHODS AND RESULTS: Human fetal and neonatal rat lungs contain ECFCs with robust proliferative potential, secondary colony formation on replating, and de novo blood vessel formation in vivo when transplanted into immunodeficient mice. In contrast, human fetal lung ECFCs exposed to hyperoxia in vitro and neonatal rat ECFCs isolated from hyperoxic alveolar growth-arrested rat lungs mimicking bronchopulmonary dysplasia proliferated less, showed decreased clonogenic capacity, and formed fewer capillary-like networks. Intrajugular administration of human cord blood-derived ECFCs after established arrested alveolar growth restored lung function, alveolar and lung vascular growth, and attenuated pulmonary hypertension. Lung ECFC colony- and capillary-like network-forming capabilities were also restored. Low ECFC engraftment and the protective effect of cell-free ECFC-derived conditioned media suggest a paracrine effect. Long-term (10 months) assessment of ECFC therapy showed no adverse effects with persistent improvement in lung structure, exercise capacity, and pulmonary hypertension. CONCLUSIONS: Impaired ECFC function may contribute to arrested alveolar growth. Cord blood-derived ECFC therapy may offer new therapeutic options for lung diseases characterized by alveolar damage.

Differentiation of mouse induced pluripotent stem cells into alveolar epithelial cells in vitro for use in vivo.

Alveolar epithelial cells (AECs) differentiated from induced pluripotent stem cells (iPSCs) represent new opportunities in lung tissue engineering and cell therapy. In this study, we modified a two-step protocol for embryonic stem cells that resulted in a yield of ∼9% surfactant protein C (SPC)(+) alveolar epithelial type II (AEC II) cells from mouse iPSCs in a 12-day period. The differentiated iPSCs showed morphological characteristics similar to those of AEC II cells. When differentiated iPSCs were seeded and cultured in a decellularized mouse lung scaffold, the cells reformed an alveolar structure and expressed SPC or T1α protein (markers of AEC II or AEC I cells, respectively). Finally, the differentiated iPSCs were instilled intratracheally into a bleomycin-induced mouse acute lung injury model. The transplanted cells integrated into the lung alveolar structure and expressed SPC and T1α. Significantly reduced lung inflammation and decreased collagen deposition were observed following differentiated iPSC transplantation. In conclusion, we report a simple and rapid protocol for in vitro differentiation of mouse iPSCs into AECs. Differentiated iPSCs show potential for regenerating three-dimensional alveolar lung structure and can be used to abrogate lung injury.

Alveolar adenoma resected by thoracoscopic surgery.

Alveolar adenoma, a rare benign pulmonary neoplasm, usually presents as asymptomatic. Since first described in 1986, no more than 35 cases have been reported in the English medical literature. Here we report a case of 48-year-old woman who suffered from this tumor, the patient is doing well 4 years after thoracoscopic lobectomy.

Longitudinal, noninvasive monitoring of compensatory lung growth in mice after pneumonectomy via (3)He and (1)H magnetic resonance imaging.

In rodents and some other mammals, partial pneumonectomy (PNX) of adult lungs results in rapid compensatory lung growth. In the past, quantification of compensatory lung growth and realveolarization could only be accomplished after killing the animal, removal of lungs, and histologic analysis of lungs at single time points. Hyperpolarized (3)He diffusion magnetic resonance imaging (MRI) allows in vivo morphometry of human lungs; our group has adapted this technique for application to mouse lungs. Through imaging, we can obtain maps of lung microstructural parameters that allow quantification of morphometric and physiologic measurements. In this study, we employed our (3)He MRI technique to image in vivo morphometry at baseline and to serially assess compensatory growth after left PNX of mice. (1)H and hyperpolarized (3)He diffusion MRI were performed at baseline (pre-PNX), 3-days, and 30-days after PNX. Compared with the individual mouse's own baseline, MRI was able to detect and serially quantify changes in lung volume, alveolar surface area, alveolar number, and regional changes in alveolar size that occurred during the course of post-PNX lung growth. These results are consistent with morphometry measurements reported in the literature for mouse post-PNX compensatory lung growth. In addition, we were also able to serially assess and quantify changes in the physiologic parameter of lung compliance during the course of compensatory lung growth; this was consistent with flexiVent data. With these techniques, we now have a noninvasive, in vivo method to serially assess the effectiveness of therapeutic interventions on post-PNX lung growth in the same mouse.

Alveolar adenoma combined with multifocal cysts: case report and literature review.

Alveolar adenoma is an extremely rare and benign pulmonary neoplasm; it is always asymptomatic and is usually detected incidentally on routine chest X-radiography. Typically on imaging examinations, alveolar adenoma exhibits as a peripheral, solitary, cystic nodule in the lung, which may easily imitate other lung lesions, consequently leading to difficulties in the differential diagnosis of this condition. Surgical resection is the primary treatment option. The diagnosis of alveolar adenoma is mainly based on postoperative histopathology, with features of proliferative type 2 alveolar epithelial cells and septal mesenchyme. The present case was a 60-year-old woman with alveolar adenoma, combined with systemic mutifocal cystic lesions. She underwent surgery following the obvious enlargement of this mass and a cystic nodule 7 cm in maximum diameter was resected. Postoperative histopathology confirmed a diagnosis of alveolar adenoma; her prognosis was favourable. In addition to reporting a rare case of alveolar adenoma coexisting with multifocal cysts, the English-language literature was reviewed for similar cases of alveolar adenoma.

Reduction of intraoperative air leaks with Progel in pulmonary resection: a comprehensive review.

Intraoperative alveolar air leaks (IOALs) occur in 75% of patients during pulmonary resection. Despite routine use of sutures and stapling devices, they remain a significant problem in the daily practice of thoracic surgery. Air leaks that persist beyond postoperative day 5 often result in increased costs and complications. Several large meta-analyses have determined that sealants as a class reduce postoperative air leak duration and time to chest drain removal, but these results did not necessarily correlate with a reduction in length of postoperative hospital stay. These analyses grouped surgical sealants together of necessity, but differences in efficacy may exist due to the differing product characteristics, study protocols, surgical procedures, and study endpoints. Progel, currently the only pleural surgical sealant FDA-approved for use in lung resection, has demonstrated efficacy and safety in two controlled clinical studies and superiority over standard air leak closure methods in reducing IOALs and length of hospital stay. This paper will review these findings and report on real-world experience with this recently approved pleural sealant.

Alveolar epithelial dynamics in postpneumonectomy lung growth.

The intimate anatomic and functional relationship between epithelial cells and endothelial cells within the alveolus suggests the likelihood of a coordinated response during postpneumonectomy lung growth. To define the population dynamics and potential contribution of alveolar epithelial cells to alveolar angiogenesis, we studied alveolar Type II and I cells during the 21 days after pneumonectomy. Alveolar Type II cells were defined and isolated by flow cytometry using a CD45(-) , MHC class II(+) , phosphine(+) phenotype. These phenotypically defined alveolar Type II cells demonstrated an increase in cell number after pneumonectomy; the increase in cell number preceded the increase in Type I (T1α(+) ) cells. Using a parabiotic wild type/GFP pneumonectomy model, <3% of the Type II cells and 1% of the Type I cells were positive for GFP-a finding consistent with the absence of a blood-borne contribution to alveolar epithelial cells. The CD45(-) , MHC class II(+) , phosphine(+) Type II cells demonstrated the active transcription of angiogenesis-related genes both before and after pneumonectomy. When the Type II cells on Day 7 after pneumonectomy were compared to nonsurgical controls, 10 genes demonstrated significantly increased expression (P<0.05). In contrast to the normal adult Type II cells, there was notable expression of inflammation-associated genes (Ccl2, Cxcl2, Ifng) as well as genes associated with epithelial growth (Ereg, Lep). Together, the data suggest an active contribution of local alveolar Type II cells to alveolar growth.

Endobronchial valves for persistent postoperative pulmonary air leak: accurate monitoring and functional implications.

An alveolar-pleural fistula is a communication between the pulmonary parenchyma distal to a segmental bronchus and the pleural space. A postoperative pulmonary expiratory air leak after an anatomic pulmonary resection is usually managed conservatively. The use of endobronchial valves is a minimal invasive method that may be effective for the treatment of a persistent postoperative pulmonary air leak. We present and discuss the advantages of a digital thoracic drainage system for the accurate, objective and reproducible air leak assessment during endobronchial valve placement. Our case also illustrates that, even after lobectomy, lobar exclusion with valves allows air leak resolution without atelectasis and with moderate functional alteration. We discuss the anatomic and physiologic changes induced by valves placed for air leak closure.