Loss Of Pulmonary Function Research Articles

Citrullination, a novel posttranslational modification of elastin, is involved in COPD pathogenesis.

Elastin is an extracellular matrix protein (ECM) that supports elasticity of the lung, and in patients with chronic obstructive pulmonary disease (COPD) and emphysema, the structural changes that reduce the amount of elastic recoil, lead to loss of pulmonary function. We recently demonstrated that elastin is a target of peptidyl arginine deiminase (PAD) enzyme-induced citrullination, thereby leading to enhanced susceptibility of this ECM protein to proteolysis. This study aimed to investigate the impact of PAD activity in vivo and furthermore assessed whether pharmacological inhibition of PAD activity protects against pulmonary emphysema. Using a Serpina1a-e knockout mouse model, previously shown to develop inflammation-mediated emphysema, we validated the involvement of PADs in airway disease. In line with emphysema development, intratracheal administration of lipopolysaccharide in combination with PADs provoked significant airspace enlargement (P < 0.001) and diminished lung function, including loss of lung tissue elastance (P = 0.0217) and increases in lung volumes (P = 0.0463). Intraperitoneal treatment of mice with the PAD inhibitor, BB-Cl-amidine, prevented PAD/LPS-mediated lung function decline and emphysema and reduced levels of citrullinated airway elastin (P = 0.0199). These results provide evidence for the impact of PADs on lung function decline, indicating promising potential for the future development of PAD-based therapeutics for preserving lung function in patients with COPD.NEW & NOTEWORTHY This study provides evidence for the impact of peptidyl arginine deiminase (PAD) enzymes on lung function decline, indicating promising potential for the future development of PAD-based therapeutics for preserving lung function in patients with COPD.

Update on the Role of Chest Imaging in Cystic Fibrosis.

Cystic fibrosis is a genetic disease with multisystem involvement and associated morbidity and mortality that are most directly related to progressive lung disease. The hallmark findings of cystic fibrosis in the lungs are chronic inflammation and infection, leading to progressive loss of pulmonary function and often requiring lung transplant. Predominant lung findings include mucous plugging, bronchiectasis, and air trapping, often with associated atelectasis, consolidation, and emphysema; these findings form the basis of several clinical scoring systems that are used for imaging assessment. Recently, there have been major breakthroughs in the pharmacologic management of cystic fibrosis, including highly effective modulator therapies that directly target the underlying cystic fibrosis transmembrane conductance regulator molecular defect, often leading to remarkable improvements in lung function and quality of life with corresponding significant improvements in imaging markers. The authors review current guidelines regarding cystic fibrosis with respect to disease monitoring, identifying complications, and managing advanced lung disease. In addition, they discuss the evolving role of imaging, including current trends, emerging technologies, and proposed updates to imaging guidelines endorsed by international expert committees on cystic fibrosis, which favor increased use of cross-sectional imaging to enable earlier detection of structural changes in early disease and more sensitive detection of acute changes in advanced disease. It is important for radiologists to be familiar with these trends and updates so that they can most effectively assist clinicians in guiding the management of patients with cystic fibrosis in all stages of disease. ©RSNA, 2024.

Pirfenidone in Idiopathic Pulmonary Fibrosis: Real-World Observation on Efficacy and Safety, Focus on Patients Undergoing Antithrombotic and Anticoagulant.

Idiopathic pulmonary fibrosis (IPF) is a rare and progressive interstitial lung disease characterized by irreversible distortion of lung architecture and subsequent loss of pulmonary function. Pirfenidone is an antifibrotic agent associated with increased progression-free survival and overall survival rates, but it carries multiple side effects. The aim of the study was to examine the efficacy and safety profile of pirfenidone in a real-life context, with a focus on the concomitant use of antithrombotic and/or anticoagulant treatments. The clinical and functional data (forced vital capacity [FVC], forced expiratory volume in 1 s [FEV1], diffusing lung capacity for carbon monoxide [DLCO], and 6 min walking test distance [6MWD]) of all IPF patients treated with pirfenidone and referred to our two centers between 2019 and 2022 were retrospectively analyzed at baseline, 6 and 12 months after the start of treatment. A total of 55 IPF subjects undergoing pirfenidone treatment were included in the analysis (45.5% females, median [IQR] age at disease onset 68.0 [10.0] years, median [IQR] age at baseline 69.0 [10.8] years). Compared to baseline, at 12 months, FVC (86.0% vs. 80.0%; p = 0.023) and DLCO (44.0% vs. 40.0%; p = 0.002) were significantly reduced, while FEV1 (p = 0.304) and 6MWD (p = 0.276) remained stable; no significant change was recorded at 6 months. Most of the reported adverse events were mild or moderate. Gastrointestinal intolerance (9.1%) was the main cause of treatment discontinuation. A total of 5% of patients reported at least one minor bleeding event, although all episodes occurred in those receiving concomitant antithrombotic or anticoagulant. Overall, this real-life experience confirms the efficacy and safety profile of pirfenidone in the case of the concomitant use of antithrombotic and/or anticoagulant drugs.

Thoracoscopic pulmonary resection combined with real-time image-guided percutaneous ablation for multiple pulmonary nodules: a novel surgical approach and literature review.

Due to the widespread use of computed tomography (CT) screening and advances in diagnostic techniques, an increasing number of patients with multiple pulmonary nodules are being detected and pathologically diagnosed as synchronous multiple primary lung cancers (sMPLC). It has become a new challenge to treat multiple pulmonary nodules and obtain a favorable prognosis while minimizing the perioperative risk for patients. The purpose of this study was to summarize the preliminary experience with a hybrid surgery combining pulmonary resection and ablation for the treatment of sMPLC and to discuss the feasibility of this novel procedure with a literature review. This is a retrospective non-randomized controlled study. From January 1, 2022 to July 1, 2023, four patients underwent hybrid surgery combining thoracoscopic pulmonary resection and percutaneous pulmonary ablation for multiple pulmonary nodules. Patients were followed up at 3, 6 and 12 months postoperatively and the last follow-up was on November 30, 2023. Clinical characteristics, perioperative outcomes, pulmonary function recovery and oncologic prognosis were recorded. Meanwhile we did a literature review of studies on hybridized pulmonary surgery for the treatment of multiple pulmonary nodules. All the four patients were female, aged 52 to 70 years, and had no severe cardiopulmonary dysfunction on preoperative examination. Hybrid surgery of simultaneous pulmonary resection and ablation were performed in these patients to treat 2 to 4 pulmonary nodules, assisted by intraoperative real-time guide of C-arm X-ray machine. The operation time was from 155 to 240 minutes, and intraoperative blood loss was from 50 to 200 mL. Postoperative hospital stay was 2 to 7 days, thoracic drainage duration was 2 to 6 days, and pleural drainage volume was 300-1,770 mL. One patient presented with a bronchopleural fistula due to pulmonary ablation; the fistula was identified and sutured during thoracoscopic surgery and the patient recovered well. No postoperative 90-day complications occurred. After 3 months postoperatively, performance status scores for these patients recovered to 80 to 100. No tumor recurrence or metastasis was detected during the follow-up period. Hybrid procedures combining minimally invasive pulmonary resection with ablation are particularly suitable for the simultaneous treatment of sMPLC. Patients had less loss of pulmonary function, fewer perioperative complications, and favorable oncologic prognosis. Hybrid surgery is expected to be a better treatment option for patients with sMPLC.

Enhanced radiation sensitivity, decreased DNA damage repair, and differentiation defects in airway stem cells derived from patients with chronic obstructive pulmonary disease.

Radiation therapy (RT) is a common treatment for lung cancer. Still, it can lead to irreversible loss of pulmonary function and a significant reduction in quality of life for one-third of patients. Preexisting comorbidities, such as chronic obstructive pulmonary disease (COPD), are frequent in patients with lung cancer and further increase the risk of complications. Because lung stem cells are crucial for the regeneration of lung tissue following injury, we hypothesized that airway stem cells from patients with COPD with lung cancer might contribute to increased radiation sensitivity. We used the air-liquid interface model, a three-dimensional (3D) culture system, to compare the radiation response of primary human airway stem cells from healthy and patients with COPD. We found that COPD-derived airway stem cells, compared to healthy airway stem cell cultures, exhibited disproportionate pathological mucociliary differentiation, aberrant cell cycle checkpoints, residual DNA damage, reduced survival of stem cells and self-renewal, and terminally differentiated cells post-irradiation, which could be reversed by blocking the Notch pathway using small-molecule γ-secretase inhibitors. Our findings shed light on the mechanisms underlying the increased radiation sensitivity of COPD and suggest that airway stem cells reflect part of the pathological remodeling seen in lung tissue from patients with lung cancer receiving thoracic RT.

Neutrophil-Derived Peptidyl Arginine Deiminase Activity Contributes to Pulmonary Emphysema by Enhancing Elastin Degradation.

In chronic obstructive pulmonary disease (COPD), inflammation gives rise to protease-mediated degradation of the key extracellular matrix protein, elastin, which causes irreversible loss of pulmonary function. Intervention against proteolysis has met with limited success in COPD, due in part to our incomplete understanding of the mechanisms that underlie disease pathogenesis. Peptidyl arginine deiminase (PAD) enzymes are a known modifier of proteolytic susceptibility, but their involvement in COPD in the lungs of affected individuals is underexplored. In this study, we showed that enzyme isotypes PAD2 and PAD4 are present in primary granules of neutrophils and that cells from people with COPD release increased levels of PADs when compared with neutrophils of healthy control subjects. By examining bronchoalveolar lavage and lung tissue samples of patients with COPD or matched smoking and nonsmoking counterparts with normal lung function, we reveal that COPD presents with markedly increased airway concentrations of PADs. Ex vivo, we established citrullinated elastin in the peripheral airways of people with COPD, and invitro, elastin citrullination significantly enhanced its proteolytic degradation by serine and matrix metalloproteinases, including neutrophil elastase and matrix metalloprotease-12, respectively. These results provide a mechanism by which neutrophil-released PADs affect lung function decline, indicating promise for the future development of PAD-based therapeutics for preserving lung function in patients with COPD.

Multipotent adult progenitor cells prevent functional impairment and improve development in inflammation driven detriment of preterm ovine lungs

BackgroundPerinatal inflammation increases the risk for bronchopulmonary dysplasia in preterm neonates, but the underlying pathophysiological mechanisms remain largely unknown. Given their anti-inflammatory and regenerative capacity, multipotent adult progenitor cells (MAPC) are a promising cell-based therapy to prevent and/or treat the negative pulmonary consequences of perinatal inflammation in the preterm neonate. Therefore, the pathophysiology underlying adverse preterm lung outcomes following perinatal inflammation and pulmonary benefits of MAPC treatment at the interface of prenatal inflammatory and postnatal ventilation exposures were elucidated. MethodsInstrumented ovine fetuses were exposed to intra-amniotic lipopolysaccharide (LPS 5 mg) at 125 days gestation to induce adverse systemic and peripheral organ outcomes. MAPC (10 × 106 cells) or saline were administered intravenously two days post LPS exposure. Fetuses were delivered preterm five days post MAPC treatment and either killed humanely immediately or mechanically ventilated for 72 h. ResultsAntenatal LPS exposure resulted in inflammation and decreased alveolar maturation in the preterm lung. Additionally, LPS-exposed ventilated lambs showed continued pulmonary inflammation and cell junction loss accompanied by pulmonary edema, ultimately resulting in higher oxygen demand. MAPC therapy modulated lung inflammation, prevented loss of epithelial and endothelial barriers and improved lung maturation in utero. These MAPC-driven improvements remained evident postnatally, and prevented concomitant pulmonary edema and functional loss. ConclusionIn conclusion, prenatal inflammation sensitizes the underdeveloped preterm lung to subsequent postnatal inflammation, resulting in injury, disturbed development and functional impairment. MAPC therapy partially prevents these changes and is therefore a promising approach for preterm infants to prevent adverse pulmonary outcomes.

Finite element analysis and clinical study of chest wall reconstruction using carbon fiber artificial rib

Carbon fiber composites are emerging as a promising new biomaterial for chest wall reconstruction implants due to their mechanical properties and biocompatibility. This work evaluates the biomechanics of carbon fiber artificial ribs using finite element analysis and clinical implementation. Static simulations of normal breathing process show the maximum stress on the implant is only 2.83 MPa, far below the material ultimate strength of 60 MPa, indicating the excellent fit for maintaining respiratory function. Dynamic collision simulations demonstrate the artificial rib model could withstand a 4 kg rigid object impact at 2 m/s without fracture. Reconstructing the artificial rib with a human rib in the finite element analysis model increases the overall stress tolerance. The impact force required for fracture increases 48% compared to the artificial rib alone, suggesting improved strength from rib integration. Clinically, 10 of 13 patients receiving the artificial rib implants show no significant loss of pulmonary function based on spirometry tests. Based on our findings, the combined simulations and clinical results validate the strong mechanical performance and biocompatibility of the carbon fiber artificial ribs for chest wall reconstruction under static and dynamic loading while maintaining normal respiratory function.

Pulmonary Fibrosis and Diabetes Mellitus: Two coins with the same face.

Idiopathic pulmonary fibrosis (IPF) constitutes a long-term disease with a complex pathophysiology composed of multiple molecular actors that lead to the deposition of extracellular matrix, the loss of pulmonary function and ultimately the patient's death. Despite the approval of pirfenidone and nintedanib for the treatment of the disease, lung transplant is the only long-term solution to fully recover the respiratory capacity and gain quality of life. One of the risk factors for the development of IPF is the pre-existing condition of diabetes mellitus. Both, IPF and diabetes mellitus, share similar pathological damage mechanisms, including inflammation, endoplasmic reticulum stress, mitochondrial failure, oxidative stress, senescence and signaling from glycated proteins through receptors. In this critical review article, we provide information about this interrelationship, examining molecular mediators that play an essential role in both diseases and identify targets of interest for the development of potential drugs. We review the findings of clinical trials examining the progression of IPF and how novel molecules may be used to stop this process. The results highlight the importance of early detection and addressing multiple therapeutic targets simultaneously to achieve better therapeutic efficacy and potentially reverse lung fibrosis.

Risk factors for loss of pulmonary function after wedge resection for peripheral ground-glass opacity dominant lung cancer.

This study aimed to identify the risk factors for pulmonary functional deterioration after wedge resection for early-stage lung cancer with ground-glass opacity, which remain unclear, particularly in low-risk patients. We analysed 237 patients who underwent wedge resection for peripheral early-stage lung cancer in JCOG0804/WJOG4507L, a phase III, single-arm confirmatory trial. The changes in forced expiratory volume in 1 s were calculated pre- and postoperatively, and a cutoff value of -10%, the previously reported reduction rate after lobectomy, was used to divide the patients into 2 groups: the severely reduced group (≤-10%) and normal group (>-10%). These groups were compared to identify predictors for severe reduction. Thirty-seven (16%) patients experienced severe reduction. Lesions with a total tumour size ≥1 cm were significantly more frequent in the severely reduced group than in the normal group (89.2% vs 71.5%; P = 0.024). A total tumour size of ≥1 cm [odds ratio (OR), 3.287; 95% confidence interval (CI), 1.114-9.699: P = 0.031] and pleural indentation (OR, 2.474; 95% CI, 1.039-5.890: P = 0.041) were significant predictive factors in the univariable analysis. In the multivariable analysis, pleural indentation (OR, 2.667; 95% CI, 1.082-6.574; P = 0.033) was an independent predictive factor, whereas smoking status and total tumour size were marginally significant. Of the low-risk patients who underwent pulmonary wedge resection for early-stage lung cancer, 16% experienced severe reduction in pulmonary function. Pleural indentation may be a risk factor for severely reduced pulmonary function in pulmonary wedge resection.

Protective role of CFTR during fungal infection of cystic fibrosis bronchial epithelial cells with Aspergillus fumigatus.

Lung infection with the fungus Aspergillus fumigatus (Af) is a common complication in cystic fibrosis (CF) and is associated with loss of pulmonary function. We established a fungal epithelial co-culture model to examine the impact of Af infection on CF bronchial epithelial barrier function using Af strains 10AF and AF293-GFP, and the CFBE41o- cell line homozygous for the F508del mutation with (CF+CFTR) and without (CF) normal CFTR expression. Following exposure of the epithelial surface to Af conidia, formation of germlings (early stages of fungal growth) was detected after 9-12 hours and hyphae (mature fungal growth) after 12-24 hours. During fungal morphogenesis, bronchial epithelial cells showed signs of damage including rounding, and partial detachment after 24 hours. Fluorescently labeled conidia were internalized after 6 hours and more internalized conidia were observed in CF compared to CF+CFTR cells. Infection of the apical surface with 10AF conidia, germlings, or hyphae was performed to determine growth stage-specific effects on tight junction protein zona occludens protein 1 (ZO-1) expression and transepithelial electrical resistance (TER). In response to infection with conidia or germlings, epithelial barrier function degraded time-dependently (based on ZO-1 immunofluorescence and TER) with a delayed onset in CF+CFTR cell monolayers and required viable fungi and apical application. Infection with hyphae caused an earlier onset and faster rate of decline in TER compared to conidia and germlings. Gliotoxin, a major Af virulence factor, caused a rapid decline in TER and induced a transient chloride secretory response in CF+CFTR but not CF cells. Our findings suggest growth and internalization of Af result in deleterious effects on bronchial epithelial barrier function that occurred more rapidly in the absence of CFTR. Bronchial epithelial barrier breakdown was time-dependent and morphotype-specific and mimicked by acute administration of gliotoxin. Our study also suggests a protective role for CFTR by turning on CFTR-dependent chloride transport in response to gliotoxin, a mechanism that will support mucociliary clearance, and could delay the loss of epithelial integrity during fungal development in vivo.

Changes in pulmonary function in lung cancer patients after segmentectomy or lobectomy: a retrospective, non-intervention, observation study.

Pulmonary segmentectomy (SE) became an increasingly popular method for resection of early-stage lung cancer. This study aims to compare the impact of single SE (SSE), multiple SE (MSE) and lobectomy (LE) on postoperative pulmonary function in patients with NSCLC. Medical records of a total of 1284 patients who underwent LE (n = 493), SSE (n = 558) and MSE (n = 233) at Shanghai Pulmonary Hospital from January 2013 to October, 2020 were retrospectively analysed. Pulmonary function tests (PFTs) were performed preoperatively and 12 months after surgery. SSE was associated with a significantly smaller decline in the PFT values compared to MSE and LE. There was a poor consistency between the observed and expected (O/E) loss of pulmonary function in all study groups (P < 0.05). Both LE and SE resulted in similar O/E ratios of all PFT parameters (P > 0.05). Overall loss of pulmonary function was much greater after LE than after both SSE and MSE. MSE was associated with higher postoperative pulmonary function decline compared to SSE but was still beneficial over LE. Both LE and SE groups had similar PFT loss per segment (P > 0.05).

Clinical diagnosis and treatment of multiple pulmonary nodules

CT screening has markedly reduced the lung cancer mortality in high-risk population and increased the detection of early-stage pulmonary neoplasms, including multiple pulmonary nodules, especially those with a ground-glass appearance on CT. Multiple primary lung cancer (MPLC) constitutes a specific subtype of lung cancer with indolent biological behaviors, which is predominantly early-stage adenocarcinoma. Although MPLC progresses slowly with rare lymphatic metastasis, existence of synchronous lesions and distributed location of these nodules still pose difficulty for the management of such patients. One single operation is usually insufficient to eradicate all neoplastic lesions, whereas repeated surgical procedures bring about another dilemma: whether clinical benefits of surgical treatment outweigh loss of pulmonary function following multiple operations. Therefore, despite the anxiety for treatment among MPLC patients, whether and how to treat the patient should be assessed meticulously. Currently there is a heated discussion upon the timing of clinical intervention, operation mode and the application of local therapy in MPLC. Based on clinical experience of our multiple disciplinary team, we have summarized and commented on the evaluation, surgical treatment, non-surgical local treatment, targeted therapy and immunotherapy of MPLC in this article to provide further insight into this field.

Quantitative analysis of lung function and airway remodeling using ventilation/perfusion single photon emission tomography/computed tomography and HRCT in patients with chronic obstructive pulmonary disease and asthma.

To investigate the role of V/P SPECT/CT and HRCT quantitative parameters in evaluating COPD and asthma disease severity, airway obstructivity-grade, ventilation and perfusion distribution patterns, airway remodeling, and lung parenchymal changes. Fifty-three subjects who underwent V/P SPECT/CT, HRCT, and pulmonary function tests (PFTs) were included. Preserved lung ventilation (PLVF), perfusion function (PLPF), airway obstructivity-grade (OG), proportion of anatomical volume, ventilation and perfusion contribution of each lobe, and V/P distribution patterns were evaluated using V/P SPECT/CT. The quantitative parameters of HRCT included CT bronchial and CT pulmonary function parameters. In addition, the correlation and difference of V/P SPECT/CT-, HRCT-, and PFT-related parameters were compared. There was a statistically significant difference between severe asthma and severe-very severe COPD in CT bronchial parameters, like WA, LA and AA, in the lung segment airways (P < 0.05). CT bronchial parameters, like as WT and WA, were statistically significant (p < 0.05) among asthma patients. The EI of severe-very severe COPD was different from that of the disease severity groups in asthma patients (P < 0.05). The airway obstructivity-grade, PLVF and PLPF differed significantly among the severe-very severe COPD and mild-moderate asthma patients (P < 0.05). And the PLPF was statistically significant among the disease severity groups in asthma and COPD (P < 0.05). OG and PLVF, PLPF, and PFT parameters were significantly correlated, with the FEV1 correlation being the most significant (r = - 0.901, r = 0.915, and r = 0.836, respectively; P < 0.01). There was a strong negative correlation between OG and PLVF (r = - 0.945) and OG and PLPF (r = - 0.853) and a strong positive correlation between PLPF and PLVF (r = 0.872). In addition, OG, PLVF, and PLPF were moderately to strongly correlated with CT lung function parameters (r = - 0.673 to - 0.839; P < 0.01), while lowly to moderately correlated with most CT bronchial parameters (r = - 0.366 to - 0.663, P < 0.01). There were three different V/P distribution patterns, including matched, mismatched, and reverse mismatched patterns. Last, the CT volume overestimated the contribution in the upper lobes and underestimated the lower lobes' contribution to overall function. Quantitative assessment of ventilation and perfusion abnormalities and the degree of pulmonary functional loss by V/P SPECT/CT shows promise as an objective measure to assess the severity of disease and lung function to guide localized treatments. There are differences between HRCT parameters and SPECT/CT parameters among the disease severity groups in asthma and COPD, which may enhance, to some extent, the understanding of complex physiological mechanisms in asthma and COPD.

Hippo signaling impairs alveolar epithelial regeneration in pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) consists of fibrotic alveolar remodeling and progressive loss of pulmonary function. Genetic and experimental evidence indicate that chronic alveolar injury and failure to properly repair the respiratory epithelium are intrinsic to IPF pathogenesis. Loss of alveolar type 2 (AT2) stem cells or mutations that either impair their self-renewal and/or impair their differentiation into AT1 cells can serve as a trigger of pulmonary fibrosis. Recent reports indicate increased YAP activity in respiratory epithelial cells in IPF lungs. Individual IPF epithelial cells with aberrant YAP activation in bronchiolized regions frequently co-express AT1, AT2, conducting airway selective markers and even mesenchymal or EMT markers, demonstrating 'indeterminate' states of differentiation and suggesting that aberrant YAP signaling might promote pulmonary fibrosis. Yet, Yap and Taz have recently also been shown to be important for AT1 cell maintenance and alveolar epithelial regeneration after Streptococcus pneumoniae induced injury. To investigate how epithelial Yap/Taz might promote pulmonary fibrosis or drive alveolar epithelial regeneration, we inactivated the Hippo pathway in AT2 stem cells resulting in increased nuclear Yap/Taz and found that this promotes their alveolar regenerative capacity and reduces pulmonary fibrosis following bleomycin injury by pushing them along the AT1 cell lineage. Vice versa, inactivation of both Yap1 and Wwtr1 (encoding Taz) or Wwtr1 alone in AT2 cells stem cells impaired alveolar epithelial regeneration and resulted in increased pulmonary fibrosis upon bleomycin injury. Interestingly, inactivation of only Yap1 in AT2 stem cells promoted alveolar epithelial regeneration and reduced pulmonary fibrosis. Together, these data suggest that epithelial Yap promotes, and epithelial Taz reduces pulmonary fibrosis suggesting that targeting Yap but not Taz mediated transcription might help promote AT1 cell regeneration and treat pulmonary fibrosis.

VATS phrenic nerve harvesting for brachial plexus neurotization: literature review and our experience.

Brachial plexus traumatic lesions often lead to severe upper extremity deficits that dramatically compromise quality of life of mostly young patients. Optimal treatment aims to restore elbow flexion transferring various donor nerves. Phrenic nerve (PN) is a powerful source of transferable axons and, despite supraclavicular sectioning being the most used technique, it can be harvested through video-assisted thoracoscopic surgery (VATS). About PN harvesting, less than 20 articles were found in Literature. Most of them are clinical case-reports or case-series or expert opinions. Most of these studies are from China and East Asia and very rarely from Europe; none from Italy. Therefore, we present our experience in PN VATS harvesting in two patients, first cases reported in Italy. Few papers explore risks and benefits of PN as a donor site for brachial plexus reconstruction. There is no clear consensus in the literature whether a traditional approach or minimally invasive surgery is advisable to harvest PN for neurotization. Currently there's no clear indication nor a definitive contraindication about routine use of PN for surgical treatment of BPTLs, it's mostly a matter of choosing the best donor nerve for every single patient. This choice depends on the patient's characteristics, type of traumatic lesion, time from the traumatic event and on the center's experience. The only real concern about using PN as a donor is the potential loss of pulmonary function. In our center two patients with complete brachial plexus avulsion underwent PN transfer via VATS in 2021. Usually, recovery of muscle function depends on time between injury and surgical repair. A commonly accepted recommendation is to perform surgery within six months from the traumatic lesion12. In our experience, the time between trauma and surgery was five months for patient A and six months for patient B. Even if some authors13 consider previous thoracic trauma with rib fractures a major contraindication for homolateral PN harvesting, we believe that the presence of pleural adhesions should not exclude a patient from surgery. No intra or postoperative complications were observed. Both patients were discharged on IV postoperative day. An intense rehabilitation program within three months after surgery is mandatory and regular follow-up is needed to monitor any improvement. No respiratory symptoms or discomfort is recorded up to now. Nerve transfer is a safe and reliable surgical reconstructive procedure and phrenic nerve, due to its pure motor nature, is a very good donor for brachial plexus injuries14. VATS is a valid procedure to guarantee a much longer nerve, avoiding any graft use, and doesn't seem to determine significant pulmonary function loss. Previous thoracic trauma, rib fractures and pneumothorax are commonly considered contraindications for VATS harvesting. However, a major trauma leading to BPTL often implies homolateral thoracic trauma with or without rib fracture or pneumothorax. This could be a reasonable justification to reconsider those contraindications and extend the potential cohort of patients that could benefit from this technique.

Outcomes and pulmonary function after sleeve lobectomy compared with pneumonectomy in patients with non-small cell lung cancer.

Sleeve lobectomy is recommended to avoid pneumonectomy and preserve pulmonary function in patients with central lung cancer. However, the relationship between postoperative pulmonary functional loss and resected lung parenchyma volume has not been fully characterized. The aim of this study was to evaluate the relationship between pulmonary function and lung volume in patients undergoing sleeve lobectomy or pneumonectomy. A total of 61 lung cancer patients who had undergone pneumonectomy or sleeve lobectomy were analyzed retrospectively. Among them, 20 patients performed pulmonary function tests, including vital capacity (VC) and forced expiratory volume in 1 s (FEV1) tests, preoperatively and then about 6months after surgery. VC and FEV1 ratios were calculated (measured postoperative respiratory function/predicted postoperative respiratory function) as the standardized pulmonary functional loss ratio. Thirty-day operation-related mortality was significantly lower after sleeve lobectomy (3.2%) than pneumonectomy (9.6%). The 5-year relapse-free survival rate was 46.67% versus 29.03%, and the 5-year overall survival rate was 63.33% versus 38.71% in patients receiving sleeve lobectomy versus pneumonectomy. The VC ratio in the pneumonectomy group was better than in the sleeve lobectomy group (1.003 ± 0.117 vs. 0.779 ± 0.12; p=0.0008), as was the FEV1 ratio (1.132 ± 0.226 vs. 0.851 ± 0.063; p=0.0038). Both short-term and long-term outcomes were better with sleeve lobectomy than pneumonectomy. However, actual postoperative pulmonary function after pneumonectomy may be better than clinicians expect, and pneumonectomy should still be considered a treatment option for patients with sufficient pulmonary reserve and in whom sleeve lobectomy is less likely to be curative.

EFFECT OF ELEXACAFTOR/TEZACAFTOR/IVACAFTOR ON ANNUAL RATE OF LUNG FUNCTION DECLINE IN PEOPLE WITH CYSTIC FIBROSIS

Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in people with cystic fibrosis (CF) with ≥ 1 F508del-CFTR allele in Phase 3 clinical trials. ELX/TEZ/IVA treatment led to improved lung function, with increases in percent predicted forced expiratory volume in 1second (ppFEV1) and Cystic Fibrosis Questionnaire-Revised respiratory domain score. Here, we evaluated the impact of ELX/TEZ/IVA on the rate of lung function decline over time by comparing changes in ppFEV1 in participants from the Phase 3 trials with a matched group of people with CF from the US Cystic Fibrosis Foundation Patient Registry not eligible for cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy. Participants treated with ELX/TEZ/IVA had on average no loss of pulmonary function over a 2-year period (mean annualized rate of change in ppFEV1, +0.39 percentage points [95% CI, -0.06 to 0.85]) compared with a 1.92 percentage point annual decline (95% CI, -2.16 to -1.69) in ppFEV1 in untreated controls. ELX/TEZ/IVA is the first CFTR modulator therapy shown to halt lung function decline over an extended time period.

Extracellular vesicles isolated from hyperuricemia patients might aggravate airway inflammation of COPD via senescence-associated pathway

BackgroundsChronic obstructive pulmonary disease (COPD) is a major health issue resulting in significant mortality worldwide. Due to the high heterogeneity and unclear pathogenesis, the management and therapy of COPD are still challenging until now. Elevated serum uric acid(SUA) levels seem to be associated with the inflammatory level in patients with COPD. However, the underlying mechanism is not yet clearly established. In the current research, we aim to elucidate the effect of high SUA levels on airway inflammation among COPD patients.MethodsThrough bioinformatic analysis, the common potential key genes were determined in both COPD and hyperuricemia (HUA) patients. A total of 68 COPD patients aged 50—75-year were included in the study, and their clinical parameters, including baseline characteristics, lung function test, as well as blood chemistry test were recorded. These parameters were then compared between the COPD patients with and without HUA. Hematoxylin & Eosin (HE), immunofluorescence (IF), and Masson trichrome staining were performed to demonstrate the pathological changes in the lung tissues. Furthermore, we isolated extracellular vesicles (EVs) from plasma, sputum, and bronchoalveolar lavage fluid (BALF) samples and detected the expression of inflammatory factor (Interleukin-6 (IL-6), IL-8 and COPD related proteases (antitrypsin and elastase) between two groups. Additionally, we treated the human bronchial epithelial (HBE) cells with cigarette smoke extract (CSE), and EVs were derived from the plasma in vitro experiments. The critical pathway involving the relationship between COPD and HUA was eventually validated based on the results of RNA sequencing (RNA-seq) and western blot (WB).ResultsIn the study, the COPD patients co-existing with HUA were found to have more loss of pulmonary function compared with those COPD patients without HUA. The lung tissue samples of patients who had co-existing COPD and HUA indicated greater inflammatory cell infiltration, more severe airway destruction and even fibrosis. Furthermore, the high SUA level could exacerbate the progress of airway inflammation in COPD through the transfer of EVs. In vitro experiments, we determined that EVs isolated from plasma, sputum, and BALF played pivotal roles in the CSE-induced inflammation of HBE. The EVs in HUA patients might exacerbate both systemic inflammation and airway inflammatory response via the senescence-related pathway.ConclusionThe pulmonary function and clinical indicators of COPD patients with HUA were worse than those without HUA, which may be caused by the increased airway inflammatory response through the EVs in the patient's peripheral blood. Moreover, it might mediate the EVs via senescence-related pathways in COPD patients with HUA.

RF19 | PSUN351 Glycoprotein-NMB (GPNMB) is Pro-Tumorigenic in Lymphangioleiomyomatosis (LAM)

Abstract Lymphangioleiomyomatosis (LAM) is an estrogen-sensitive lung disease found almost exclusively in women. LAM is characterized by the hyperproliferation of smooth muscle cells creating small tumors throughout the lungs, resulting in the formation of large cysts that replace normal alveolar space. Growth of these tumors and progression of cyst development leads to loss of pulmonary function, and sometimes subsequent lung transplantation. LAM tumor cells contain mutations in one of the tuberous sclerosis genes (TSC1 or TSC2), leading to constitutive activation of the mTORC1 pathway. In fact, mTOR inhibitors are commonly used to treat LAM; however, these drugs are not always effective and have significant side effects, suggesting the need for new therapeutic targets. Additionally, tumors recur even after lung transplantation and LAM cells are found in circulating body fluids, suggesting a metastatic nature of LAM, and a question of the origin of the LAM cell. Due to LAM's estrogen sensitivity, female specificity, and metastatic nature, we previously proposed that LAM cells originate from the uterine myometrium. We therefore designed a uterine-specific TSC2-null mouse model where all of the mice generate uterine tumors characteristic of LAM and half develop lung metastases, suggesting that indeed LAM tumors may be derived from the uterus. Notably, our collaborators recently utilized single cell RNA sequencing with human LAM lung lesions, and found that TSC2-null cells have a strong uterine profile. Using bulk RNASeq analysis of uterine tissue from our mouse model, when focusing on genes regulated by estrogen and TSC2, we discovered increased expression of melanocytic markers, including Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB). GPNMB is known to be oncogenic in other cancers and has been shown to be expressed intracellularly in benign cells, but both intracellularly and on the cell surface of tumor cells making GPNMB a good cell surface drug target. This melanocytic marker was not only highly expressed in our mouse model, it was also expressed in TSC2-null cell lines, as well as in human LAM patient lung and uteri samples. Knocking down GPNMB expression by siRNA directed against GPNMB mRNA decreased proliferation, migration, and invasion in TSC2-null cells. We also found that GPNMB's large ectodomain is released from the cell surface of TSC2-null cells and potentially mediated by the protease, Adam10. The ectodomain specifically is implicated in mediating GPNMB's effects on tumor growth. Finally, knocking out GPNMB in TSC2-null cells using CRISPR/Cas9 decreased xenograft tumor growth in mice. Overall, our data thus far demonstrate that GPNMB promotes TSC2-null tumor growth and metastasis. Importantly, the GPNMB ectodomain is a potential biomarker of human LAM, as we detect a significant difference in GPNMB ectodomain levels in patient blood as compared with healthy controls. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Sunday, June 12, 2022 12:36 p.m. - 12:41 p.m.