CEACAM6 as a Novel Therapeutic Target to Boost HO-1-mediated Antioxidant Defense in COPD.

Rationale: Tobacco smoking and air pollution are primary causes of chronic obstructive pulmonary disease (COPD). However, only a minority of smokers develop COPD. The mechanisms underlying the defense against nitrosative/oxidative stress in nonsusceptible smokers to COPD remain largely unresolved. Objectives: To investigate the defense mechanisms against nitrosative/oxidative stress that possibly prevent COPD development or progression. Methods: Four cohorts were investigated: 1) sputum samples (healthy, n = 4; COPD, n = 37), 2) lung tissue samples (healthy, n = 13; smokers without COPD, n = 10; smoker+COPD, n = 17), 3) pulmonary lobectomy tissue samples (no/mild emphysema, n = 6), and 4) blood samples (healthy, n = 6; COPD, n = 18). We screened 3-nitrotyrosine (3-NT) levels, as indication of nitrosative/oxidative stress, in human samples. We established a novel in vitro model of a cigarette smoke extract (CSE)-resistant cell line and studied 3-NT formation, antioxidant capacity, and transcriptomic profiles. Results were validated in lung tissue, isolated primary cells, and an ex vivo model using adeno-associated virus-mediated gene transduction and human precision-cut lung slices. Measurements and Main Results: 3-NT levels correlate with COPD severity of patients. In CSE-resistant cells, nitrosative/oxidative stress upon CSE treatment was attenuated, paralleled by profound upregulation of heme oxygenase-1 (HO-1). We identified carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) as a negative regulator of HO-1-mediated nitrosative/oxidative stress defense in human alveolar type 2 epithelial cells (hAEC2s). Consistently, inhibition of HO-1 activity in hAEC2s increased the susceptibility toward CSE-induced damage. Epithelium-specific CEACAM6 overexpression increased nitrosative/oxidative stress and cell death in human precision-cut lung slices on CSE treatment. Conclusions: CEACAM6 expression determines the hAEC2 sensitivity to nitrosative/oxidative stress triggering emphysema development/progression in susceptible smokers.

Anticancer Effects of Spiperone in C57BL/6 Mice with Emphysema and Lung Carcinoma.

The antitumor and antimetastatic activity of dopamine D2 receptor antagonists spiperone was studied in C57BL/6 mice in a model of combined pathology (emphysema and lung cancer). Emphysema was induced by administration of LPS and cigarette smoke extract. Lung cancer was induced by injection of Lewis lung carcinoma cells into the lung. It has been shown that under conditions of combined lung pathology, spiperone prevents inflammatory infiltration and emphysematous expansion of the lungs and reduces the size of the primary tumor node, the number of metastases, and the area of the lungs affected by metastases. Spiperone reduces the number of cancer stem cells (CSCs) in the lungs and blood of mice with combined pathology. CSCs isolated from the lungs and blood of mice with combined pathology treated with spiperone had a significantly lower potential to form a tumorosphere in vitro than CSCs from untreated mice with emphysema and lung carcinoma. Thus, blockade of dopamine D2 receptors is a promising approach for correcting combined lung pathology and can be used in the development of a method for treating lung cancer in patients with emphysema.

Fetal Lung Cells Transfer Improves Emphysematous Change in a Mouse Model of Neutrophil Elastase-Induced Lung Emphysema.

Recently, several studies for lung regeneration have been reported. However, regenerating the lung tissue by the transfer of any cells directly to the lung has been hardly successful. The aim of this study was to evaluate the effect of fetal lung cells (FLCs) in a mouse model of lung emphysema. C57BL/6 mice were stimulated with neutrophil elastase (NE) intra-tracheally (i.t.) to generate lung emphysema. To collect fetal lung cells, C57BL/6-Tg (CAG-EGFP) mice were bred for 14 days. Before delivery, the bred mice were euthanized, and fetal lungs were harvested from the fetal mice and the cells were collected. The FLCs were transferred i.t. 24 h after the NE instillation. Four weeks after the NE instillation, mice were euthanized, and the samples were collected. The mean linear intercept (MLI) was significantly prolonged in the NE instillation group compared to the control group. However, in the FLCs transfer group stimulated with NE, the MLI became shorter than the NE-stimulated group without an FLCs transfer. This result shows that an FLCs transfer inhibited the progression of lung emphysema. Additionally, motility of the mice was also improved by the FLCs transfer. These results indicate that transfer of the FLCs, which were presumed to be progenitor cells for lung tissue, may improve the emphysematous change.

The Japanese Herbal (Kampo) Medicine Hochuekkito Attenuates Lung Inflammation in Lung Emphysema.

Chronic obstructive pulmonary disease (COPD) is a systemic inflammatory disorder. It often causes weight loss, which is considered a poor prognostic factor. A Japanese herbal Kampo medicine, Hochuekkito (TJ-41), has been reported to prevent systemic inflammation and weight loss in COPD patients, but the underlying biological mechanisms remain unknown. In the present study, we investigated the role of TJ-41 in vivo using a mouse model of lung emphysema. We used lung epithelium-specific Taz conditional knockout mice (Taz CKO mice) as the lung emphysema model mimicking the chronic pulmonary inflammation in COPD. Acute inflammation was induced by intratracheal lipopolysaccharide administration, simulating COPD exacerbation. Mice were fed a diet containing 2% TJ-41 or a control diet. Taz CKO mice showed increased numbers of inflammatory cells in the bronchoalveolar lavage fluid compared to control mice. This effect was reduced by TJ-41 treatment. In the acute exacerbation model, TJ-41 mitigated the increased numbers of inflammatory cells in the bronchoalveolar lavage fluid and attenuated lung inflammation in histopathological studies. Additional in vitro experiments using the human macrophage cell line U-937 demonstrated that lipopolysaccharide-induced tumor necrosis factor-alpha expression was significantly downregulated by TJ-41. These results suggest that TJ-41 has anti-inflammatory effects in lung emphysema both in the chronic phase and during an acute exacerbation. In conclusion, our study sheds light on the anti-inflammatory effects of TJ-41 in lung emphysema. This establishes its potential as a new anti-inflammatory therapy and a preventive medicine for exacerbations during the long-time maintenance of COPD patients.

Adverse outcome pathways as a tool for the design of testing strategies to support the safety assessment of emerging advanced materials at the nanoscale.

Toxicity testing and regulation of advanced materials at the nanoscale, i.e. nanosafety, is challenged by the growing number of nanomaterials and their property variants requiring assessment for potential human health impacts. The existing animal-reliant toxicity testing tools are onerous in terms of time and resources and are less and less in line with the international effort to reduce animal experiments. Thus, there is a need for faster, cheaper, sensitive and effective animal alternatives that are supported by mechanistic evidence. More importantly, there is an urgency for developing alternative testing strategies that help justify the strategic prioritization of testing or targeting the most apparent adverse outcomes, selection of specific endpoints and assays and identifying nanomaterials of high concern. The Adverse Outcome Pathway (AOP) framework is a systematic process that uses the available mechanistic information concerning a toxicological response and describes causal or mechanistic linkages between a molecular initiating event, a series of intermediate key events and the adverse outcome. The AOP framework provides pragmatic insights to promote the development of alternative testing strategies. This review will detail a brief overview of the AOP framework and its application to nanotoxicology, tools for developing AOPs and the role of toxicogenomics, and summarize various AOPs of relevance to inhalation toxicity of nanomaterials that are currently under various stages of development. The review also presents a network of AOPs derived from connecting all AOPs, which shows that several adverse outcomes induced by nanomaterials originate from a molecular initiating event that describes the interaction of nanomaterials with lung cells and involve similar intermediate key events. Finally, using the example of an established AOP for lung fibrosis, the review will discuss various in vitro tests available for assessing lung fibrosis and how the information can be used to support a tiered testing strategy for lung fibrosis. The AOPs and AOP network enable deeper understanding of mechanisms involved in inhalation toxicity of nanomaterials and provide a strategy for the development of alternative test methods for hazard and risk assessment of nanomaterials.

Use of 3-D navigation to target the site of autologous blood installation for lung volume reduction in bullous emphysema.

Bronchoscopic lung volume reduction (BLVR) using intrabullous autologous blood instillation has been reported in single cases where other techniques are not possible. We present the use of three-dimensional navigation to instill autologous blood into emphysematous bullae for BLVR. A 62-year-old man presented with increasing dyspnea, due to emphysema with a conglomerate of giant bullae with two particularly large bullae. Surgical treatment was refused, so bronchoscopic autologous blood instillation into the bronchial segment leading to the large bullae was attempted, but was unsuccessful; blood failed to penetrate into the bullous cavity. Dyspnea worsened over the following year. We therefore performed another bronchoscopy and punctured a large bulla with a needle and created a tunnel from the central airways. Puncture position and direction were determined using a prototype of an electromagnetic navigation system. Under fluoroscopic guidance, a catheter was placed via the tunnel into the bulla and blood was instilled. This resulted in an almost complete shrinkage of the bullae, reduction of residual volume, and marked improvement in dyspnea within 4 months. To our knowledge, this is the first reported case of successful BLVR by navigated bronchoscopy with transbronchial puncture, dilatation, and autologous blood instillation into a giant bulla.

Pericytes and Smooth Muscle Cells Circulating in the Blood as Markers of Impaired Angiogenesis during Combined Metabolic Impairments and Lung Emphysema.

The changes in endothelial progenitor cells and progenitor cells of angiogenesis, pericytes and smooth muscle cells, were studied in female C57BL/6 mice with a combination of metabolic impairments induced by injections of sodium glutamate and lung emphysema modeled by the administration of cigarette smoke extract. It was observed that sodium glutamate significantly enhances pathological changes in the lungs (inflammation and lung emphysema) induced by the administration of cigarette smoke extract. Recruiting of endothelial progenitor cells (CD45-CD31+CD34+ and CD31+CD34+CD146-) and progenitor cells of angiogenesis (CD45-CD117+CD309+) was registered in the injured lungs. Angiogenesis impairment induced by combined exposure is related to altered migration of pericytes (CD31-CD34-CD146+) and smooth muscle cells (CD31-CD34+CD146+) in emphysema-like enlarged lung tissue.

[Endoscopic bronchial valve treatment of bronchopleural fistala and air leakage]. / Endoskopicheskaya klapannaya bronkhoblokatsiya pri lechenii bronkhoplevral'nykh svishchei i utechki vozdukha.

OBJECTIVE: To evaluate an effectiveness of endobronchial valve treatment of patients with bronchopleural fistulas and prolonged air leakage. MATERIAL AND METHODS: Endobronchial valve treatment was analyzed in 115 patients with bronchopleural fistulas or postoperative air leakage. All patients were divided into 5 groups depending on disease: bullous emphysema, acute purulent lung diseases, chronic purulent lung and pleural diseases, bullous emphysema complicated by pneumothorax with failed pleural cavity, other lung diseases associated with prolonged postoperative air leakage. RESULTS: Endobronchial valve treatment was effective in more than 70% patients. There were no intraoperative and postoperative complications. CONCLUSION: Endobronchial valve treatment is a highly effective minimally invasive method for treating patients with bronchopleural fistulas and postoperative air leakage.

Cigarette smoking and smoking-attributable diseases among Estonian physicians: a cross-sectional study.

BACKGROUND: Smoking is a risk factor for several diseases. Physicians are role models for their patients. Physicians who smoke underestimate the health risks of smoking and may be less likely to offer advice to help their patients to quit. The aim of this study was to: provide an overview of smoking behaviour among Estonian physicians; assess the relationship between smoking and ischaemic heart disease (IHD), chronic bronchitis (CB), and lung emphysema (LE); and estimate fractions of prevalences of the three diseases attributable to smoking. METHODS: Self-administered questionnaires were sent to practising physicians (n = 5666) in Estonia in 2014. Prevalence of smoking and relative risks for IHD, CB and LE as well as the risks of IHD, CB and LE attributable to smoking were calculated by age and sex. Post-stratification was used to compensate non-response. RESULTS: There were 535 male and 2404 female physicians participating. The prevalence of daily smoking was 12.4% (95% CI 10.4-14.4%) among men and 5.0% (95% CI 4.4-5.6%) among women. Mean duration of smoking among male and female daily smokers was 28.6 (95% CI 26.1-31.1) and 28.6 (95% CI 27.1-30.2) years. Compared to lifelong non-smokers, the age-adjusted risk for IHD was 1.29 times (95% CI 0.88-1.89) higher for men, but 1.69 times (95% CI 1.17-2.40) lower for all women who have ever smoked. The risk for CB was 2.29 (95% CI 1.30-4.03) times higher for smokers among men and, 1.32 (95% CI 0.95-1.82) among women; the risk ratio for LE was 4.92 (95% CI 1.14-21.1) among men and 2.45 (95% CI 0.63-9.52) among women. The smoking-attributable risk for IHD was 3.2% (95% CI 2.3-4.1%) among men and - 0.1% (95% CI -0.7-0.4%) among women; for CB 6.9% (95% CI 6.0-7.8%) and 4.2% (95% CI 3.5-4.8%); and for LE 18.8% (95% CI 17.0-22.5%) and 22.6% (95% CI 18.5-26.9%), respectively. CONCLUSION: Prevalence of daily smoking was relatively low among Estonian physicians (and twice lower among female physicians). The risk attributable to smoking was higher for LE and CB than for IHD.

Pulmonary Microvascular Blood Flow in Mild Chronic Obstructive Pulmonary Disease and Emphysema. The MESA COPD Study.

RATIONALE: Smoking-related microvascular loss causes end-organ damage in the kidneys, heart, and brain. Basic research suggests a similar process in the lungs, but no large studies have assessed pulmonary microvascular blood flow (PMBF) in early chronic lung disease. OBJECTIVES: To investigate whether PMBF is reduced in mild as well as more severe chronic obstructive pulmonary disease (COPD) and emphysema. METHODS: PMBF was measured using gadolinium-enhanced magnetic resonance imaging (MRI) among smokers with COPD and control subjects age 50 to 79 years without clinical cardiovascular disease. COPD severity was defined by standard criteria. Emphysema on computed tomography (CT) was defined by the percentage of lung regions below -950 Hounsfield units (-950 HU) and by radiologists using a standard protocol. We adjusted for potential confounders, including smoking, oxygenation, and left ventricular cardiac output. MEASUREMENTS AND MAIN RESULTS: Among 144 participants, PMBF was reduced by 30% in mild COPD, by 29% in moderate COPD, and by 52% in severe COPD (all P < 0.01 vs. control subjects). PMBF was reduced with greater percentage emphysema-950HU and radiologist-defined emphysema, particularly panlobular and centrilobular emphysema (all P ≤ 0.01). Registration of MRI and CT images revealed that PMBF was reduced in mild COPD in both nonemphysematous and emphysematous lung regions. Associations for PMBF were independent of measures of small airways disease on CT and gas trapping largely because emphysema and small airways disease occurred in different smokers. CONCLUSIONS: PMBF was reduced in mild COPD, including in regions of lung without frank emphysema, and may represent a distinct pathological process from small airways disease. PMBF may provide an imaging biomarker for therapeutic strategies targeting the pulmonary microvasculature.

Impact of Bronchoscopic Lung Volume Reduction with Valves on the Pulmonary Gas Exchange.

Introduction: Bronchoscopic lung volume reduction (BLVR) with endobronchial valves has been shown to be a safe and effective treatment for patients with severe lung emphysema. Previous studies have reported a benefit in pulmonary function, exercise capacity, and quality of life after BLVR-treatment. The effect of BLVR with valves on the pulmonary gas exchange and its association with clinical outcomes has not been analyzed to date. The primary goal of this study was to investigate the impact of BLVR on the pulmonary gas exchange and the impact of the target lobe selection in patients with discordant target lobes in high-resolution computed tomography (HRCT) scan and perfusion scan on the pulmonary gas exchange and clinical outcomes. Methods: In this single-center study, we retrospectively analyzed pulmonary function tests, 6-min-walk-tests, HRCT scans, perfusion scans, and blood gas analyses in 77 patients over the course of 6 months following BLVR treatment. Results: We observed that complete lobar occlusion with bronchoscopic valves leads to a transient impairment of pulmonary gas exchange. Despite this, an overall positive clinical outcome could be shown in patients treated with endobronchial valves. If the target lobe selection based on HRCT and perfusion scans is discrepant, a selection based on the HRCT scan tends to be associated with a better outcome than a selection based on the perfusion scan. Conclusions: Complete lobar occlusion with bronchoscopic valves leads to a transient impairment of pulmonary gas exchange but nevertheless results in an overall positive clinical outcome.

Nonintubated versus Intubated Lung Volume Reduction Surgery in Patients with End-Stage Lung Emphysema and Hypercapnia.

Lung volume reduction surgery (LVRS) represents an important treatment option in carefully selected patients with end-stage lung emphysema. The aim of this study was to assess the efficacy and safety of nonintubated LVRS compared to intubated LVRS in patients with preoperative hypercapnia and lung emphysema. Between April 2019 and February 2021, n = 92 patients with end-stage lung emphysema and preoperative hypercapnia undergoing unilateral video-assisted thoracoscopic LVRS (VATS-LVRS) performed in epidural anesthesia and mild sedation (nonintubated, group 1) or conventional general anesthesia (intubated, control, group 2) were prospectively enrolled in this study. Data were retrospectively analyzed. In all patients, low-flow veno-venous extracorporeal lung support (low-flow VV ECLS) was applied as a bridge through LVRS. Ninety-day mortality was considered as the primary outcome. Secondary endpoints included: chest tube duration, hospital stay, intubation and conversion to general anesthesia. Intergroup analysis showed no significant difference between the baseline data and patients' demographics. N = 36 patients underwent nonintubated surgery. VATS-LVRS under general anesthesia was performed in n = 56 patients. The mean duration of postoperative VV ECLS support was 3 ± 1 day in group 1 compared to 4 ± 1 in group 2. The 90-day mortality rate was 3% in group 1 compared to 7% in group 2. In group 1, all chest tubes were removed 5 ± 1 day (range 4-32 days) and 8 ± 1 day (range 4-44 days) in the control group after the surgery (p < 0.02). Prolonged chest tube therapy (>8 days) was observed in n = 3 patients in group 1 and n = 11 patients in the control group. The mean ICU stay was 4 ± 1 days in group 1 compared to 8 ± 2 days in the control group (p = 0.04). The mean hospital stay was significantly shorter in the nonintubated group 1 (6 ± 2 days vs. 10 ± 4 days, p = 0.01). Conversion to general anesthesia was necessary in one patient due to severe pleural adhesions. Nonintubated VATS-LVRS in patients with end-stage lung emphysema and hypercapnia is effective and well tolerated. Compared to general anesthesia, a reduction in mortality, chest tube duration, ICU and hospital stay and lower rate of prolonged air leak was observed. VV ECLS increases intraoperative safety and mitigates postoperative complications in such "high-risk" patients.

Spontaneous Pneumothorax Secondary to Bullous Lung Emphysema Positive for Cannabinoids upon Toxicological Examination.

Cannabis can be related to respiratory diseases, but the relationship between smoking marijuana and the development of a pneumothorax has scarcely been investigated. We aimed to analyze, in patients with a history of cannabis smoking abuse submitted to lung apicectomy for a primary spontaneous pneumothorax (PSP), the correlation between the presence of cannabinoids in the resected lung and the detection of bullous emphysema within the same tissue. Patients undergoing lung apicectomy for a PSP were prospectively enrolled, and the correlation between the presence of cannabinoids in the resected lung tissue and histological finding of bullous emphysema was investigated with Fisher's exact test. There were 21 male patients, with a median age of 27 years. The cannabinoids found by the toxicological examination in surgical specimens were mainly delta-9-tetrahydrocannabinol (THC), cannabinol (CBN), and cannabidiol (CBD). In 14/21 patients, cannabinoids were detected in the resected lung tissue, and bullous emphysema was present in 13/14 of these (93%), while bullous emphysema was found in only 1/7 (14%) of the remaining patients who were negative for cannabinoids in the lung tissue, and the difference was found to be statistically significant (p < 0.0009). Our study demonstrated the presence of bullous emphysema in most cannabinoid-positive patients and its absence in most of those who were cannabinoid-negative, supporting the correlation between cannabinoids in the lung tissue and bullous emphysema with the development of a "secondary" spontaneous pneumothorax.

GOLD stage-specific phenotyping of emphysema and airway disease using quantitative computed tomography.

Background: In chronic obstructive pulmonary disease (COPD) abnormal lung function is related to emphysema and airway obstruction, but their relative contribution in each GOLD-stage is not fully understood. In this study, we used quantitative computed tomography (QCT) parameters for phenotyping of emphysema and airway abnormalities, and to investigate the relative contribution of QCT emphysema and airway parameters to airflow limitation specifically in each GOLD stage. Methods: Non-contrast computed tomography (CT) of 492 patients with COPD former GOLD 0 COPD and COPD stages GOLD 1-4 were evaluated using fully automated software for quantitative CT. Total lung volume (TLV), emphysema index (EI), mean lung density (MLD), and airway wall thickness (WT), total diameter (TD), lumen area (LA), and wall percentage (WP) were calculated for the entire lung, as well as for all lung lobes separately. Results from the 3rd-8th airway generation were aggregated (WT3-8, TD3-8, LA3-8, WP3-8). All subjects underwent whole-body plethysmography (FEV1%pred, VC, RV, TLC). Results: EI was higher with increasing GOLD stages with 1.0 ± 1.8% in GOLD 0, 4.5 ± 9.9% in GOLD 1, 19.4 ± 15.8% in GOLD 2, 32.7 ± 13.4% in GOLD 3 and 41.4 ± 10.0% in GOLD 4 subjects (p < 0.001). WP3-8 showed no essential differences between GOLD 0 and GOLD 1, tended to be higher in GOLD 2 with 52.4 ± 7.2%, and was lower in GOLD 4 with 50.6 ± 5.9% (p = 0.010 - p = 0.960). In the upper lobes WP3-8 showed no significant differences between the GOLD stages (p = 0.824), while in the lower lobes the lowest WP3-8 was found in GOLD 0/1 with 49.9 ± 6.5%, while higher values were detected in GOLD 2 with 51.9 ± 6.4% and in GOLD 3/4 with 51.0 ± 6.0% (p < 0.05). In a multilinear regression analysis, the dependent variable FEV1%pred can be predicted by a combination of both the independent variables EI (p < 0.001) and WP3-8 (p < 0.001). Conclusion: QCT parameters showed a significant increase of emphysema from GOLD 0-4 COPD. Airway changes showed a different spatial pattern with higher values of relative wall thickness in the lower lobes until GOLD 2 and subsequent lower values in GOLD3/4, whereas there were no significant differences in the upper lobes. Both, EI and WP5-8 are independently correlated with lung function decline.

Thoracoscopic giant lung bullaectomy: our initial experience.

BACKGROUND: Giant lung bullae (GLB) are rare, and the only currently available management involves either an open surgical resection (thoracotomy) or the newer minimally invasive resection consisting of video-assisted thoracoscopic surgery (VATS). The aim of our study was to evaluate the possible influence of GLBs pulmonary attachment on patient's post-operative complications. METHODS: A retrospective analysis included all consecutive patients with GLBs who underwent bullae's surgical resection from 7/2007 to 12/2018. GLBs patient's individual characteristics, including demographics, comorbidities, and clinical pre-operative, surgical intra-operative and post-operative data were evaluated. RESULTS: 20 patients with GLBs, 15 males and 5 females with average age of 48.9 years (range, 22-67 years) underwent 21 surgical procedures. The GLBs were located in the right lung in 12 patients, in the left lung in seven patients, and in both lungs in one patient. Fifteen patients (75%) were symptomatic on admission and underwent urgent surgery. Five asymptomatic patients (25%) were operated on electively. Thirteen from 21 surgical procedures (61.9%) were VATS bullectomy, while the other eight were thoracotomies (38.1%). Complications included pneumonia successfully treated with intravenous antibacterial therapy in two thoracotomy patients and in one VATS patient (three patients, 14.2%) and a prolonged air leak in two thoracotomy and four VATS patients (six patients, 28.5%). Out of 21 GLBs, eight had a wide attachment with lung parenchyma (wide-based bullae's) and 13 had a short attachment (short-based bullae's). Two re-operated patients, with prolonged air leak complicated with empyema, had a wide-based GLBs. The median hospital stay was nine days. All patients completed the 24-month follow-up. CONCLUSIONS: Minimally invasive video-assisted thoracoscopic surgery as an open thoracotomy surgery is a safe and effective for giant lung bullae (GLB). Patients with wide-based GLBs were more likely to develop postoperative prolonged air leak that requiring re-operation.

Development and multimodal characterization of an elastase-induced emphysema mouse disease model for the COPD frequent bacterial exacerbator phenotype.

Chronic obstructive pulmonary disease (COPD) patients undergo infectious exacerbations whose frequency identifies a clinically meaningful phenotype. Mouse models have been mostly used to separately study both COPD and the infectious processes, but a reliable model of the COPD frequent exacerbator phenotype is still lacking. Accordingly, we first established a model of single bacterial exacerbation by nontypeable Haemophilus influenzae (NTHi) infection on mice with emphysema-like lesions. We characterized this single exacerbation model combining both noninvasive in vivo imaging and ex vivo techniques, obtaining longitudinal information about bacterial load and the extent of the developing lesions and host responses. Bacterial load disappeared 48 hours post-infection (hpi). However, lung recovery, measured using tests of pulmonary function and the disappearance of lung inflammation as revealed by micro-computed X-ray tomography, was delayed until 3 weeks post-infection (wpi). Then, to emulate the frequent exacerbator phenotype, we performed two recurrent episodes of NTHi infection on the emphysematous murine lung. Consistent with the amplified infectious insult, bacterial load reduction was now observed 96 hpi, and lung function recovery and disappearance of lesions on anatomical lung images did not happen until 12 wpi. Finally, as a proof of principle of the use of the model, we showed that azithromycin successfully cleared the recurrent infection, confirming this macrolide utility to ameliorate infectious exacerbation. In conclusion, we present a mouse model of recurrent bacterial infection of the emphysematous lung, aimed to facilitate investigating the COPD frequent exacerbator phenotype by providing complementary, dynamic information of both infectious and inflammatory processes.

An integrative analysis to distinguish between emphysema (EML) and alpha-1 antitrypsin deficiency-related emphysema (ADL)-A systems biology approach.

Lung Emphysema is an abnormal enlargement of the air sacs followed by the destruction of alveolar walls without any prominent fibrosis. This study primarily identifies the differentially expressed genes (DEGs), interactions between them, and their significant involvement in the activated signaling cascades. The dataset with ID GSE1122 (five normal lung tissue samples, five of usual emphysema, and five of alpha-1 antitrypsin deficiency-related emphysema) from the gene expression omnibus (GEO) was analyzed using the GEO2R tool. The physical association between the DEGs were mapped using the STRING tool and was visualized in the Cytoscape software. The enriched functional processes were identified with the ClueGO plugin's help from Cytoscape. Further integrative functional annotation was performed by implying the GeneGo Metacore™ to distinguish the enriched pathway maps, process networks, and GO processes. The results from this analysis revealed the critical signaling cascades that have been either activated or inhibited due to identified DEGs. We found the activated pathways such as immune response IL-1 signaling pathway, positive regulation of smooth muscle migration, BMP signaling pathway, positive regulation of leukocyte migration, NIK/NF-kappB signaling, and cytochrome-c oxidase activity. Finally, we mapped four crucial genes (CCL5, ALK, TAC1, CD74, and HLA-DOA) by comparing the functional annotations that could be significantly influential in emphysema molecular pathogenesis. Our study provides insights into the pathogenesis of emphysema and helps in developing potential drug targets against emphysema.

Lung volume reduction surgery: from National Emphysema Treatment Trial to non-intubated awake video-assisted thoracoscopic surgery.

Chronic obstructive pulmonary disease (COPD) is a major public health problem. Loss of elastic recoil, hyperinflation and obstruction of the expiratory airflow lead to an increased breathing work, which results in dyspnea during minimal physical activity of the patients. Reduction of the lung volume in these patients leads to improvement of dyspnea, physical activity and quality of life in these patients. Beside endoscopic lung volume reduction (ELVR), lung volume reduction surgery (LVRS) represents an important and valuable treatment option for patients with advanced lung emphysema. Since the National Emphysema Treatment Trial (NETT), thoracic surgery experienced a remarkable evolution of the surgical techniques enabling safe surgery and quick recovery in this critically ill patient cohort. A paradigm shift from open surgical approaches to most minimally invasive techniques accompanied by improvement of anesthesiologic management of these patients was evident. Moreover, indications for LVRS, which were originally described in the NETT, were extended to apply for further groups of patients with advanced lung emphysema, enabling significant clinical improvement in well-selected patients with a low perioperative morbidity and mortality. The current review will give an overview of the historical approaches for LVRS, highlight the indications for LVRS and discuss the development of the surgical approaches.

[The two major complications of tobacco in a single image!] / Les deux complications majeures du tabac en une seule image!

Smoking is the leading cause of preventable death worldwide, it is responsible for 90% of bronchopulmonary cancers and is the main cause of chronic bronchitis and emphysema, two disorders which contribute to chronic obstructive pulmonary disease (COPD). We here report the case of a 58-year old not weaned chronic tabagic patient with a 2-month history of diffuse abdominal pain evolving in a context of alteration of the general state. Clinical examination showed generally poor health. Pleuropulmonary examination objectified reduction of vesicular breath sounds in the right hemithorax and diffuse abdominal susceptibility and massive left subclavicular lymphadenopathy. Thoraco-abdominal CT scan showed pleural, intra-abdominal and retroperitoneal tissue infiltration and diffuse bilateral lung emphysema (Figure). Bronchial fibroscopy objectified bud obstructing the orifice of the apical bronchus of the right upper lobar bronchus. Anatomopathologic study of bronchial biopsy and lymph node biopsy showed non-differentiated carcinoma. Evolution was marked by patient's death after two weeks. This study aims to highlight fatal outcome due to these two complications due to tobacco use in the same patient in order to emphasize the importance of prevention awareness of the damages of tobacco use and on smoking cessation.