Downregulation of Mirlet7 miRNA family promotes Tc17 differentiation and emphysema via de-repression of RORγt.

Environmental air irritants including nanosized carbon black (nCB) can drive systemic inflammation, promoting chronic obstructive pulmonary disease (COPD) and emphysema development. The let-7 microRNA (Mirlet7 miRNA) family is associated with IL-17-driven T cell inflammation, a canonical signature of lung inflammation. Recent evidence suggests the Mirlet7 family is downregulated in patients with COPD, however, whether this repression conveys a functional consequence on emphysema pathology has not been elucidated. Here, we show that overall expression of the Mirlet7 clusters, Mirlet7b/Mirlet7c2 and Mirlet7a1/Mirlet7f1/Mirlet7d, are reduced in the lungs and T cells of smokers with emphysema as well as in mice with cigarette smoke (CS)- or nCB-elicited emphysema. We demonstrate that loss of the Mirlet7b/Mirlet7c2 cluster in T cells predisposed mice to exaggerated CS- or nCB-elicited emphysema. Furthermore, ablation of the Mirlet7b/Mirlet7c2 cluster enhanced CD8+IL17a+ T cells (Tc17) formation in emphysema development in mice. Additionally, transgenic mice overexpressing Mirlet7g in T cells are resistant to Tc17 and CD4+IL17a+ T cells (Th17) development when exposed to nCB. Mechanistically, our findings reveal the master regulator of Tc17/Th17 differentiation, RAR-related orphan receptor gamma t (RORγt), as a direct target of Mirlet7 in T cells. Overall, our findings shed light on the Mirlet7/RORγt axis with Mirlet7 acting as a molecular brake in the generation of Tc17 cells and suggest a novel therapeutic approach for tempering the augmented IL-17-mediated response in emphysema.

Endobronchial valves for emphysema and persistent air-leak: 10-year experience in an Asian country.

BACKGROUND: Endobronchial valve (EBV) therapy, a validated method for bronchoscopic lung volume reduction (BLVR) in severe emphysema, has been explored for persistent air-leak (PAL) management. However, its effectiveness and safety in the Asian population require further real-world evaluation. In this study, we assessed the outcomes of treatment with EBV within this demographic. METHODS: We conducted a retrospective analysis of medical records from 11 Korean centers. For the emphysema cohort, inclusion criteria were patients diagnosed with emphysema who underwent bronchoscopy intended for BLVR. We assessed these patients for clinical outcomes of chronic obstructive pulmonary disease. All patients with PAL who underwent treatment with EBV were included. We identified the underlying causes of PAL and evaluated clinical outcomes after the procedure. RESULTS: The severe emphysema cohort comprised 192 patients with an average age of 70.3 years, and 95.8% of them were men. Ultimately, 137 underwent treatment with EBV. Three months after the procedure, the BLVR group demonstrated a significant improvement in forced expiratory volume in 1 s (+160 mL vs. +30 mL; P = 0.009). Radiographic evidence of lung volume reduction 6 months after BLVR was significantly associated with improved survival (adjusted hazard ratio 0.020; 95% confidence interval 0.038-0.650; P = 0.010). Although pneumothorax was more common in the BLVR group (18.9% vs. 3.8%; P = 0.018), death was higher in the no-BLVR group (38.5% vs. 54.5%, P = 0.001), whereas other adverse events were comparable between the groups. Within the subset of 18 patients with PAL, the predominant causes of air-leak included spontaneous secondary pneumothorax (44.0%), parapneumonic effusion/empyema (22.2%), and post-lung resection surgery (16.7%). Following the treatment, the majority (77.8%) successfully had their chest tubes removed. Post-procedural complications were minimal, with two incidences of hemoptysis and one of empyema, all of which were effectively managed. CONCLUSIONS: Treatment with EBV provides substantial clinical benefits in the management of emphysema and PAL in the Asian population, suggesting a favorable outcome for this therapeutic approach.

[Effect of SHP-1 knockout in airway epithelial cells on emphysema phenotype in chronic obstructive pulmonary disease in mice].

Objective: To construct and characterize conditional Src homology region 2 protein tyrosine phosphatase 1 (SHP-1) knockout mice in airway epithelial cells and to observe the effect of defective SHP-1 expression in airway epithelial cells on the emphysema phenotype in chronic obstructive pulmonary disease (COPD). Methods: To detect the expression of SHP-1 in the airway epithelium of COPD patients. CRISPR/Cas9 technology was used to construct SHP-1flox/flox transgenic mice, which were mated with airway epithelial Clara protein 10-cyclase recombinase and estrogen receptor fusion transgenic mice (CC10-CreER+/+), and after intraperitoneal injection of tamoxifen, airway epithelial SHP-1 knockout mice were obtained (SHP-1flox/floxCC10-CreER+/-, SHP-1Δ/Δ). Mouse tail and lung tissue DNA was extracted and PCR amplified to discriminate the genotype of the mice; the knockout effect of SHP-1 gene in airway epithelial cells was verified by qRT-PCR, Western blotting, and immunofluorescence. In addition, an emphysema mouse model was constructed using elastase to assess the severity of emphysema in each group of mice. Results: Airway epithelial SHP-1 was significantly downregulated in COPD patients. Genotyping confirmed that SHP-1Δ/Δ mice expressed CC10-CreER and SHP-1-flox. After tamoxifen induction, we demonstrated the absence of SHP-1 protein expression in airway epithelial cells of SHP-1Δ/Δ mice at the DNA, RNA, and protein levels, indicating that airway epithelial cell-specific SHP-1 knockout mice had been successfully constructed. In the emphysema animal model, SHP-1Δ/Δ mice had a more severe emphysema phenotype compared with the control group, which was manifested by disorganization of alveolar structure in lung tissue and rupture and fusion of alveolar walls to form pulmonary alveoli. Conclusions: The present study successfully established and characterized the SHP-1 knockout mouse model of airway epithelial cells, which provides a new experimental tool for the in-depth elucidation of the role of SHP-1 in the emphysema process of COPD and its mechanism.

Comparative analysis of antibodies to four major periodontal bacteria in respiratory diseases: a cohort study.

OBJECTIVES: To make a descriptive comparison of antibodies to four major periodontal bacteria and their relation to the respiratory diseases asthma and bronchitis/emphysema, and to cancer incidence. METHODS: The serum of a random sample of men with no history of cancer incidence (n=621) was analysed by the ELISA method for antibody levels of four periodontal bacteria; the anaerobes of the so-called red complex Tannerella forsythia (TF), Porphyromonas gingivalis (PG), and Treponema denticola (TD), and the facultative anaerobe Aggregatibacter actinomycetemcomitans (AA). The antibody readings were divided into quartiles and the distribution of cases of the relevant diseases as compared with the non-cases. Comparisons of the quartile distributions were by the Pearson χ2 test. Data and serum from the Oslo II study of Norwegian men from 2000 were used. The ELISA analyses were performed on thawed frozen serum. Cancer data from 17.5 years of follow-up were provided by the Norwegian Cancer Registry. RESULTS: In all, 52 men had reported asthma and 23 men had bronchitis/emphysema at the health screening. Results on cancer incidence are given for all respiratory cancers, n=23, and bronchi and lung cancers separately, n=18. Stratified analyses were performed for the four endpoints showing significant association with low levels of TD antibodies for bronchitis; p=0.035. Both TF and TD were significant for low levels of antibodies among daily smokers; p=0.030 for TF and p<0.001 for TD in the analysis of the full study sample. For PG and AA, no such associations were observed. An association with respiratory cancers was not observed. CONCLUSION: A low level of TD was associated with bronchitis/emphysema compared with the rest of the cohort. In the total study sample, low levels of antibodies to both TF and TD were associated with daily smoking.

Early-life house dust mite aeroallergen exposure augments cigarette smoke-induced myeloid inflammation and emphysema in mice.

BACKGROUND: Longitudinal studies have identified childhood asthma as a risk factor for obstructive pulmonary disease (COPD) and asthma-COPD overlap (ACO) where persistent airflow limitation can develop more aggressively. However, a causal link between childhood asthma and COPD/ACO remains to be established. Our study aimed to model the natural history of childhood asthma and COPD and to investigate the cellular/molecular mechanisms that drive disease progression. METHODS: Allergic airways disease was established in three-week-old young C57BL/6 mice using house dust mite (HDM) extract. Mice were subsequently exposed to cigarette smoke (CS) and HDM for 8 weeks. Airspace enlargement (emphysema) was measured by the mean linear intercept method. Flow cytometry was utilised to phenotype lung immune cells. Bulk RNA-sequencing was performed on lung tissue. Volatile organic compounds (VOCs) in bronchoalveolar lavage-fluid were analysed to screen for disease-specific biomarkers. RESULTS: Chronic CS exposure induced emphysema that was significantly augmented by HDM challenge. Increased emphysematous changes were associated with more abundant immune cell lung infiltration consisting of neutrophils, interstitial macrophages, eosinophils and lymphocytes. Transcriptomic analyses identified a gene signature where disease-specific changes induced by HDM or CS alone were conserved in the HDM-CS group, and further revealed an enrichment of Mmp12, Il33 and Il13, and gene expression consistent with greater expansion of alternatively activated macrophages. VOC analysis also identified four compounds increased by CS exposure that were paradoxically reduced in the HDM-CS group. CONCLUSIONS: Early-life allergic airways disease worsened emphysematous lung pathology in CS-exposed mice and markedly alters the lung transcriptome.

Body composition impacts outcome of bronchoscopic lung volume reduction in patients with severe emphysema: a fully automated CT-based analysis.

Chronic Obstructive Pulmonary Disease (COPD) is characterized by progressive and irreversible airflow limitation, with individual body composition influencing disease severity. Severe emphysema worsens symptoms through hyperinflation, which can be relieved by bronchoscopic lung volume reduction (BLVR). To investigate how body composition, assessed through CT scans, impacts outcomes in emphysema patients undergoing BLVR. Fully automated CT-based body composition analysis (BCA) was performed in patients with end-stage emphysema receiving BLVR with valves. Post-interventional muscle and adipose tissues were quantified, body size-adjusted, and compared to baseline parameters. Between January 2015 and December 2022, 300 patients with severe emphysema underwent endobronchial valve treatment. Significant improvements were seen in outcome parameters, which were defined as changes in pulmonary function, physical performance, and quality of life (QoL) post-treatment. Muscle volume remained stable (1.632 vs. 1.635 for muscle bone adjusted ratio (BAR) at baseline and after 6 months respectively), while bone adjusted adipose tissue volumes, especially total and pericardial adipose tissue, showed significant increase (2.86 vs. 3.00 and 0.16 vs. 0.17, respectively). Moderate to strong correlations between bone adjusted muscle volume and weaker correlations between adipose tissue volumes and outcome parameters (pulmonary function, QoL and physical performance) were observed. Particularly after 6-month, bone adjusted muscle volume changes positively corresponded to improved outcomes (ΔForced expiratory volume in 1 s [FEV1], r = 0.440; ΔInspiratory vital capacity [IVC], r = 0.397; Δ6Minute walking distance [6MWD], r = 0.509 and ΔCOPD assessment test [CAT], r = -0.324; all p < 0.001). Group stratification by bone adjusted muscle volume changes revealed that groups with substantial muscle gain experienced a greater clinical benefit in pulmonary function improvements, QoL and physical performance (ΔFEV1%, 5.5 vs. 39.5; ΔIVC%, 4.3 vs. 28.4; Δ6MWDm, 14 vs. 110; ΔCATpts, -2 vs. -3.5 for groups with ΔMuscle, BAR% < -10 vs. > 10, respectively). BCA results among patients divided by the minimal clinically important difference for forced expiratory volume of the first second (FEV1) showed significant differences in bone-adjusted muscle and intramuscular adipose tissue (IMAT) volumes and their respective changes after 6 months (ΔMuscle, BAR% -5 vs. 3.4 and ΔIMAT, BAR% -0.62 vs. 0.60 for groups with ΔFEV1 ≤ 100 mL vs > 100 mL). Altered body composition, especially increased muscle volume, is associated with functional improvements in BLVR-treated patients.

Mechanism of circRNA_SMG6 mediating lung macrophage ECM degradation via miR-570-3p in microplastics-induced emphysema.

Microplastics (MPs) are plastic particles < 5 mm in diameter, of which polystyrene microplastics (PS-MPs) are representative type. The extracellular matrix (ECM) degradation of macrophages is associated with the development of emphysema. Additionally, circular RNAs (circRNAs) have a regulatory role in epigenetic mechanisms related to lung disease. However, the mechanisms of the ECM degradation and circRNAs in MPs-induced emphysema are still unclear. In our study, Sprague-Dawley (SD) rats were treated with 0, 0.5, 1.0 and 2.0 mg/m3 100 nm PS-MPs for 90 days in an inhalation experiment. PS-MPs-exposed rats showed elevated airway resistance and pulmonary dysfunction. Lung histopathology exhibited inflammatory cell infiltration, septal thickening and alveolar dilatation. Exposure to PS-MPs was able to induce elevated levels of ECM degradation-related markers MMP9 and MMP12, as well as reduced levels of elastin in rat lung tissues. CircRNA_SMG6 is a non-coding RNA (ncRNA) with a homologous circular structure in human, rat and mouse. The expression level of circRNA_SMG6 was decreased in both rat lung tissues exposed to PS-MPs and PS-MPs-treated THP-1 cells. The luciferase reporter gene demonstrated that circRNA_SMG6 combined with miR-570-3p and co-regulated PTEN, the target gene of miR-570-3p. Moreover, overexpression of circRNA_SMG6 or inhibition of miR-570-3p attenuated PS-MPs-induced ECM degradation in THP-1 cells. Taken together, circRNA_SMG6 may have a significant function in the deterioration of emphysema caused by PS-MPs-induced macrophage ECM degradation by regulating miR-570-3p. Our findings reveal a novel mechanism of emphysema caused by PS-MPs and provide valuable information for assessing the health risks of MPs.

Protective effect of liver X receptor on cigarette smoke and lipopolysaccharide induced airway inflammation and emphysema in mice.

OBJECTIVE: The aim of this study is to assess the impact of Liver X receptors (LXRs) on airway inflammation, airway remodeling, and lipid deposition induced by cigarette smoke and lipopolysaccharide (LPS) exposure in the lung. METHODS: Wild mice and LXR-deficient mice were exposed to cigarette smoke and LPS to induce airway inflammation and remodeling. In addition, some wild mice received intraperitoneal treatment with the LXR agonist GW3965 before exposure to cigarette smoke and LPS. Lung tissue and bronchoalveolar lavage fluid were collected to evaluate airway inflammation, airway remodeling and lipid deposition. RESULTS: Exposure to cigarette smoke and LPS resulted in airway inflammation, emphysema and lipid accumulation in wild mice. These mice also exhibited downregulated LXRα and ABCA1 in the lung. Treatment with GW3965 mitigated inflammation, remodeling and lipid deposition, while the deletion of LXRs exacerbated these effects. Furthermore, GW3965 treatment following exposure to cigarette smoke and LPS increased LXRα and ABCA1 expression and attenuated MyD88 expression in wild mice. CONCLUSION: LXRs demonstrate the potential to mitigate cigarette smoke and LPS- induced airway inflammation, emphysema and lipid disposition in mice.

[Pulmonary lipofibroblasts in adults and alveolar regeneration in emphysema]. / Lipofibroblastes pulmonaires chez l'adulte et régénération alvéolaire au cours de l'emphysème.

Lipofibroblasts form a sub-population of fibroblasts located in the mesenchymal alveolar stem cell niche. They show close proximity with alveolar epithelial type 2 cells and play a key role in alveolar development and lung homeostasis. Their role in various diseases such as acute respiratory distress syndrome, pulmonary fibrosis and emphysema is progressively better understood. Through the activation of signaling pathways such as PPARg lipofibroblasts may help to induce endogenous alveolar regeneration.

Relationship of computed tomography-based measurements with symptom perception and quality of life in patients with severe asthma.

BACKGROUND: Symptom perception and quality of life (QOL) are important domains for properly managing severe asthma. This study aimed to assess the relationship between airway structural and parenchymal variables measured using chest computed tomography (CT) and subjective symptom perception and QOL in patients with severe asthma enrolled in the Korean Severe Asthma Registry. METHODS: This study used CT-based objective measurements, including airway wall thickness (WT), hydraulic diameter, functional small airway disease (fSAD), and emphysematous lung (Emph), to assess their association with subjective symptom (cough, dyspnea, wheezing, and sputum) perception measured using the visual analog scale, and QOL measured by the Severe Asthma Questionnaire (SAQ). RESULTS: A total of 94 patients with severe asthma were enrolled in this study. The WT and fSAD% were significantly positively associated with cough and dyspnea, respectively. For QOL, WT and Emph% showed significant negative associations with the SAQ. However, there was no significant association between lung function and symptom perception or between lung function and QOL. CONCLUSION: Overall, WT, fSAD%, and Emph% measured using chest CT were associated with subjective symptom perception and QOL in patients with severe asthma. This study provides a basis for clarifying the clinical correlates of imaging-derived metrics and for understanding the mechanisms of respiratory symptom perception.

Emphysematous Pancreatitis as a Life-Threatening Condition: A Case Report and Review of the Literature.

Emphysematous pancreatitis represents the presence of gas within or around the pancreas on the ground of necrotizing pancreatitis due to superinfection with gas-forming bacteria. This entity is diagnosed on clinical grounds and on the basis of radiologic findings. Computed tomography is the preferred imaging modality used to detect this life-threating condition. The management of emphysematous pancreatitis consists of conservative measures, image-guided percutaneous catheter drainage or endoscopic therapy, and surgical intervention, which is delayed as long as possible and undertaken only in patients who continue to deteriorate despite conservative management. Due to its high mortality rate, early and prompt recognition and treatment of emphysematous pancreatitis are crucial and require individualized treatment with the involvement of a multidisciplinary team. Here, we present a case of emphysematous pancreatitis as an unusual occurrence and discuss disease features and treatment options in order to facilitate diagnostics and therapy.

Ampliación de variables de la eficacia del entrenamiento del diafragma en pacientes con EPOC. Revisión sistemática / Expansion of variables of the effectiveness of diaphragm training in patients with COPD. Systematic review

Antecedentes: La enfermedad pulmonar obstructiva crónica (EPOC) produce una obstrucción al flujo de aire de los pulmones que genera tos, mucosidad y dificultad respiratoria. Presenta una alta morbimortalidad y tiene una prevalencia del 10,3% en todo el mundo. Recientemente se ha sugerido el uso del entrenamiento diafragmático en estos pacientes. Objetivo: El objetivo fue examinar la evidencia disponible sobre la eficacia del entrenamiento del diafragma sobre el FEV1, la prueba de la marcha de 6 minutos, la saturación de oxígeno, el tiempo inspiratorio, el tiempo espiratorio y la escala de supervivencia de la EPOC (BODE). Material y métodos: Se realizó una revisión sistemática siguiendo la declaración PRISMA. Resultados: Los resultados mostraron que el entrenamiento del diafragma es efectivo en pacientes con EPOC para mejorar el FEV1. Conclusiones: La prueba de la marcha de 6 minutos y la saturación de oxígeno; sin embargo, no es efectivo para las variables tiempo inspiratorio, tiempo espiratorio y escala de supervivencia de la EPOC (BODE). (AU)

Background: Chronic obstructive pulmonary disease (COPD) causes an obstruction to the airflow of the lungs, causing coughing, mucus, and difficulty breathing. It has a high morbidity and mortality with a prevalence of 10.3% worldwide. The use of diaphragmatic training in these patients has recently been suggested. Objective: The objective was to examine the available evidence on the effectiveness of diaphragm training on FEV1, 6-minute walk test, oxygen saturation, inspiratory time, expiratory time and COPD survival scale (BODE). Material and methods: A systematic review was carried out following the PRISMA regulations. Results: The results showed that diaphragm training is effective in patients with chronic obstructive pulmonary disease to improve FEV1. Conclusion: 6-minute walk test and oxygen saturation; however, it is not effective for the variables inspiratory time, expiratory time and the COPD survival scale (BODE). (AU)

Respiratory Oscillometry and Functional Performance in Different COPD Phenotypes.

Purpose: Chronic obstructive pulmonary disease (COPD) phenotypes may introduce different characteristics that need to be known to improve treatment. Respiratory oscillometry provides a detailed analysis and may offer insight into the pathophysiology of COPD. In this paper, we used this method to evaluate the differences in respiratory mechanics of COPD phenotypes. Patients and Methods: This study investigated a sample of 83 volunteers, being divided into control group (CG = 20), emphysema (n = 23), CB (n = 20) and asthma-COPD overlap syndrome (ACOS, n = 20). These analyses were performed before and after bronchodilator (BD) use. Functional capacity was evaluated using the Glittre­ADL test, handgrip strength and respiratory pressures. Results: Initially it was observed that oscillometry provided a detailed description of the COPD phenotypes, which was consistent with the involved pathophysiology. A correlation between oscillometry and functional capacity was observed (r=-0.541; p = 0.0001), particularly in the emphysema phenotype (r = -0.496, p = 0.031). BD response was different among the studied phenotypes. This resulted in an accurate discrimination of ACOS from CB [area under the receiver operating curve (AUC) = 0.84] and emphysema (AUC = 0.82). Conclusion: These results offer evidence that oscillatory indices may enhance the comprehension and identification of COPD phenotypes, thereby potentially improving the support provided to these patients.

Clinicopathological factors associated with sentinel lymph node detection in non-small-cell lung cancer.

BACKGROUND: Mapping of the pulmonary lymphatic system by near-infrared (NIR) fluorescence imaging might not always identify the first lymph node relay. The aim of this study was to determine the clinicopathologic factors allowing the identification of sentinel lymph nodes (SLNs) by NIR fluorescence imaging in thoracic surgery for non-small-cell lung cancer (NSCLC). METHODS: We conducted a retrospective review of 92 patients treated for suspected or confirmed cN0 lung cancer with curative intent who underwent an intraoperative injection of indocyanine green (ICG) either by direct peritumoral injection or by endobronchial injection using electromagnetic navigational bronchoscopy (ENB). After exclusion of patients for technical failure, benign disease and metastasis, we analyzed the clinicopathologic findings of 65 patients treated for localized-stage NSCLC, comparing the group with identification of SLNs (SLN-positive group) with the group without identification of SLNs (SLN-negative group). RESULTS: Forty-eight patients (73.8%) were SLN-positive. Patients with SLN positivity were more frequently female (50%) than the SLN-negative patients were (11.8%) (p = 0.006). The mean value of diffusing capacity for carbon monoxide (DLCO) was lower among the patients in the SLN-negative group (64.7% ± 16.7%) than the SLN-positive group (77.6% ± 17.2%, p < 0.01). The ratio of forced expiratory volume in one second to forced vital capacity (FEV1/FCV) was higher in the SLN-positive group (69.0% vs. 60.8%, p = 0.02). Patients who were SLN-negative were characterized by a severe degree of emphysema (p = 0.003). There was no significant difference in pathologic characteristics. On univariate analyses, age, female sex, DLCO, FEV1/FVC, degree of emphysema, and tumor size were significantly associated with SLN detection. On multivariate analysis, DLCO > 75% (HR = 4.92, 95% CI: 1.27-24.7; p = 0.03) and female sex (HR = 5.55, 95% CI: 1.25-39.33; p = 0.04) were independently associated with SLN detection. CONCLUSIONS: At a time of resurgence in the use of the sentinel lymph node mapping technique in the field of thoracic surgery, this study enabled us to identify, using multivariate analysis, two predictive factors for success: DLCO > 75% and female sex. Larger datasets are needed to confirm our results.