Respiratory Research最新文献

Background: The intricacies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing acute lung injury (ALI) and modulating inflammatory factor dynamics in vivo remain poorly elucidated. The present study endeavors to explore the impact of the recombinant SARS-CoV-2 spike protein S1 subunit (S1SP) on ALI and inflammatory factor profiles in mice, aiming to uncover potential therapeutic targets and intervention strategies for the prevention and management of Coronavirus Disease 2019 (COVID-19).

Methods: To mimic COVID-19 infection, K18-hACE2 transgenic mice were intratracheally instilled with S1SP, while C57BL/6 mice were administered LPS to form a positive control group. This setup facilitated the examination of lung injury severity, inflammatory factor levels, and alterations in signaling pathways in mice mimicking COVID-19 infection. Histopathological assessment through HE staining, along with analysis of lung wet/dry ratio and ultrasound imaging, revealed severe lung injury.

Results: After molding, K18-hACE2 mice exhibited a pronounced reduction in body weight and showed more significant lung injury (P < 0.05). Notably, there was a significant elevation in vascular permeability, total protein, and total white blood cells in bronchoalveolar lavage fluid (BALF) (P < 0.05), indicative of tissue damage. Additionally, the tight junction of lung tissue was compromised (P < 0.05), accompanied by intense oxidative stress marked by decreased SOD activity and elevated MDA content (P < 0.05). Cytokine levels, including IL-6, IL-1β, TNF-α, and MIG, were significantly upregulated in both BALF and serum of S1SP + K18 mice (P < 0.05). Furthermore, S1SP prominently augmented the expression of p-p65/P65 and attenuated IκBα expression in the NF-κB signaling pathway of humanized mice (P < 0.05), corroborating a heightened inflammatory response at the tissue level (P < 0.05).

Conclusion: The administration of S1SP to K18-hACE2 mice resulted in severe lung injury, enhanced vascular permeability, and compromised epithelial barrier function in vivo. This was accompanied by disruption of lung tight junctions, the manifestation of severe oxidative stress and a cytokine storm, as well as the activation of the NF-κB signaling pathway, highlighting key pathological processes underlying COVID-19-induced lung injury.

Background: Despite international guidelines for lung protective ventilation in neonatal or pediatric acute respiratory distress syndrome (nARDS/ pARDS), prospective data on bedside monitoring tools for regional ventilation distribution and lung mechanics are still rare. As a bedside and radiation-free procedure, electrical impedance tomography (EIT) offers a practical and safe approach for analyzing regional ventilation distributions. Recent trials in adults have shown the efficacy of an individualized EIT guided strategy for the improvement of ventilator induced lung injury (VILI).

Methods: We performed a single-center prospective feasibility study from November/2021 to December/2023 in the department of neonatal and pediatric intensive care medicine at the University Children´s Hospital in Bonn. All patients with diagnosis of nARDS (or history of perinatal lung disease-PLD)/ pARDS were screened for study inclusion. In all patients a decremental PEEP (positive end-expiratory pressure) trial was performed with a continuous EIT monitoring for an individual analysis of the EIT guided pixel compliance (C_EIT) and PEEP finding (EIT-PEEP). In the offline analysis, further EIT derived indices, such as global inhomogeneity index (GI), and center of ventilation (CoV), were calculated.

Results: Overall, 40 EIT measurements were performed in 26 neonatal and pediatric patients (nARDS/PLD, n = 6; and pARDS, n = 20) within a predefined decremental PEEP trial. Thirteen patients were classified as having severe nARDS (PLD)/ pARDS with an Oxygen Saturation Index (OSI) > 12 or Oxygenation Index (OI) > 16. In-hospital mortality rate was 27% in the overall cohort. The median EIT-PEEP (11mbar) was calculated as lowest, as compared to the clinically set PEEP (11.5mbar, p < 0.001), and the ARDSnetwork PEEP table recommendation (ARDSnet-PEEP, 14mbar, p = 0.018). In patients with nARDS/PLD, the EIT-PEEP was calculated 3mbar below the clinically set PEEP (p = 0.058) and 11 mbar below the ARDSnet-PEEP (p = 0.01). In the linear regression analysis, EIT-PEEP and the dynamic compliance (C_DYN) at -2mbar presented a significant correlation with a Cohen´s R² of 0.265 (β: 0.886, p = 0.005).

Conclusion: EIT is feasible and can be performed safely in patients with diagnosis of nARDS/PLD and pARDS, even during ongoing extracorporeal membrane oxygenation (ECMO) support. An individualized PEEP finding strategy according to the EIT compliance might optimize regional ventilation distribution in these patients and can potentially decrease VILI.

Clinical trial registration: The study was registered at the German Clinical Trials Register (GCT; trial number: DRKS 00034905, Registration Date 15.08.2024). The registration was performed retrospectively after inclusion of the last patient.

Background: Recruitment maneuvers are used to prevent atelectasis, or partial lung collapse, and to help prevent ventilator induced lung injury. Recruitment techniques remain a topic of debate due to the possibility for damage as they necessitate higher transpulmonary pressures, which are associated with inducing lung injury. We aim to evaluate and probe injury mechanisms and potential pressure inhomogeneities, expressed as heterogeneous lung recruitment and overdistension, by associating organ level compliances with continuous regional strains during the application of stepwise escalation contrasted with sustained inflation maneuvers.

Methods: An established breathing mimicry electromechanical system integrated with high spatio-temporal digital image correlation techniques coupled the global pressure-volume response of the lung with local deformations. Compliances, pressures, strains, heterogeneities and the expansion evolution pertaining to the inflation phase of two recruitment methods were quantified and contrasted.

Results: Significant differences between the organ- and tissue-level responses of the sustained inflation versus escalation maneuver were found. The escalation maneuver exhibited greater starting compliance, whereas the sustained inflation showed increased inflation compliance. The localized strain distribution for the sustained inflation yielded increased 75th percentile strain, 90th percentile strain, and range at maximum inflation compared to the escalation maneuver.

Conclusions: Local and global findings indicate the escalation maneuver exhibits more homogeneous lung recruitment compared to sustained inflation. We also observe a correspondence between the significant organ-level compliance differences between the two maneuvers and the disparities observed in the evolutionary progression of localized strain distributions throughout inflation.

Background: Human precision-cut lung slices (hPCLS) are a unique platform for functional, mechanistic, and drug discovery studies in the field of respiratory research. However, tissue availability, generation, and cultivation time represent important challenges for their usage. Therefore, the present study evaluated the efficacy of a specifically designed tissue preservation solution, TiProtec, complete or in absence (-) of iron chelators, for long-term cold storage of hPCLS.

Methods: hPCLS were generated from peritumor control tissues and stored in DMEM/F-12, TiProtec, or TiProtec (-) for up to 28 days. Viability, metabolic activity, and tissue structure were determined. Moreover, bulk-RNA sequencing was used to study transcriptional changes, regulated signaling pathways, and cellular composition after cold storage. Induction of cold storage-associated senescence was determined by transcriptomics and immunofluorescence (IF). Finally, cold-stored hPCLS were exposed to a fibrotic cocktail and early fibrotic changes were assessed by RT-qPCR and IF.

Results: Here, we found that TiProtec preserves the viability, metabolic activity, transcriptional profile, as well as cellular composition of hPCLS for up to 14 days. Cold storage did not significantly induce cellular senescence in hPCLS. Moreover, TiProtec downregulated pathways associated with cell death, inflammation, and hypoxia while activating pathways protective against oxidative stress. Cold-stored hPCLS remained responsive to fibrotic stimuli and upregulated extracellular matrix-related genes such as fibronectin and collagen 1 as well as alpha-smooth muscle actin, a marker for myofibroblasts.

Conclusions: Optimized long-term cold storage of hPCLS preserves their viability, metabolic activity, transcriptional profile, and cellular composition for up to 14 days, specifically in TiProtec. Finally, our study demonstrated that cold-stored hPCLS can be used for on-demand mechanistic studies relevant for respiratory research.

Background: To develop effective strategies for controlling asthma, a thorough assessment of its disease burden is essential. In this study, we examined long-term trends in the asthma burden in China over the past three decades and analyzed its epidemiological features.

Methods: We assessed the burden of asthma in China via the global burden of disease (GBD) 2021 database, focusing on prevalence, incidence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life years (DALYs). Additionally, we employed joinpoint analysis and age-period-cohort (apc) methods to interpret the epidemiological characteristics of asthma. Finally, we analyzed the attributable burden of asthma to gain a comprehensive understanding of its impact.

Results: The age-standardized incidence rate (ASIR) and mortality rate (ASMR) for both sexes in China shifted from 524.81 (95% UI: 421.31, 672.76) to 314.17 (95% UI: 283.22, 494.10) and from 5.82 (95% UI: 4.46, 8.50) to 1.47 (95% UI: 1.15, 1.79) per 100,000 population between 1990 and 2021. According to joinpoint analysis, the average annual percentage change (AAPC) in the age-standardized incidence rate was - 1.2 (95% CI: - 1.4, - 1.1), indicating a gradual but fluctuating decline (with significant turning points in 2005 and 2014). The apc fitting results suggest that the prevalence is now lower than it was in the past and that the relative prevalence risk is high among adolescents and middle-aged to elderly individuals, possibly due to different pathophysiological mechanisms. In 2021, the primary asthma-related burdens were metabolic risks, especially obesity.

Conclusions: In conclusion, we found that the disease burden of asthma in China has significantly decreased. However, it remains a major concern among adolescents and elderly individuals. Metabolic risk factors, particularly obesity, are the main contributors to the asthma burden. It is essential to address specific risk factors and develop targeted public health strategies for different age groups.

Background: Bronchopleural fistulas (BPFs) are severe medical condition with high mortality. When the conventional surgical therapy failed, endobronchial intervention could function as the supplementary option. Several studies reported successful endobronchial managements of BPFs whereas the optimal strategies remain elusive.

Methods: We retrospectively reviewed the medical records of patients with BPFs underwent endobronchial interventions with Vaseline gauze, shape-adjustable silicone plug, sutured silicone tube or covered metallic stent in our institution.

Results: From 2018 to 2024, a total of 30 patients (11 females VS. 19 males; mean age 48.03 ± 20.33 years) with primary etiology of tumor (n = 19), empyema (n = 6), gastro-bronchial fistula (n = 1), lung infection with immune suppressed status (n = 1) and spontaneous pneumothorax (n = 3) were treated. Different occlusive materials were placed including covered metallic stent (n = 6), shape-adjustable silicone plug (n = 4), sutured silicone tube (n = 1) and Vaseline gauze(s) (n = 21). The dislocation of devices occurred in two patients with covered metallic stent occlusion. On the first day post procedure, 17 patients (56.7%) had complete resolution of the fistulas, compared with 13 patients (43.3%) had incomplete resolution. At the end of the first week post procedure, 19 patients (63.3%) showed complete resolution and 10 patients (33.3%) with partial resolution, whereas one patient (3.3%) failed to have effective closure of the fistula. The representative computer tomography images showed the closure of fistulas and ameliorated hydropneumothorax.

Conclusion: Four endobronchial interventional maneuvers, the Vaseline gauze, shape-adjustable silicone plug, sutured silicone tube and covered metallic stent, showed both safe and effective managements for patients with BPFs.

Background: Acute respiratory distress syndrome (ARDS) remains a life-threatening pulmonary condition with persistently high mortality rates despite significant advancements in supportive care. Its complex pathophysiology involves an intricate interplay of molecular and cellular processes, including cytokine storms, oxidative stress, programmed cell death, and disruption of the alveolar-capillary barrier. These mechanisms drive localized lung injury and contribute to systemic inflammatory response syndrome and multiple organ dysfunction syndrome. Unlike prior reviews that primarily focus on isolated mechanisms, this narrative review synthesizes the key pathophysiological processes of ARDS across molecular, cellular, tissue, and organ levels.

Main body: By integrating classical theories with recent research advancements, we provide a comprehensive analysis of how inflammatory mediators, metabolic reprogramming, oxidative stress, and immune dysregulation synergistically drive ARDS onset and progression. Furthermore, we critically evaluate current evidence-based therapeutic strategies, such as lung-protective ventilation and prone positioning, while exploring innovative therapies, including stem cell therapy, gene therapy, and immunotherapy. We emphasize the significance of ARDS subtypes and their inherent heterogeneity in guiding the development of personalized treatment strategies.

Conclusions: This narrative review provides fresh perspectives for future research, ultimately enhancing patient outcomes and optimizing management approaches in ARDS.

Background: Despite its heterogeneity, there is currently limited data in pleural infection phenotyping. Using pleural fluid characteristics, pleural infection can be classified into microbiological-positive pleural infection (MPPI) and microbiological-negative pleural infection (MNPI). This study aimed to evaluate the prognostic significance of microbiological positivity in pleural infection, and to evaluate the performance of RAPID (renal, age, purulence, infection source, dietary factor) score in these subgroups.

Methods: Consecutive patients hospitalized for pleural infection over a 10-year period in two acute-care hospitals in Hong Kong were evaluated. According to the pleural fluid characteristics, they were classified into MPPI and MNPI, respectively. Survival was evaluated using multivariate Cox regression analysis. Performance of RAPID score to predict mortality at 3-month and 1-year was evaluated using C-statistics.

Results: In total, 381 patients with pleural infection were included. They were classified into MPPI (n = 169) and MNPI (n = 212), respectively. The MPPI group had more elderly home residence and use of large-bore chest tube, and higher Charlson comorbidity index and RAPID score, compared to the MNPI group. Length-of-stay, the need of surgery and intensive care were similar between the two groups. MPPI was associated with significantly increased risk of mortality (adjusted hazard ratio [aHR] 1.46, 95% CI 1.08-1.98). Three-month mortality was significantly higher in MPPI compared to MNPI (24.9% vs. 10.4%, p < 0.001; adjusted odd ratio 2.05, 95% CI 1.11-3.80). The trend continued at 1, 3, 5 and 7 years. RAPID score predicted 3-month and 1-year mortality in both groups (C-statistics, MPPI 0.71, 0.75; MNPI 0.84, 0.81). In the MPPI group, presence of Staphylococcus aureus (aHR 2.26, 95% CI 1.43-3.57) and Gram-negative organisms other than Enterobacteriaceae (aHR 2.00, 95% CI 1.10-3.61) were associated with worse survival, while presence of Streptococcus anginosus group was associated better survival (aHR 0.50, 95% CI 0.32-0.78), when compared to their absence.

Conclusions: Pleural fluid microbiological positivity is independently associated with increased mortality in patients with pleural infections. This finding should complement the RAPID score in risk stratification and inform future research aimed at improving outcomes in this patient population.

Background: Tuberculous pleural effusion (TPE) is a challenging extrapulmonary manifestation of tuberculosis, with traditional diagnostic methods often involving invasive surgery and being time-consuming. While various machine learning and statistical models have been proposed for TPE diagnosis, these methods are typically limited by complexities in data processing and difficulties in feature integration. Therefore, this study aims to develop a diagnostic model for TPE using ChatGPT-4, a large language model (LLM), and compare its performance with traditional logistic regression and machine learning models. By highlighting the advantages of LLMs in handling complex clinical data, identifying interrelationships between features, and improving diagnostic accuracy, this study seeks to provide a more efficient and precise solution for the early diagnosis of TPE.

Methods: We conducted a cross-sectional study, collecting clinical data from 109 TPE and 54 non-TPE patients for analysis, selecting 73 features from over 600 initial variables. The performance of the LLM was compared with logistic regression and machine learning models (k-Nearest Neighbors, Random Forest, Support Vector Machines) using metrics like area under the curve (AUC), F1 score, sensitivity, and specificity.

Results: The LLM showed comparable performance to machine learning models, outperforming logistic regression in sensitivity, specificity, and overall diagnostic accuracy. Key features such as adenosine deaminase (ADA) levels and monocyte percentage were effectively integrated into the model. We also developed a Python package ( https://pypi.org/project/tpeai/ ) for rapid TPE diagnosis based on clinical data.

Conclusions: The LLM-based model offers a non-surgical, accurate, and cost-effective method for early TPE diagnosis. The Python package provides a user-friendly tool for clinicians, with potential for broader use. Further validation in larger datasets is needed to optimize the model for clinical application.

Myofibroblasts accumulation contributes to airway remodeling, with the mechanisms being poorly understood. It is steroid-insensitive and has not been therapeutically targeted in asthma. In this study, we explored the potential of yes-associated protein (YAP) as a therapeutic target for myofibroblasts formation in asthma, by revealing the novel role and mechanisms by which YAP activation in type II alveolar epithelial (ATII) cells promotes the fibroblast-to-myofibroblast transition in vitro and in vivo. By performing immunofluorescence staining, we showed that myofibroblasts were increased in the bronchial walls and alveolar parenchyma in clinical asthmatic and house dust mite (HDM)-induced mouse lung samples. This was accompanied by YAP overexpression and nuclear translocation in ATII cells, and connective tissue growth factor (CTGF) upregulation. In vitro, HDM or combination of rhIL-1β with rhTNF-α upregulated and activated YAP in human primary ATII cells and A549 cells, but not in the bronchial epithelial cells, BEAS-2B. This effect was mediated by F-actin polymerization and could be suppressed by pretreatment with latrunculin A but not budesonide. Inhibition of YAP/transcriptional coactivator with PDZ-binding motif (TAZ) in A549 cells by pretreatment with YAP/TAZ siRNA or verteporfin, but not budesonide, impaired the fibroblast-to-myofibroblast transition in vitro. In vivo, verteporfin partly or completely prevented HDM-induced bronchial or alveolar myofibroblast accumulation, and significantly suppressed CTGF expression and collagen deposition in mouse lungs, without profoundly affecting airway inflammation. Our results provide novel mechanistic insights into airway remodeling, and holds promise for the development of novel therapeutic strategies.