Respiratory Research最新文献

Background: Subject-ventilator asynchrony (SVA) was shown to be associated with negative clinical outcomes. To elucidate pathophysiology pathways and effects of SVA on lung tissue histology a reproducible animal model of artificially induced asynchrony was developed and evaluated.

Methods: Alterations in ventilator parameters were used to induce the three main types of asynchrony: ineffective efforts (IE), auto-triggering (AT), and double-triggering (DT). Airway flow and pressure, as well as oesophageal pressure waveforms, were recorded, asynchrony cycles were manually classified and the asynchrony index (AIX) was calculated. Bench tests were conducted on an active lung simulator with ventilator settings altered cycle by cycle. The developed algorithm was evaluated in three pilot experiments and a study in pigs ventilated for twelve hours with AIX = 25%.

Results: IE and AT were induced reliably and fail-safe by end-expiratory hold and adjustment of respiratory rate, respectively. DT was provoked using airway pressure ramp prolongation, however not controlled specifically in the pilots. In the subsequent study, an AIX = 28.8% [24.0%-34.4%] was induced and maintained over twelve hours.

Conclusions: The method allows to reproducibly induce and maintain three clinically relevant types of SVA observed in ventilated patients and may thus serve as a useful tool for future investigations on cellular and inflammatory effects of asynchrony.

Introduction: Pyroptosis, inflammatory necrosis of cells, is a programmed cell death involved in the pathological process of diseases. Endoplasmic reticulum stress (ERS), as a protective stress response of cell, decreases the unfold protein concentration to inhibit the unfold protein agglutination. Whereas the relationship between endoplasmic reticulum stress and pyroptosis in pulmonary hypertension (PH) remain unknown. Previous evident indicated that circular RNA (circRNA) can participate in several biological process, including cell pyroptosis. However, the mechanism of circRNA regulate pyroptosis of pulmonary artery smooth muscle cells through endoplasmic reticulum stress still unclear. Here, we proved that circSSR1 was down-regulate expression during hypoxia in pulmonary artery smooth muscle cells, and over-expression of circSSR1 inhibit pyroptosis both in vitro and in vivo under hypoxic. Our experiments have indicated that circSSR1 could promote host gene SSR1 translation via m6A to activate ERS leading to pulmonary artery smooth muscle cell pyroptosis. In addition, our results showed that G3BP1 as upstream regulator mediate the expression of circSSR1 under hypoxia. These results highlight a new regulatory mechanism for pyroptosis and provide a potential therapy target for pulmonary hypertension.

Methods: RNA-FISH and qRT-PCR were showed the location of circSSR1 and expression change. RNA pull-down and RIP verify the circSSR1 combine with YTHDF1. Western blotting, PI staining and LDH release were used to explore the role of circSSR1 in PASMCs pyroptosis.

Results: CircSSR1 was markedly downregulated in hypoxic PASMCs. Knockdown CircSSR1 inhibited hypoxia induced PASMCs pyroptosis in vivo and in vitro. Mechanistically, circSSR1 combine with YTHDF1 to promote SSR1 protein translation rely on m6A, activating pyroptosis via endoplasmic reticulum stress. Furthermore, G3BP1 induce circSSR1 degradation under hypoxic.

Conclusion: Our findings clarify the role of circSSR1 up-regulated parental protein SSR1 expression mediate endoplasmic reticulum stress leading to pyroptosis in PASMCs, ultimately promoting the development of pulmonary hypertension.

Background: Accurate prediction of short-term mortality in acute pulmonary embolism (APE) is very important. The aim of the present study was to analyze the prognostic role of radiomics values of epicardial adipose tissue (EAT) in APE.

Methods: Overall, 508 patients were included into the study, 209 female (42.1%), mean age, 64.7 ± 14.8 years. 4.6%and 12.4% died (7- and 30-day mortality, respectively). For external validation, a cohort of 186 patients was further analysed. 20.2% and 27.7% died (7- and 30-day mortality, respectively). CTPA was performed at admission for every patient before any previous treatment on multi-slice CT scanners. A trained radiologist, blinded to patient outcomes, semiautomatically segmented the EAT on a dedicated workstation using ImageJ software. Extraction of radiomic features was applied using the pyradiomics library. After correction for correlation among features and feature cleansing by random forest and feature ranking, we implemented feature signatures using 247 features of each patient. In total, 26 feature combinations with different feature class combinations were identified. Patients were randomly assigned to a training and a validation cohort with a ratio of 7:3. We characterized two models (30-day and 7-day mortality). The models incorporate a combination of 13 features of seven different image feature classes.

Findings: We fitted the characterized models to a validation cohort (n = 169) in order to test accuracy of our models. We observed an AUC of 0.776 (CI 0.671-0.881) and an AUC of 0.724 (CI 0.628-0.820) for the prediction of 30-day mortality and 7-day mortality, respectively. The overall percentage of correct prediction in this regard was 88% and 79% in the validation cohorts. Lastly, the AUC in an independent external validation cohort was 0.721 (CI 0.633-0.808) and 0.750 (CI 0.657-0.842), respectively.

Interpretation: Radiomics parameters of EAT are strongly associated with mortality in patients with APE.

Clinical trial number: Not applicable.

Background: Extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation (BTT) has expanded considerably, though evidence-based selection criteria and long-term outcome data are lacking. The purpose of this study was to evaluate whether risk factors often used to exclude patients from ECMO BTT-specifically older age and not yet being listed for transplant-are validated by long-term outcomes.

Methods: To ensure minimum 5-year follow-up, a retrospective cohort study was performed of adult patients actively listed for lung transplantation at a high-volume center and bridged on ECMO between January 2012 and December 2017. Data was collected through January 1, 2023.

Results: Among 50 patients bridged on ECMO, 25 survived to transplant. Median age at listing was 58 (interquartile range [IQR], 42-65) in the transplanted group and 65 (IQR, 56.5-69) in the deceased group (P = 0.051). One-year, 3-year, and 5-year survival were 88% (22/25), 60% (15/25), and 44% (11/25), respectively, with eight patients still living at the time of review. Median time spent at home during the year post-transplant was 340 days (IQR, 314-355). Older age at listing was a negative predictor of survival on ECMO to transplant (odds ratio 0.92 [95% confidence interval, 0.86-0.99], P = 0.01). Thirteen patients were placed on ECMO prior to being listed and three were listed the same day as ECMO cannulation, with 10/16 transplanted. No significant difference in post-transplant survival was found between patients placed on ECMO prior to listing (n = 10) and those already listed (n = 15) (P = 0.93, log-rank). Serial post-transplant spirometry up to 5 years and surveillance transbronchial biopsy demonstrated good allograft function and low rates of cellular rejection.

Conclusions: In one of the oldest cohorts of ECMO BTT patients described, favorable survival outcomes and allograft function were observed up to 5 years irrespective of whether patients were previously listed or bridged to decision. Despite inherent limitations to this retrospective, single-center study, the data presented support the feasibility of ECMO BTT in older and not previously listed advanced lung disease patients.

Background: Interstitial pneumonia with autoimmune features (IPAF), which does not meet any of the criteria for connective tissue diseases (CTD), has been attracting an attention in patients with idiopathic interstitial pneumonia (IIP). However, the biomarkers that reflect the clinical course of these patients have not been fully elucidated.

Objective: To identify useful serum biomarkers reflecting CTD-related features and favorable prognoses in patients with IIP.

Methods: This was a post hoc analysis of a prospective and multicenter cohort study between 2015 and 2020. Newly diagnosed patients with IIP were consecutively enrolled, and 74 autoimmune features and autoantibodies were comprehensively checked during IIP diagnosis. Serum levels of CXCL10, CXCL1, CCL2, BAFF, angiopoietin-2, and leptin were evaluated at the time of IIP diagnosis.

Results: Two hundred twenty-two patients (159 men and 63 women) with IIP were enrolled. The median observation duration was 36 months. The median age was 71 years old, and median %forced vital capacity (FVC) was 84.1% at the time of IIP diagnosis. The proportion of patients who met the classification criteria for IPAF was 11.7%. In patients with high serum CXCL10, changes in both %FVC and %diffusion lung capacity for carbon monoxide at one year were significantly higher than those in patients with low CXCL10 (p = 0.014 and p = 0.009, respectively), whereas these changes were not significant for other chemokines and cytokines. High CXCL10 levels were associated with acute/subacute onset (p < 0.001) and the diagnosis of nonspecific interstitial pneumonia with organizing pneumonia overlap (p = 0.003). High CXCL10 levels were related to a higher classification of IPAF (relative risk for IPAF was 3.320, 95%CI: 1.571-7.019, p = 0.003) and lower classification of progressive pulmonary fibrosis (PPF; relative risk for PPF was 0.309, 95%CI: 0.100-0.953, p = 0.027) compared to those with low CXCL10. Finally, survival was higher in patients with IPF and high CXCL10 (p = 0.044), and high CXCL10 was a significant prognostic factor in multivariate Cox proportional hazards models (hazard ratio 0.368, p = 0.005).

Conclusions: High serum levels of CXCL10 are associated with CTD-related features, the favorable clinical course, and survival in patients with IIP, especially IPF.

Clinical trial number: Not applicable.

Background: As one of the most common traffic-related pollutants, diesel exhaust (DE) confers high risk for cardiovascular and respiratory diseases. However, its impact on pulmonary vessels is still unclear.

Methods: To explore the effects of DE exposure on pulmonary vascular remodeling, our study analyzed the number and volume of small pulmonary vessels in the diesel engine testers (the DET group) from Luoyang Diesel Engine Factory and the controls (the non-DET group) from the local water company, using spirometry and carbon content in airway macrophage (CCAM) in sputum. And then we constructed a rat model of chronic DE exposure, in which 12 rats were divided into the DE group (6 rats with 16-week DE exposure) and the control group (6 rats with 16-week clean air exposure). During right heart catheterization, right ventricular systolic pressure (RVSP) was assessed by manometry. Macrophage migration inhibitory factor (MIF) in lung tissues and bronchoalveolar lavage fluid (BALF) were measured by qRT-PCR and ELISA, respectively. Histopathological analysis for cardiovascular remodeling was also performed.

Results: In DET cohort, the number and volume of small pulmonary vessels in CT were positively correlated with CCAM in sputum (P<0.05). Rat model revealed that chronic DE-exposed rats had elevated RVSP, along with increased wall thickness of pulmonary small vessels and right the ventricle. What's more, the MIF levels in BALF and lung tissues were higher in DE-exposed rats than the controls.

Conclusion: Apart from airway remodeling, DE also induces pulmonary vascular remodeling, which will lead to cardiopulmonary dysfunction.

Background: Exposure to a hypobaric hypoxic environment at high altitudes can lead to lung injury. In this study, we aimed to determine whether curcumin (Cur) could improve lung barrier function and protect against high-altitude-associated acute lung injury.

Methods: Two hundred healthy rats were randomly divided into standard control, high-altitude control (HC), salidroside (40 mg/kg, positive control), and Cur (200 mg/kg) groups. Each group was further divided into five subgroups. Basic vital signs, lung injury histopathology, routine blood parameters, plasma lactate level, and arterial blood gas indicators were evaluated. Protein and inflammatory factor (tumor necrosis factor α (TNF-α), interleukin [IL]-1β, IL-6, and IL-10) concentrations in bronchoalveolar lavage fluid (BALF) were determined using the bicinchoninic acid method and enzyme-linked immunosorbent assay, respectively. Inflammation-related and lung barrier function-related proteins were analyzed using immunoblotting.

Results: Cur improved blood routine indicators such as hemoglobin and hematocrit and reduced the BALF protein content and TNF-α, IL-1β, and IL-6 levels compared with those in the HC group. It increased IL-10 levels and reduced pulmonary capillary congestion, alveolar hemorrhage, and the degree of pulmonary interstitial edema. It increased oxygen partial pressure, oxygen saturation, carbonic acid hydrogen radical, and base excess levels, and the expression of zonula occludens 1, occludin, claudin-4, and reduced carbon dioxide partial pressure, plasma lactic acid, and the expression of phospho-nuclear factor kappa.

Conclusions: Exposure to a high-altitude environment for 48 h resulted in severe lung injury in rats. Cur improved lung barrier function and alleviated acute lung injury in rats at high altitudes.

Background: Although crackles on chest auscultation represent a fundamental component of the diagnostic suspect for fibrotic interstitial lung disease (ILD), their reliability has not been properly studied. We assessed the agreement among respiratory physicians on the presence and changes over time of audible crackles collected in a prospective longitudinal cohort of patients with fibrotic ILD.

Methods: Lung sounds were digitally recorded at baseline and after 12 months at eight anatomical sites. Nine respiratory physicians blindly assessed randomized couples of recordings obtained from the same anatomical site at different timepoints. The physicians indicated the presence of crackles in individual recordings and which recording from each couple eventually had more intense crackles. Fleiss' kappa coefficient was used to measure inter- and intra-rater agreement.

Results: Fifty-two patients, mostly with a diagnosis of IPF (n = 40, 76.9%) were prospectively enrolled between October 2019 and May 2021. The final acoustic dataset included 702 single recordings, corresponding to 351 couples of recordings from baseline and 12-months timepoints. Kappa coefficient was 0.57 (95% CI 0.55-0.58) for the presence of crackles and 0.42 (95% CI 0.41-0.43) for acoustic change. Intra-rater agreement, measured for three respiratory physicians on three repeated assessments, ranged from good to excellent for the presence of crackles (κ = 0.87, κ = 0.86, κ = 0.79), and from moderate to good for acoustic change (κ = 0.75, κ = 0.76, κ = 0.57).

Conclusions: Agreement between respiratory physicians for the presence of crackles and acoustic change was acceptable, suggesting that crackles represent a reliable acoustic finding in patients with fibrotic ILD. Their role as a lung-derived indicator of disease progression merits further studies.

Background: Chronic obstructive pulmonary disease (COPD) is a widespread respiratory disease. This study examines extracellular vesicles (EVs) and proteins contained in EVs in COPD.

Methods: Blood samples were collected from 40 COPD patients and 10 health controls. Cytokines including IFN-γ, TNF-α, IL-1β, IL-6, IL-8, and IL-17, were measured by ELISA. Small EVs samples were extracted from plasma and identified by transmission electron microscope (TEM), nanoparticle tracking analysis (NTA), and Western blot. Protein components contained in EVs were analyzed by Tandem Mass Tags (TMT) to identify differential proteins. Treg-derived EV was extracted and added to isolated CD8⁺, Treg, and Th17 subsets to assess its effect on T-lymphocytes.

Results: ELISA revealed higher levels of all cytokines and flow cytometry suggested a higher proportion of Treg and Th17 cells in COPD patients. After identification, TMT analysis identified 207 unique protein components, including five potential COPD biomarkers: BTRC, TRIM28, CD209, NCOA3, and SSR3. Flow cytometry revealed that Treg-derived EVs inhibited differentiation into CD8⁺, CD4⁺, and Th17 cells.

Conclusion: The study shows that cytokines, T-lymphocyte subsets differences in COPD and Treg-derived EVs influence T-lymphocyte differentiation. Identified biomarkers may assist in understanding COPD pathogenesis, prognosis, and therapy. The study contributes to COPD biomarker research.

Background: In recent years, e-cigarettes have been used as alternatives among adult smokers. However, the impact of e-cigarette use on human bronchial epithelial (HBE) cells remains controversial.

Methods: We collected primary HBE cells of healthy nonsmokers and chronic obstructive pulmonary disease (COPD) smokers, and analyzed the impact of e- cigarette vapor extract (ECE) or cigarette smoke extract (CSE) on HBE cell differentiation and injury by single-cell RNA sequencing, immunostaining, HE staining, qPCR and ELISA. We obtained serum and sputum from healthy non- smokers, smokers and e-cigarette users, and analyzed cell injury markers and mucin proteins.

Results: ECE treatment led to a distinct differentiation program of ciliated cells and unique patterns of their cell-cell communications compared with CSE. ECE treatment caused increased Notch signaling strength in a ciliated cell subpopulation, and HBE cell remodeling and injury including hypoplasia of ciliated cells and club cells, and shorter cilia. ECE-induced hypoplasia of ciliated cells and shorter cilia were ameliorated by the Notch signaling inhibition.

Conclusions: This study reveals distinct characteristics in e-cigarette vapor-induced airway epithelial remodeling, pointing to Notch signaling pathway as a potential targeted intervention for e-cigarette vapor-caused ciliated cell differentiation defects and cilia injury. In addition, a decrease in SCGB1A1 proteins is associated with e- cigarette users, indicating a potential lung injury marker for e-cigarette users.