Respiratory Research最新文献

Asthma is a heterogeneous disease characterized by chronic airway inflammation and reversible airflow obstruction. Particularly in severe asthma, airway mucus plugs can contribute to substantial and persistent airflow obstruction, despite inhaled corticosteroid and bronchodilator treatment. Consequently, it is important that clinicians assess and treat mucus plugs. Increased mucus production and airway eosinophilia caused by type 2 (T2) inflammation contributes to mucus plug formation and persistence. Several biologics are available to target T2 inflammation in asthma and studies have described their effects on airway mucus plugs using mucus plug scoring derived from computed tomography scans. However, the outcomes, designs and populations of the various studies have not been comprehensively summarized. A literature search was performed to identify primary publications examining the effects of biologics on mucus plugs in patients with moderate-to-severe asthma, organizing studies by design and study population. Three placebo-controlled randomized controlled trials (RCTs) were identified; one RCT of tezepelumab in patients across baseline blood eosinophil counts (BECs) and fractional exhaled nitric oxide (FeNO) levels and two RCTs of dupilumab in those with elevated BECs or sputum eosinophils and/or elevated FeNO levels. Across these RCTs, biologic treatment decreased mucus plug scores compared with placebo. In the tezepelumab RCT, greater effects were observed in patients with T2-high asthma, highlighting the association between mucus plugging and T2 inflammation. Among T2-high populations, effects were of a similar magnitude across biologics studied. Other biologics (benralizumab, mepolizumab, omalizumab and reslizumab) were evaluated in observational studies without a placebo control, demonstrating reductions in mucus plug scores after treatment. In several studies, decreases in mucus plugs with biologic treatment were associated with improvements in functional outcomes, including pre-bronchodilator forced expiratory volume in 1 second (pre-BD FEV₁), air trapping, ventilation defects assessed by magnetic resonance imaging, asthma control and health-related quality of life. All studies showed residual plugs after biologic intervention, demonstrating a need for further understanding of how best to quantify and characterize mucus plugs to predict their response to treatment and develop optimal, individualised treatment strategies. This review highlights the relevance of assessing and targeting mucus plugs in clinical practice to help optimise patient outcomes.

Background: The COVID-19 pandemic resulted in over 7 million reported deaths and over 700.4 million reported infections to-date. Many individuals who recover from COVID-19 report prolonged dyspnea, sometimes persisting for months. Furthermore, COVID-19 has been linked to systemic and neuronal inflammation which may have downstream impacts on the neural control of breathing. Therefore, we hypothesized that individuals recovered from COVID-19 may exhibit changes in their ventilatory chemosensitivity to carbon dioxide and hypoxia, and that these changes may be linked to systemic inflammation.

Methods: To test this hypothesis, we measured baseline ventilatory patterns and chemoreflex sensitivity in individuals recovered from COVID-19 (n = 77) and individuals with no prior COVID-19 infection (n = 41). Peripheral venous blood samples were also collected for inflammatory biomarker expression and profiling.

Results: Recovered participants demonstrated a small but progressive decrease in the hypercapnic ventilatory response under a co-stimulus with hypoxia (control vs. 24-month post-recovery; p = 0.023). Additionally, we identified several significant correlations between plasma inflammatory markers and ventilatory chemoreflex characteristics, including a positive correlation between SAA and CRP and the ventilatory response to hypoxia (p < 0.05 within recovered and control cohorts). Finally, expression of six vascular inflammatory markers (Myoglobin, NGAL, MMP-2, OPN, IGFBP-4, and Cystatin C) was unexpectedly decreased in recovered participants compared to the control cohort for up to one-year post recovery.

Conclusions: Overall, this data indicates that COVID-19 and other acute viral infections may have a modest impact on the chemoreflex control of breathing as well as systemic inflammatory profiles, and that these changes may be linked to each other. These findings may strengthen our understanding of the pathology of long-COVID symptoms.

Background: Ventilation distribution assessed by electrical impedance tomography (EIT) has great interests in acute respiratory distress syndrome (ARDS). The aim of the study was to explore ARDS phenotypes based on left-right and ventral-dorsal ventilation distribution and to investigate their clinical characteristics and outcomes.

Method: This retrospective study included ARDS patients from two ICUs who underwent mechanical ventilation and EIT monitoring. Asymmetry index (AI) was defined as the right-to-left ventilation difference in percentage. Based on the AI at low PEEP (0-3 cmH₂O), patients were classified as asymmetric (|AI| > 20%) or symmetric (|AI| ≤ 20%) phenotype. Asymmetric phenotype was divided into right (R, AI > 20%) and left (L, AI < -20%) subphenotypes. Based on the median center of ventilation (CoV) of the study population at low PEEP, symmetric phenotype was further divided into ventral (V, CoV < 42.2%) and non-ventral (NV, CoV ≥ 42.2%) subphenotypes.

Result: A total of 217 patients with ARDS during positive end-expiratory pressure (PEEP) titration was analyzed. At low PEEP, 95 patients were defined as asymmetric phenotype and 122 were symmetric (|AI| 36.0% [28.0, 48.0] vs. 8.0% [4.0, 16.5]; p < 0.001). Among asymmetric phenotype, 69 were R subphenotype and 26 were L. R Subphenotype had higher BMI than L (p = 0.037). Among symmetric phenotype, 61 were V subphenotype and 61 were NV. V subphenotype had higher BMI (p = 0.027), more extrapulmonary ARDS (p = 0.010), and better lung recruitability (p = 0.021) than NV. From low to high PEEP (15-18 cmH₂O), 47 patients remained asymmetric phenotype, 48 transitioned from asymmetric to symmetric, 97 remained symmetric, 25 transitioned from symmetric to asymmetric. Patients who remained asymmetric phenotype had fewer 28-day ventilator-free days than those who transitioned to symmetric (p = 0.009).

Conclusion: Based on AI and CoV, EIT enabled rapid phenotyping of ARDS. In symmetric ARDS, V subphenotype had higher BMI, extrapulmonary ARDS incidence, and lung recruitability. In asymmetric ARDS, improvment of symmetry during PEEP titration was related to better outcome. The asymmetry of lung ventilation might be a potential lung injury target in ARDS.

Background: Increasing evidence indicates that tumor cells alter mitochondrial morphology, regulated through fusion, fission, and mitophagy, to meet the demands of rapid proliferation and enhance survival. As a key regulator of mitochondrial dynamics, the biological role and mechanism of MTP18 in lung adenocarcinoma (LUAD) remain unclear.

Methods: MTP18 expression and prognostic value were analyzed using TCGA datasets and validated in clinical cohorts via qRT-PCR and IHC. Functional assays (CCK-8, Transwell, flow cytometry) were performed in MTP18-overexpressing or silenced A549 and PC9 cells. The regulatory mechanism involving mitochondrial dynamics, reactive oxygen species (ROS), and the PI3K/AKT pathway was elucidated using specific pharmacological modulators (Mdivi-1, MYLS22, NAC, H2O2, LY294002, 740Y-P) and transmission electron microscopy.

Results: MTP18 was significantly upregulated in LUAD and correlated with poor patient survival. Functionally, MTP18 overexpression promoted cell proliferation, metastasis, and S-phase entry, while inhibiting apoptosis. Mechanistically, MTP18 induced excessive mitochondrial fission, leading to a robust accumulation of intracellular ROS. This elevated oxidative stress acted as a second messenger to trigger the phosphorylation of PI3K and AKT. Blocking fission or scavenging ROS effectively abrogated MTP18-mediated pathway activation and malignant phenotypes. Additionally, preliminary analysis suggested an association between MTP18 and an immunosuppressive microenvironment.

Conclusions: MTP18 functions as a novel oncogenic driver in LUAD by orchestrating a "fission-ROS-PI3K/AKT" signaling axis. Targeting MTP18-mediated mitochondrial dynamics offers a promising therapeutic strategy to disrupt both tumor growth and metabolic adaptation in LUAD.

Rationale: In the INSPIRE trial, patients diagnosed with Idiopathic Pulmonary Fibrosis (IPF) failed to demonstrate improved survival after treatment with IFN-gamma-1β. This outcome became the impetus to develop more personalized approaches to the diagnosis, classification, and management of pulmonary fibrosis.

Objective: The present study was designed to assess autoantibody profiles in a randomly selected group of INSPIRE trial participants in order to better define IPF on a molecular diagnostic level and define subsets with potentially different underlying disease processes.

Methods: We performed conventional, gel-based protein and RNA immunoprecipitation (IP) on 483 plasma specimens derived from patients enrolled in both the treatment and placebo arms of INSPIRE. Tandem immunoprecipitation and mass spectrometry proteomics (IP-to-MS) of selected specimens was used to confirm conventional IP interpretation and to identify unknown autoantigens.

Results: Based on conventional IP approaches, approximately 30% of trial participants had evidence of autoimmune disease-specific autoantibodies and another ~ 10% had evidence of autoantibodies of unknown specificity. IP-to-MS revealed additional autoantigens, including Annexin 11.

Conclusions: IP analyses demonstrated an unexpectedly high prevalence of autoantibodies potentially indicative of underlying connective tissue disease-associated ILD, underscoring the importance of classification schemes incorporating unbiased autoantibody profiling.