Respiratory Research最新文献

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.

Background: Impaired airway epithelial barrier function is a pathogenic driver in a subset of individuals with asthma. MicroRNAs, small RNAs that function as post-transcriptional regulators of gene expression, may be involved in the regulation of the airway epithelial barrier. This study aimed to determine if microRNAs cause epithelial barrier dysfunction through the targeting of mRNAs involved in maintaining airway epithelial barrier integrity.

Methods: Primary human bronchial epithelial cells cultured at air-liquid interface were stimulated with cytokines reflecting different asthma endotypes. Barrier integrity was assessed by FITC-labelled dextran flux. Differentially expressed epithelial barrier-related genes and microRNAs were identified by next-generation RNA sequencing and qPCR. Results were validated with microRNA pull-down, treatment with microRNA mimics and antagomirs, respectively, and evaluated in airway samples from subjects with asthma.

Results: A combination of IL-17A and TNFα, mimicking Th17 inflammation, was identified as a strong driver of epithelial barrier disruption, as compared to IL-4 + IL-13, IL-6 + sIL-6R, and TGFβ. Several microRNAs induced by IL-17A and TNFα stimulation were predicted to target barrier-related genes, which exhibited decreased expression in the same model. Of these microRNAs, miR-146a-3p and miR-363-3p were consistently induced in multiple donors. MicroRNA pull-down, overexpression, and knockdown experiments indicated a potential role for miR-363-3p interacting with several barrier-related genes, including CLDN8, PCDH1, and PTEN. Bronchial lavage samples demonstrated an increase of miR-363-3p in individuals with asthma compared to healthy controls, as well as a positive correlation between miR-363-3p and the number of airway eosinophils and neutrophils.

Conclusions: Our results support the role of microRNAs as mediators of cytokine-induced airway epithelial barrier dysfunction. Specifically, miR-363-3p appears to contribute to epithelial damage by targeting and suppressing gene expressions of several key barrier components, including CLDN8, PCDH1, and PTEN, suggesting a novel role for this microRNA in Th17-driven airway disease. A better understanding of microRNA networks and their role in asthma pathogenesis may lead to novel biomarkers and therapeutic targets, which are currently needed for individuals with T2-low asthma and in Th17-driven asthma.