Respir. Res. [JOURNAL]
Sun
200 papers
Targeting inflammation and coagulation: MMP-9 deficiency exacerbates sepsis induced acute lung injury through fibrinogen-driven inflammation.
Chen J, Zhang J, Yan Z … +5 more , Zhu C, Chen X, Sun Z, Li Q, Chen Z
Respir Res · 2026 Jun · PMID 42332737 · Full text
Sepsis is caused by a dysregulated host response to infection, characterized by multiorgan failure in which the lung is the primary target. Although matrix metalloproteinase-9 (MMP9), a macrophage-derived protease, is kn...
Sepsis is caused by a dysregulated host response to infection, characterized by multiorgan failure in which the lung is the primary target. Although matrix metalloproteinase-9 (MMP9), a macrophage-derived protease, is known to degrade extracellular matrix proteins during inflammation, its specific role in sepsis-induced lung injury (SALI) remains to be elucidated. This study elucidates the protective function of MMP9 in SALI and validated its translational potential as an early diagnostic biomarker that integrates coagulation-inflammation crosstalk. First, we integrated human blood bulk RNA-seq data and an in-house LPS-induced murine ALI model to extract coagulation-related sepsis DEGs (Cos-Gs), constructed a PPI network, and applied two-sample Mendelian randomization (MR), which identified MMP9 as a causal protection gene. Additionally, we performed molecular docking using the ZDOCK server and 100 ns molecular dynamics simulations with Gromacs to explore the interaction between MMP9 and fibrinogen. Next, in vivo studies using CLP-operated MMP9 and WT mice demonstrated that MMP9 deficiency reduced survival, increased pulmonary fibrinogen accumulation, and elevated IL-6/TNF-α release. Furthermore, in macrophages, fibrinogen synergized with LPS to amplify cytokines via MAPK hyperactivation, a process that was suppressed by rmMMP9 through fibrinogen degradation and subsequent MAPK inhibition. Molecular docking results showed a ZDOCK score of 1845.832 for the interaction between MMP9 and the fibrinogen α-chain, and the 100 ns molecular dynamics simulations confirmed the MMP9-α-chain complex maintained stable RMSD (0.4 to 0.5 nm) in a low-energy state. Finally, The ROC/XGBoost-SHAP models confirmed that MMP9 (AUC = 0.711) was the dominant predictor of SALI, outperforming IL-6 and matching TNF-α/CRP with external nomogram validation. Collectively, our findings indicated that MMP9 protects against SALI by suppressing fibrin-driven MAPK hyperactivation and cytokine release through its fibrinolytic activity, thereby establishing MMMP9 as a mechanistically grounded biomarker for early risk stratification.
Long-term chest CT abnormalities up to 4.5 years after COVID-19 hospitalization and their association with dyspnea and fatigue: a prospective cohort study.
Stavem K, Einvik G, Lerum TV … +7 more , Meltzer C, Rodriguez JR, Ashraf H, Lakxsan SR, Gleditsch J, Skjønsberg OH, Aaløkken TM
Respir Res · 2026 Jun · PMID 42332713 · Full text
BACKGROUND: Long-term pulmonary sequelae following hospitalization for COVID-19 remain incompletely characterized, and few studies have reported radiological outcomes beyond 2 years. This study investigated the persisten...
BACKGROUND: Long-term pulmonary sequelae following hospitalization for COVID-19 remain incompletely characterized, and few studies have reported radiological outcomes beyond 2 years. This study investigated the persistence of chest CT abnormalities up to 4.5 years after hospitalization for COVID-19 and their association with current dyspnea and fatigue. METHODS: This longitudinal cohort study included patients hospitalized for COVID-19 in 2020. Chest CT was performed 3 months after hospital admission, with follow-up imaging after 12 months and 4.5 years in patients with persisting abnormalities. CT images were evaluated using a CT severity score (CSS) on a 0-12 scale, which was subsequently recoded to an abbreviated CSS (aCSS) on a 0-3 scale. Trends in CT abnormalities and their determinants were analyzed using multivariable mixed effects ordinal regression. RESULTS: In total, 187 patients underwent chest CT at 3 months. Among patients with persistent abnormalities, 99 completed follow-up CT at 12 months and 54 at 4.5 years. Dyspnea (33%) and fatigue (61%) remained common at 4.5 years; however, correlations between current symptoms and aCSS were weak. Greater severity of the initial disease and older age were strong predictors of CT abnormalities. Regression analysis showed a gradual reduction in ground glass opacities (GGO) severity over time, whereas parenchymal bands increased and were associated with initial severity as assessed by the WHO 8-point ordinal scale for clinical improvement. Mosaic attenuation decreased during follow-up, but remained associated with the severity of the initial COVID-19 episode. CONCLUSIONS: From 3 months to 4.5 years after hospitalization, GGO and mosaic attenuation decreased, whereas parenchymal bands increased, with minimal change beyond 12 months. CT abnormalities were associated with initial disease severity and age but showed little association with dyspnea or fatigue.
Metabolic rewiring at the pyruvate node contributes to severe pneumonia and attenuation of T cell responses in serotype 3 Streptococcus pneumoniae infection.
Takeshita K, Vidal AGJ, Vidal JE
Respir Res · 2026 Jun · PMID 42332709 · Full text
BACKGROUND: Serotype 3 (ST3) Streptococcus pneumoniae remains a major cause of invasive pneumococcal disease and pneumonia despite PCV13 introduction, in part due to potent immune evasion properties. The contribution of...
BACKGROUND: Serotype 3 (ST3) Streptococcus pneumoniae remains a major cause of invasive pneumococcal disease and pneumonia despite PCV13 introduction, in part due to potent immune evasion properties. The contribution of the pyruvate metabolic node (SpxB/LctO pathways) to ST3 pathogenesis is poorly defined. METHODS: We investigated oxygen-dependent fitness, colonization efficiency, and lung pathology in the ST3-strain WU2 and isogenic ΔspxB, ΔlctO, and ΔspxBΔlctO mutants. In vitro growth was assessed under nasopharyngeal (21% O₂) and alveolar (14% O₂) conditions. Murine pneumonia models evaluated survival, bacterial burdens, histopathology, and lung gene expression analyses (RNA-seq and quantitative RT-PCR). RESULTS: ST3-strain exhibited a unique oxygen-sensitive growth defect at 21% O₂, alleviated by spxB deletion, indicating metabolic burden from pyruvate flux. In mice, wild-type WU2 caused severe suppurative bronchopneumonia, alveolar consolidation, hemorrhage, and perivascular inflammation, whereas the ΔspxB mutant showed enhanced distal lung damage, uncontrolled dissemination, and amplified inflammation. Wild-type infection uniquely induced reorganization of bronchial epithelial membranes, forming prominent bacterium-laden bleb-like structures-host-derived membrane protrusions covering intact pneumococci. These structures appeared to be associated with bacterial translocation into tissue without overt cytotoxicity and were largely absent in spxB-deficient mutants despite comparable bacterial colonization densities in the lung. RNA-seq analysis revealed SpxB-dependent reduced expression of T-cell activation (e.g., Rag1 and Themis), consistent with immune sequestration via bleb-like structures. CONCLUSIONS: The SpxB-dependent pathway contributes to ST3 pathogenesis through metabolic adaptation and is associated with bleb-like structure formation and altered host immune responses in the lung. These bacterium-laden bleb-like structures represent a novel hallmark mechanism in pneumococcal pathogenesis.
Live nontypeable Haemophilus influenzae exacerbates respiratory syncytial virus-associated lower airway inflammation.
Kawahara E, Morimoto K, Islam MS … +5 more , Yamada H, Sekiguchi T, Morita M, Mitsuyama J, Morinaga Y
Respir Res · 2026 Jun · PMID 42323699 · Full text
BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract disease in infants and immunocompromised adults, and secondary bacterial infections are recognized as important contributors to di...
BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract disease in infants and immunocompromised adults, and secondary bacterial infections are recognized as important contributors to disease severity. Recent microbiome studies have shown that Haemophilus influenzae is frequently co-detected in severe RSV cases and ranks among the bacteria most closely correlated with disease severity; however, its causal role and underlying mechanisms remain unclear. Here, we used a murine model to examine the manner in which H. influenzae influences RSV-associated airway inflammation. METHODS: We established a murine respiratory infection model by infecting mice with RSV and subsequently intratracheally inoculating them with live, ultraviolet (UV)-killed, or heat-killed nontypeable H. influenzae (NTHi). Body weight, viral and bacterial loads, bronchoalveolar lavage fluid (BALF) cytokine levels, and immune cell populations were analyzed. RESULTS: Live NTHi inoculation following RSV infection induced severe lower airway inflammation, characterized by pronounced body weight loss and lung injury along with increased CD8 T-cell accumulation and enhanced interleukin (IL)-6 inflammatory mediator production in BALF. Additionally, CD8 T-cell depletion modestly attenuated body weight loss, altered the recruited innate immune cell composition, and reduced BALF IL-6 levels. However, RSV-infected mice inoculated with UV- or heat-killed NTHi exhibited CD8 T-cell accumulation without developing body weight loss, which suggested that CD8 T-cell accumulation alone may be insufficient to drive full disease manifestation. In contrast to that observed for non-viable NTHi, live NTHi induced robust neutrophil recruitment along with strong production of inflammatory mediators. Additionally, BALF IL-6 levels showed a strong negative correlation with body weight; hence, IL-6 was identified as a potential marker associated with disease severity. CONCLUSIONS: This mouse model shows that pulmonary inoculation of live NTHi after RSV infection induces severe lower airway inflammation partially involving CD8 T cells and that IL-6 is a potential biomarker associated with disease severity. Overall, this study suggests a novel pathological role for NTHi in the exacerbation mechanism of secondary bacterial infection in RSV infection.
Commenting on "a randomized trial of continuous positive airway pressure for the asthma of obesity" by Anne E. Dixon and colleagues.
Kuang L, Shu P
Respir Res · 2026 Jun · PMID 42323646 · Full text
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Ultrasonic elastography-guided pleural biopsy followed by as-needed semi-rigid thoracoscopic pleural biopsy versus immediate semi-rigid thoracoscopic pleural biopsy for the diagnosis of pleural effusion (UPDATE-3): a protocol of randomised controlled trial.
Liao L, Ma J, Ni J … +7 more , Lin J, Zhao S, Xia Y, Liu X, Deng M, Zheng Z, Hou G
Respir Res · 2026 Jun · PMID 42321816 · Full text
INTRODUCTION: Exudative pleural effusion of an unclear aetiology remains a diagnostic challenge. Ultrasonic elastography-guided pleural biopsy (UEPB) offers a higher diagnostic yield than conventional ultrasound-guided p...
INTRODUCTION: Exudative pleural effusion of an unclear aetiology remains a diagnostic challenge. Ultrasonic elastography-guided pleural biopsy (UEPB) offers a higher diagnostic yield than conventional ultrasound-guided pleural biopsy; however, its role relative to semi-rigid thoracoscopy remains unclear. This trial is designed to determine whether UEPB is non‑inferior to semi-rigid thoracoscopy in diagnostic yield when used as the initial diagnostic procedure, and to further quantify the proportion of patients in whom semi-rigid thoracoscopy could be avoided by adopting a UEPB-first diagnostic strategy. METHODS AND ANALYSIS: In this multicentre, open-label, parallel-group, non-inferiority, randomised controlled trial conducted at five sites in China, 420 patients with exudative pleural effusion of unknown aetiology and negative cytology will be randomly assigned 1:1 to either initial UEPB (with semi-rigid thoracoscopy reserved for non-diagnostic cases) or immediate semi-rigid thoracoscopy. The primary outcome is the overall diagnostic yield of the allocated diagnostic strategy, defined as the proportion of participants in whom a specific histopathological diagnosis is stablished through the protocol-defined biopsy procedures within the allocated diagnostic pathway. A non-inferiority margin of - 5% is applied. The secondary outcomes included diagnostic sensitivity in specific disease, procedure-related adverse events, length of hospital stay, duration of chest tube drainage, thoracoscopy avoidance rate, and direct diagnostic pathway-related medical costs. DISCUSSION: This UPDATE-3 study will provide the evidence from a RCT directly comparing the a UEPB-first step-up diagnostic strategy with immediate semi-rigid thoracoscopy in patients with undiagnosed exudative pleural effusion. Should non-inferiority be established, UEPB will be validated as a sufficiently sensitive first-line biopsy technique. Furthermore, this trial will quantify the extent to which a UEPB-first strategy can safely decrease the necessity for semi-rigid thoracoscopy and optimize healthcare utilization. These findings could facilitate a paradigm shift towards a less invasive, step-up diagnostic pathway. Conversely, should non-inferiority not be established, the findings will reinforce the status of semi-rigid thoracoscopy as the diagnostic reference standard and elucidate the appropriate role of UEPB within the diagnostic algorithm. TRIAL REGISTRATION: ClinicalTrials.gov (Registration ID: NCT07419620; Registration Date: 2026-02-12).
Microbial DNA analysis of paired blood-bronchoalveolar lavage fluid in post-HSCT patients with pneumonia implying application conditions of blood as a surrogate in pathogen detection.
Li R, He X, Chen Z … +16 more , Shao J, Feng J, Wan L, Zhang M, Yang J, Tong Y, Dong B, Huang C, Qiu H, Cai Y, Niu J, Xu X, Song X, Ma J, Ge H, Zhou K
Respir Res · 2026 Jun · PMID 42316249 · Full text
BACKGROUND: Blood testing aids pneumonia diagnosis, but its effectiveness varies. Given the invasiveness of bronchoalveolar lavage fluid (BALF) sampling versus blood testing's simplicity, this study investigates when blo...
BACKGROUND: Blood testing aids pneumonia diagnosis, but its effectiveness varies. Given the invasiveness of bronchoalveolar lavage fluid (BALF) sampling versus blood testing's simplicity, this study investigates when blood can reliably substitute for BALF in detecting microbial presence, especially for pathogens. RESULTS: Metagenomic sequencing was performed on paired BALF-blood samples from 21 post-HSCT immunocompromised (ICP) and 21 immunocompetent (ICT) patients. The ICP cohort was expanded to 62 for biomarker validation. Host responses were profiled via metatranscriptomics (30 BALF samples). Microbial alpha and beta diversity differed significantly between blood and BALF in ICP, but not ICT, patients. ICP patients' BALF contained a greater diversity and abundance of microbes. A higher proportion of microbial DNA sequences in ICP patients' blood was also present in their BALF, suggesting a potentially more permeable alveolar-capillary barrier. Related genes (e.g., NABA CORE MATRISOME, extracellular matrix organization, cell-cell adhesion) were downregulated. Upregulated pathways like VEGFA-VEGFR2 signaling and Rho GTPases suggested increased vascular permeability. In ICP patients, 419 microbial sequences in blood indicated their presence in the lower respiratory tract with > 70% certainty. CONCLUSION: Host immune status significantly influences blood-BALF microbial diversity differences. Shared blood-BALF microbial DNA sequences show potential for aiding pneumonia pathogen diagnosis, offering a novel biomarker identification approach.
The crucial role of RIG-I in upregulating neutrophil CXCR2 expression through the MAPK signaling pathway in viral pneumonia.
Wang Y, Shi Q, Pan Y … +3 more , Sun X, Wang H, Zhang Y
Respir Res · 2026 Jun · PMID 42316185 · Full text
BACKGROUND: Dysregulated neutrophilic inflammation is a hallmark of severe COVID-19, but the mechanisms driving human peripheral neutrophils (HPNs) recruitment remain incompletely defined. C-X-C motif chemokine receptor...
BACKGROUND: Dysregulated neutrophilic inflammation is a hallmark of severe COVID-19, but the mechanisms driving human peripheral neutrophils (HPNs) recruitment remain incompletely defined. C-X-C motif chemokine receptor 2 (CXCR2), a key chemokine receptor on HPNs, is essential for HPNs recruitment during viral pneumonia. However, the role and underlying regulatory mechanisms of CXCR2 on HPNs during viral pneumonia remain unclear. METHODS: We enrolled 66 COVID-19 patients (30 mild, 33 severe) and 31 healthy controls (HCs). The content of HPNs and the CXCR2 expression on the HPNs were tracked using flow cytometry, RT-qPCR, and ELISA. Transcriptomic sequencing identified differential pathways in the patients. In vitro, HPNs and lung epithelial cells (A549, BEAS-2B) were stimulated with the viral mimic poly(I: C) and treated with pathway inhibitors (CXCR2: SB225002; RIG-I: BX795; MEK: PD98059). In vivo, a poly(I: C)-induced acute lung injury mouse model was used to confirm the roles of RIG-I and CXCR2 in lung injury progression. RESULTS: Severe patients exhibited a higher HPN percentage and CXCR2 expression. Higher CXCR2 expression was correlated with poor prognosis and elevated inflammatory cytokines (TNF-α, IL-6, and IL-8). In vitro, poly(I: C) triggered lung epithelial cells to produce CXCR2 ligands (CXCL1/2/8), increase pro-inflammatory factors, and promote the HPNs migration to epithelial cells. However, CXCR2 antagonists could reduce the HPNs recruitment and inflammatory factors in HPNs supernatants. Mechanistically, poly(I: C)-mediated activation of intracellular RIG-I upregulated CXCR2 expression on HPNs via the MAPK pathway. In vivo, inhibiting CXCR2, RIG-I, or depleting neutrophils significantly alleviated poly(I: C)-induced inflammatory lung injury, inflammation, and neutrophil infiltration. CONCLUSION: Our study identifies the RIG-I-MAPK-CXCR2 axis as a novel pathogenic signaling cascade that drives dysregulated neutrophilic inflammation in COVID-19, providing a basis for novel therapeutic strategies against respiratory viral infections.
Real-world persistence with antifibrotic treatments: a nationwide study on claims data in France (The REPEAT study).
Cottin V, Najean M, Arnee E … +7 more , Voulgaridou M, Dillard C, Ansolabehere X, Doublet M, Chollet J, Leroy S, Jouneau S
Respir Res · 2026 Jun · PMID 42316168 · Full text
BACKGROUND: Long-term persistence with antifibrotic drugs is crucial to slow disease progression in fibrosing ILDs but is challenging due to adverse events. Large-scale, real-world studies investigating modifiable health...
BACKGROUND: Long-term persistence with antifibrotic drugs is crucial to slow disease progression in fibrosing ILDs but is challenging due to adverse events. Large-scale, real-world studies investigating modifiable healthcare system factors associated with persistence are lacking. OBJECTIVES: The main objectives of this study were to assess the real-life persistence with antifibrotic treatments in the overall French population and to explore factors associated with patients' persistence with antifibrotic therapy. METHODS: In this retrospective observational study conducted using the French National Health Database System, all adults initiating nintedanib or pirfenidone between January 2019 and December 2021 were included. They were categorized by diagnosis (idiopathic pulmonary fibrosis, interstitial lung disease associated with systemic sclerosis, and progressive pulmonary fibrosis) using International Classification of Diseases 10th Revision codes. Persistence with antifibrotic therapy (defined as no treatment gap longer than 60 days), adherence to antifibrotic treatments, overall survival (OS), and event-free survival (EFS) were assessed. A multivariable Fine-Gray model identified factors associated with non-persistence. RESULTS: Among 4,935 incident patients, the 12-month persistence rate with antifibrotic therapy was 70.8%. The median time of follow-up for incident patients was 27 months. The median time on antifibrotic therapy was 14.1 months. Switching between antifibrotics occurred in 16.6% of patients, mainly during the first year. At 12 months, OS and EFS were 85.8% and 57.4%, respectively, with lower rates observed among patients with IPF. Regular outpatient visits, follow-up in expert centers, and early supportive interventions (day-hospitalization, temporary treatment interruptions) were associated with increased persistence whereas suboptimal follow-up (< 2 pulmonary function tests during the follow-up period) was strongly associated with non-persistence (sHR = 3.1). CONCLUSION: Structured patient follow-up and proactive management of adverse events, including treatment interruption, could be key to optimizing long-term persistence with antifibrotic therapy.
Design of a randomized controlled trial comparing hybrid care with standard care for people with pulmonary fibrosis.
Hofman DE, Moor CC, van Beek FF … +13 more , Vorselaars ADM, Overbeek MJ, van Doorn-Hogervorst K, Moonen LAA, van der Maten J, Bresser P, Loth DW, Schakenraad E, Kerstens R, van der Wal P, de Mul M, Mostard RLM, Wijsenbeek MS
Respir Res · 2026 Jun · PMID 42310732 · Full text
BACKGROUND: People with pulmonary fibrosis (PF) live with persistent dyspnea, chronic cough, and fatigue. Symptoms that impair their exercise capacity and quality of life. The need for frequent outpatient clinic visits t...
BACKGROUND: People with pulmonary fibrosis (PF) live with persistent dyspnea, chronic cough, and fatigue. Symptoms that impair their exercise capacity and quality of life. The need for frequent outpatient clinic visits to evaluate disease progression and treatment response can impose a substantial burden on people with PF. Online home monitoring has the potential to replace some of these visits. However, structural implementation and evidence on its impact on patient outcomes are lacking. Here, we describe the design of the SUITS study, a multicenter randomized controlled trial (RCT) which aims to evaluate the impact of partly replacing conventional outpatient clinic visits with home monitoring and video consultations on clinically relevant patient outcomes and efficiency of healthcare systems. METHODS: Patients will be randomized to either standard care (3-monthly outpatient clinic visits) or hybrid care. Hybrid care consists of a home monitoring program and video consultations that alternately replace outpatient clinic visits. In an online application, patients perform weekly home spirometry and pulse-oximetry measurements, fill out patient reported outcome measures (PROMs) on a regular basis, and have access to an information library with disease specific information. The primary endpoint of this RCT is the change in patient self-management from baseline to 12 months, assessed with the validated patient activation measure (PAM). DISCUSSION: In light of the insufficient implementation of a hybrid care pathway for people with PF, there is pressing need for a trial to confirm if partly replacing outpatient clinic visits with home monitoring and video consultations is both feasible and effective. REGISTRATION DETAILS: Clinicaltrials.Gov: NCT06883448, date of registration: 13-03-2025. The study was retrospectively registered. No changes were made to the IRB approved study protocol (version 1, 11-01-2024) prior to registration at ClinicalTrials.gov.
The LTI-01-2001 phase 2a trial of intrapleural LTI-01 in patients with infected, non-draining pleural effusions.
Lamb CR, Akulian J, Musani A … +21 more , Shojaee S, Chen A, Kurman J, Jani P, Senitko M, Ahmad D, Wahidi M, Ansari S, Abu-Hijleh M, Ma KC, Puchalski J, Yarmus L, Kheir F, Maldonado F, Cheng G, Alvarado C, Karan SP, Windsor B, Rahman NM, Shoemaker S, Idell S
Respir Res · 2026 Jun · PMID 42310706 · Full text
BACKGROUND: Single chain urokinase (LTI-01) intrapleural enzymatic therapy (IET) was safe and promising in a phase 1 clinical trial to overcome failed drainage in patients with pleural infection. The LTI-01-2001 phase 2a...
BACKGROUND: Single chain urokinase (LTI-01) intrapleural enzymatic therapy (IET) was safe and promising in a phase 1 clinical trial to overcome failed drainage in patients with pleural infection. The LTI-01-2001 phase 2a trial was a randomized, double-blind, placebo-controlled, multi-center, dose-ranging study in hospitalized subjects with infected, non-draining pleural effusions. METHODS: LTI-01, in doses of 400,000, 800,000 or 1,200,000 Units, or placebo was administered intrapleurally once daily for up to 3 days. The primary efficacy endpoint was incidence of treatment failure within 7 days of starting study medication. Treatment failure was defined as requiring alternative pleural therapy irrespective of subsequent treatment. Pleural opacification was a secondary endpoint and was assessed by CT imaging of the change in opacified area expressed as a percentage of the ipsilateral hemithorax (relative change) or absolute change in pleural opacification volume expressed in liters. RESULTS: 40/43 enrolled patients received LTI-01 or placebo due to constraints of the COVID-19 pandemic. There was no significant difference in incidence of treatment failure between the LTI-01 and placebo groups (OR 1.04, 95% CI 0.24,4.44, P = 0.96) while two predetermined sensitivity analyses demonstrated trends of improved efficacy in the 400,000 U group (P = 0.052 and 0.147). The absolute (Liters; L) and relative change from baseline in opacity volume were - 0.28 L (p=0.035) and - 55.8% (P = 0.064) versus placebo in the 800,000 U group, with significant reduction in absolute opacification found in the 400,000 and all LTI-01-treated groups combined (P < 0.03, respectively). There were no safety signals of concern, nor were there any episodes of intrapleural or pulmonary bleeding in LTI-01-treated patients. CONCLUSIONS: No statistically significant difference in the incidence of treatment failure was seen, potentially related to low recruitment. Trends towards efficacy were observed in predetermined sensitivity analyses at the 400,000 U dose of intrapleural LTI-01. Pleural opacification appeared most improved by the 800,000 U intrapleural LTI-01. A larger phase 2b trial is required to confirm these results or determine the efficacy of LTI-01 in patients with organizing, nondraining, infected pleural effusions. TRIAL REGISTRATION: ClinicalTrials.gov NCT04159831. Registration date: November 12, 2019.
SMC4 is a hypoxia-responsive driver of pulmonary arterial hypertension through an HIF-1α-HDAC6-p21 regulatory axis.
Lu T, Zhao Y, Zhang J … +9 more , Chen H, Bai Y, Jia J, Chen H, Yin J, Chen S, Wang W, Wang H, Yu X
Respir Res · 2026 Jun · PMID 42304413 · Full text
BACKGROUND: Pulmonary arterial hypertension (PAH) is characterized by aberrant vascular remodeling driven in part by excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs). However, the molecular dete...
BACKGROUND: Pulmonary arterial hypertension (PAH) is characterized by aberrant vascular remodeling driven in part by excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs). However, the molecular determinants underlying this cancer-like phenotype remain incompletely defined. METHODS AND RESULTS: Genomic analysis of patients with PAH revealed a significant upregulation of structural maintenance of chromosomes 4 (SMC4). In hypoxia-exposed mouse models and human PASMCs, SMC4 expression was similarly increased and localized primarily to the vascular smooth muscle layer. Functional studies demonstrated that SMC4 knockdown suppressed, whereas SMC4 overexpression enhanced, microtubule organization, cell-cycle progression, and PASMCs proliferation. Mechanistically, chromatin immunoprecipitation confirmed direct binding of HIF-1α to the SMC4 promoter, promoting its transcription under hypoxia. Co-immunoprecipitation further showed that SMC4 recruited histone deacetylase 6 (HDAC6) to repress the cyclin-dependent kinase inhibitor P21, thereby sustaining proliferative signaling. In vivo, partial genetic deficiency of SMC4 mitigated pulmonary vascular remodeling, reduced right ventricular hypertrophy, and improved hemodynamic parameters in hypoxia-induced PAH mice. CONCLUSIONS: SMC4 is a key regulator of PASMCs proliferation and pulmonary vascular remodeling through an HIF-1α-SMC4-HDAC6-P21 signaling axis. Modulation of this pathway may offer a potential therapeutic approach for PAH.
Protective effects of PRELP protein in a mouse model of pulmonary fibrosis.
Yuki M, Ishimori T, Shinozaki Y … +14 more , Kosuge H, Okuda K, Hattori M, Shuzui M, Saito M, Isago H, Tamiya H, Nakakido M, Tsumoto K, Tanaka G, Kage H, Ohnuma S, Nagase T, Mitani A
Respir Res · 2026 Jun · PMID 42298578 · Full text
BACKGROUND: Pulmonary fibrosis is a chronic progressive lung disease characterized by extensive fibrosis and poor prognosis, highlighting the urgent need for novel therapeutic strategies. This study aims to elucidate the...
BACKGROUND: Pulmonary fibrosis is a chronic progressive lung disease characterized by extensive fibrosis and poor prognosis, highlighting the urgent need for novel therapeutic strategies. This study aims to elucidate the role of the small proteoglycan proline/arginine-rich end leucine-rich repeat protein (PRELP), evaluate the protective potential of recombinant PRELP protein, and investigate its underlying molecular mechanisms. METHODS: RNA in situ hybridization was performed on lung sections prepared from control subjects and patients with idiopathic pulmonary fibrosis (IPF). In mouse experiments, we established a bleomycin (BLM)-induced lung fibrosis model using PRELP knockout mice and assessed the extent of fibrosis. Furthermore, we administered recombinant PRELP protein via the airway in wild-type mice with BLM-induced fibrosis to evaluate its effects. In vitro experiments were conducted to investigate the role of PRELP in alveolar epithelial cells and fibroblasts. RESULTS: In human lungs, PRELP expression was mainly detected in stromal regions and partly in type 2 alveolar epithelial cells. Furthermore, PRELP was broadly expressed in alveolar areas of controls but was markedly reduced in the alveolar region and localized to vessel walls in IPF patients. In mouse experiments, fibrosis was more severe in PRELP knockout mice after BLM intratracheal administration than in wild-type mice. Notably, prophylactic trans-airway administration of recombinant PRELP suppressed BLM-induced fibrosis in wild-type mice in vivo. In vitro experiments revealed that PRELP suppresses the acquisition of mesenchymal traits and enhances the maintenance of epithelial cell function in epithelial cells, while inhibiting the migratory ability of fibroblast cells. Mechanistically, PRELP suppressed fibrotic changes in epithelial cells not only through the transforming growth factor-beta (TGF-β) pathway but also via Receptor for advanced glycation end products (RAGE)/ Diaphanous 1 (DIAPH1)/ Yes-associated protein (YAP) signaling axis. CONCLUSIONS: The small proteoglycan PRELP plays a pivotal role in a mouse model of pulmonary fibrosis by suppressing the upregulation of mesenchymal markers, reinforcing epithelial cell function, and inhibiting fibroblast migration. Notably, prophylactic trans-airway administration of recombinant PRELP protected against pulmonary fibrosis, indicating that PRELP may be a promising novel protective agent for this disease.
Karacoline attenuates sepsis-induced acute lung injury by suppressing apoptosis via PPARγ-associated inhibition of JNK/ERK MAPK signaling.
Lei Z, He Y, Wang Y … +4 more , Yuan M, Chen X, Qin J, Wu X
Respir Res · 2026 Jun · PMID 42298577 · Full text
BACKGROUND: Sepsis-induced acute lung injury (SALI) is a fatal complication of sepsis with limited therapeutic options. Karacoline, a diterpenoid alkaloid from Aconitum, shows potential protective effects, but its mechan...
BACKGROUND: Sepsis-induced acute lung injury (SALI) is a fatal complication of sepsis with limited therapeutic options. Karacoline, a diterpenoid alkaloid from Aconitum, shows potential protective effects, but its mechanism in SALI remains unclear. METHODS: Network pharmacology and WGCNA identified core targets and pathways of Karacoline, with molecular docking confirming its binding to PPARγ. A cecal ligation and puncture mouse model was used to assess lung pathology, edema, barrier dysfunction, inflammatory cytokines, and apoptosis. In vitro, LPS-stimulated MH-S cells were used to evaluate apoptosis, ROS generation, mitochondrial function, and PPARγ/MAPK signaling. The PPARγ antagonist GW9662 was used to verify the involvement of PPARγ in the protective effects of Karacoline. RESULTS: Karacoline significantly alleviated lung injury, reduced the W/D ratio, decreased total protein and albumin levels in BALF, and suppressed IL-1β, IL-6, and TNF-α. Mechanistically, Karacoline upregulated PPARγ expression and inhibited ERK1/2 and JNK phosphorylation, thereby contributing to the reduction of pulmonary cell apoptosis. In vitro, Karacoline limited ROS generation, maintained mitochondrial membrane potential, and reduced LPS-induced apoptosis in MH-S cells. Moreover, GW9662 weakened the anti-apoptotic effect of Karacoline and partially reversed its inhibition of JNK/ERK activation, further supporting the involvement of PPARγ in Karacoline-mediated inhibition of JNK/ERK MAPK signaling and apoptosis. CONCLUSION: Karacoline protects against SALI by suppressing mitochondrial apoptosis, an effect closely associated with PPARγ-related inhibition of JNK/ERK MAPK signaling. These findings suggest that Karacoline may be a candidate compound worthy of further validation for sepsis-induced lung injury intervention.
Health inequities in the comorbid association between pneumoconiosis and chronic obstructive pulmonary disease: a nationwide study of age-related heterogeneity.
Liu K, Ren Y, Zhou L … +2 more , Lyu X, Wang H
Respir Res · 2026 Jun · PMID 42286646 · Full text
BACKGROUND: Pneumoconiosis patients have a higher prevalence of chronic obstructive pulmonary disease (COPD). While age is a known associated factor, its impact across different populations is unclear. METHODS: We includ...
BACKGROUND: Pneumoconiosis patients have a higher prevalence of chronic obstructive pulmonary disease (COPD). While age is a known associated factor, its impact across different populations is unclear. METHODS: We included 9,964 pneumoconiosis patients from 27 Chinese provinces. Factors were identified using multivariable logistic regression, and the non-linear age-COPD association was examined with restricted cubic spline (RCS) modelling. Stratified analysis and interaction tests assessed sociodemographic heterogeneity. Sensitivity analyses comprised RCS models with varying knots and propensity score matching. RESULTS: The prevalence of COPD among patients with pneumoconiosis was 24.1%. Each additional year of age was associated with a significant increase in the odds of COPD (adjusted odds ratio [aOR] = 1.03, 95% confidence interval [CI]: 1.03-1.04). RCS analysis revealed a significant nonlinear relationship, with the odds increasing more steeply at older ages (P for overall < 0.001; P for nonlinear = 0.002). Subgroup analyses showed substantial heterogeneity in these associations. Among urban residents and individuals covered by work-related injury insurance (WRII), the odds of COPD increased sharply and then gradually plateaued in later life. In contrast, among rural residents and those without WRII, the odds increased steadily with advancing age. Sensitivity analyses confirmed the robustness of these findings. CONCLUSION: The nonlinear relationship between age and COPD in pneumoconiosis in patients with pneumoconiosis is significantly modified by sociodemographic factors.
HLA-DRCD38 activated Th17.1 cells reflect disease activity and corticosteroid responsiveness in pulmonary sarcoidosis.
Tsukuda TK, Fujimoto M, Ohnishi H … +9 more , Ooyama K, Nakatani Y, Ito T, Terada J, Baba Y, Kubo T, Yokoyama A, Naka T, Kozuki T
Respir Res · 2026 Jun · PMID 42286635 · Full text
BACKGROUND: Sarcoidosis is a systemic granulomatous disease caused by sustained activation of CD4 T cells following exposure to unknown antigens. Th17.1 cells appear to play important roles in the pathophysiology of pulm...
BACKGROUND: Sarcoidosis is a systemic granulomatous disease caused by sustained activation of CD4 T cells following exposure to unknown antigens. Th17.1 cells appear to play important roles in the pathophysiology of pulmonary sarcoidosis by differentiating from Th17 cells through interactions with antigen-presenting cells and producing large amounts of interferon gamma. However, whether these cells promote or inhibit granulomatous inflammation and how regulatory T cells, which suppress the activity of these cells, are involved in the pathogenesis of sarcoidosis remains unclear. This exploratory study aimed to elucidate the roles of Th17.1 cells and regulatory T cells in the pathophysiology of pulmonary sarcoidosis. METHODS: We compared and evaluated the proportions and activation states of Th17.1 cells and regulatory T cells in peripheral blood (n = 34) and bronchoalveolar lavage fluid (n = 22) from patients with pulmonary sarcoidosis, and from patients with connective tissue disease-associated interstitial lung disease (n = 36, 34). We also conducted a longitudinal investigation of changes before and after corticosteroid treatment and associations with disease progression. RESULTS: The proportion of activated Th17.1 cells was higher in peripheral blood and bronchoalveolar lavage fluid from patients with pulmonary sarcoidosis than from patients with connective tissue disease-associated interstitial lung disease. However, this proportion decreased with corticosteroid administration and was associated with disease progression. The proportion of regulatory T cells was significantly lower in the lungs of sarcoidosis patients compared to those with connective tissue disease-associated interstitial lung disease. CONCLUSION: Among patients with corticosteroid-responsive pulmonary sarcoidosis, activation of Th17.1 cells reflects disease activity.
Identifying molecular signatures of parapneumonic effusion reveals HMGB2 as the disease progression biomarker.
Wu KA, Chen M, Wu KL … +11 more , Lai CH, Chang IY, Jan FW, Chin CY, Tasi PC, Wu CC, Kuo YH, Shih LJ, Wang WL, Kao YH, Yang CY
Respir Res · 2026 Jun · PMID 42277830 · Full text
BACKGROUND: Parapneumonic effusion (PPE) exacerbation is associated with high morbidity and mortality in pneumonia patients. However, the molecular signatures underlying the progression and severity of PPE remain poorly...
BACKGROUND: Parapneumonic effusion (PPE) exacerbation is associated with high morbidity and mortality in pneumonia patients. However, the molecular signatures underlying the progression and severity of PPE remain poorly understood. We therefore employed whole-transcriptome profiling to comprehensively characterize the molecular landscape associated with PPE exacerbation and its clinical manifestations. METHODS: In the discovery cohort, 26 PPE patients underwent capture-based targeted RNA sequencing and were stratified by disease severity into non-severe PPE (UPPE, n = 9) and severe PPE (n = 17), comprising CPPE (n = 12) and empyema (n = 5). Bioinformatic functional annotation was performed to delineate gene expression signatures associated with disease progression from non-severe to severe PPE. Integrated analyses of the transcriptome and secretome of pleural effusions identified high-mobility group box 2 (HMGB2) as a novel biomarker for severe PPE. In the validation cohort, 220 patients with different pleural effusion etiologies were enrolled for enzyme-linked immunosorbent assay (ELISA) analysis to evaluate HMGB2 levels. The functional relevance of HMGB2 in PPE progression was characterized in neutrophils and macrophages. RESULTS: In pneumonia patients, severe PPE was associated with higher expression of 232 genes and lower expression of 212 genes compared with non-severe PPE. Upregulated gene signatures associated with disease progression in severe PPE were enriched in neutrophil degranulation, glycolysis/gluconeogenesis, HIF-1 signaling, and inflammatory response pathways. Elevated HMGB2 levels in severe PPE enabled accurate discrimination from other pleural effusion cases, with an AUC of 0.93. In vitro infection with Streptococcus pneumoniae significantly increased HMGB2, IL1β, and IL8 expression in neutrophils and macrophages. Moreover, HMGB2 overexpression enhanced NF-κB activation as well as IL-1β and IL-8 levels in PGN-stimulated macrophages. These results suggest that HMGB2 regulates IL-1β and IL-8 via the NF-κB signaling pathway. CONCLUSIONS: Our study delineates molecular signatures driving PPE exacerbation and highlights HMGB2 as a novel biomarker and therapeutic target with potential to prevent severe PPE.
Mycoplasma pneumoniae infection impairs asthma control in pediatric patients and exacerbates allergic airway inflammation.
Yan C, Jia X, Ren X … +18 more , Chen Y, Liu X, Su A, Du B, Zhao H, Feng Y, Xue G, Cui J, Ke Y, Gan L, Feng J, Fan Z, Fu T, Xu Z, Yu Z, Yang Y, Zhang T, Yuan J
Respir Res · 2026 Jun · PMID 42277784 · Full text
OBJECTIVE: To analyze the effect of Mycoplasma pneumoniae (M. pneumoniae) infection on asthma control and its underlying characteristic mechanisms, and to provide evidence-based support for the clinical management of ast...
OBJECTIVE: To analyze the effect of Mycoplasma pneumoniae (M. pneumoniae) infection on asthma control and its underlying characteristic mechanisms, and to provide evidence-based support for the clinical management of asthma control in children with asthma. METHODS: We enrolled children with asthma and performed a retrospective medical record review, M. pneumoniae detection and isolation from respiratory samples, in vitro antibiotic susceptibility testing, and metabolomic sequencing of bacteria. An ovalbumin-induced allergic asthma model was established using BALB/c mice, which were further divided into the M. pneumoniae-infected asthma group and the non-infected asthma group. Bronchoalveolar lavage fluid from the mice was subjected to detection of M. pneumoniae DNA and 16 S rRNA gene sequencing. Lung tissues were processed for hematoxylin-eosin staining to assess inflammatory infiltration. Periodic acid-Schiff staining was used to evaluate mucus hypersecretion. Metabolomic profiling and transcriptomic analysis were also performed. RESULTS: We included 145 children with asthma in the clinical cohort. The uncontrolled asthma rate in patients with asthma and M. pneumoniae co-infection was significantly higher than that in patients with asthma only. Among the respiratory specimens, 28 M. pneumoniae nucleic acid-positive samples were identified as genotype M4-5-7-2, and all of these strains carried an A2063G mutation in the 23 S rRNA gene. In the murine asthma model, M. pneumoniae infection significantly exacerbated allergic asthma. Specifically, M. pneumoniae infection led to aggravated allergic symptoms, increased airway hyperresponsiveness, elevated serum immunoglobulin E levels, and higher pathological scores in lung tissue as shown by hematoxylin-eosin staining and periodic acid-Schiff staining. Consistently, 16 S rRNA gene sequencing and transcriptomic and metabolomic analyses showed that M. pneumoniae infection was accompanied by changes in respiratory microbiota composition and altered the phosphatidylinositol 3-kinase/protein kinase signaling pathway, as well as variations in butanoate metabolism profiles. Notably, the changes of butanoate metabolism may be correlated with sophorose, which is a metabolite produced by M. pneumoniae. CONCLUSION: This study shows that M. pneumoniae infection reduces the level of asthma control in pediatric patients with asthma. In the murine asthma model, M. pneumoniae infection exacerbates allergic airway inflammation, which may be correlated with altered butanoate metabolism induced by the infection.
Peripheral immune profiling identifies CD8⁺ T and CD4⁺ T TIGIT⁺ cells as independent prognostic markers for first-line immune checkpoint inhibitors in advanced non-small cell lung cancer.
Park J, Choi J, Lee S … +6 more , Kim CR, Lee Y, Park J, Lee Y, Shin YK, Lee SY
Respir Res · 2026 Jun · PMID 42271410 · Full text
BACKGROUND: Immune checkpoint inhibitors (ICIs) have demonstrated substantial clinical benefits in advanced non-small cell lung cancer (NSCLC); however, a subset of patients experience early disease progression despite P...
BACKGROUND: Immune checkpoint inhibitors (ICIs) have demonstrated substantial clinical benefits in advanced non-small cell lung cancer (NSCLC); however, a subset of patients experience early disease progression despite PD-L1 expression, highlighting the need for biomarkers that better reflect systemic immune competence. We performed comprehensive peripheral immune profiling of patients with advanced NSCLC receiving first-line ICI therapy. METHODS: Blood samples were collected from patients with advanced NSCLC prior to the initiation of first-line ICI-based therapy. A total of 23 lymphocyte subsets and 13 soluble immune-related factors were analyzed, and multivariate models were used to identify independent prognostic biomarkers. RESULTS: A total of 74 patients with advanced NSCLC who received first-line ICI therapy were included in this study, none of whom harbored EGFR, ALK, or ROS1 mutations. In multivariate analyses, elevated CD4⁺ T cell immunoreceptor with Ig and ITIM domains (TIGIT)⁺ frequencies independently predicted shorter progression-free survival (hazard ratio (HR) = 3.74, p < 0.001), along with increased CD8⁺ terminally differentiated effector memory T cells re-expressing CD45RA (T) cells (HR = 1.98, p = 0.01). Consistent with this finding, patients with CD4⁺ T TIGIT⁺ high group exhibited a higher proportion of non-responders (stable or progressive disease) at best response. Non-responder-to-responder transitions between first and best response assessments were observed in the CD4⁺ T TIGIT⁺ low and CD8⁺ T low groups (p = 0.023 and 0.041, respectively), but not in the corresponding high groups. Cytokine profiling revealed significantly lower granzyme B levels in the CD4⁺ T TIGIT⁺ high group (p = 0.023). CONCLUSIONS: Baseline frequencies of peripheral CD4⁺ T TIGIT⁺ and CD8⁺ T cells were independently associated with survival outcomes in advanced NSCLC patients receiving first-line ICI-based therapy, suggesting that peripheral T cell immunophenotyping at treatment initiation may provide prognostic information beyond conventional biomarkers. Further studies incorporating external validation in independent cohorts, longitudinal immune profiling, and deeper T cell subset characterization are warranted to validate these findings and to elucidate the immune dynamics underlying treatment response and resistance.
Vacuum-stabilized lung window enables real-time and simultaneous imaging of vascular and calcium responses to hypoxia in vivo.
Liu J, Shao J, Liao P … +6 more , Song X, Yang W, Yu C, Xiao R, Zhu L, Hu Q
Respir Res · 2026 Jun · PMID 42271323 · Full text
BACKGROUND: This study introduced a vacuum-stabilized lung window technique for intravital imaging, which for the first time enabled the simultaneous, high-resolution, real-time monitoring of both pulmonary arterial vasc...
BACKGROUND: This study introduced a vacuum-stabilized lung window technique for intravital imaging, which for the first time enabled the simultaneous, high-resolution, real-time monitoring of both pulmonary arterial vascular reactivity and dynamic changes in intracellular calcium signaling smooth muscle cells during acute hypoxic pulmonary vasoconstriction (HPV) in spontaneously breathing mice. METHODS: By integrating two-photon microscopy with intravascular fluorescent tracers (FITC, Evans Blue) and a smooth muscle-specific genetically encoded calcium indicator (GCaMP6f), this technique enabled stable imaging of pulmonary arteries within a diameter range of 13.95-80.16 μm and supported the systematic extraction and analysis of calcium signals from multiple regions of interest along the longitudinal axis of the vascular wall. RESULTS: Acute hypoxia (10% O, 30 min) elicited a time-dependent vasoconstriction, with an average 8% reduction in diameter of 30-50 μm pulmonary arteries. Hypoxia triggered PASMC calcium signals characterized by a distinct latency period and marked spatial heterogeneity, with the earliest calcium responses observed in 30-40 μm arteries. Pharmacological intervention with dasatinib prolonged the latency of the calcium response and enhanced the amplitude of calcium oscillations, with effects preferentially targeting vessels in the 30-50 μm range. Simultaneous recordings confirmed that the rise in intracellular calcium consistently preceded vasoconstriction, and revealed that dasatinib treatment modulated calcium-contraction coupling in a vessel size-dependent manner. CONCLUSIONS: The technological platform established in this study overcomes the limitations of traditional approaches, simultaneously monitoring pulmonary artery function and cellular Ca signaling mechanisms in HPV.
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