Lung最新文献

Purpose: Lactoferrin (LTF) plays a crucial role in iron homeostasis, immune response, and inflammation. In the context of chronic obstructive pulmonary disease (COPD), LTF's expression is significantly influenced by environmental factors, particularly cigarette smoke. The pathological mechanism by which cigarette smoke regulates LTF and affects iron metabolism in COPD remains unclear. This study aims to clarify the mechanism therein.

Methods: In this study, cigarette smoke extract (CSE) was used to construct mouse and cell models of chronic obstructive pulmonary disease (COPD). Transcriptomic and proteomic tests were performed on the lung tissues of the mouse model of COPD to screen or measure the Hub gene. The interaction network prediction of LTF-related proteins was carried out using the STRING database. The Beas-2B cell model with LTF overexpression and interference was constructed by lentivirus transfection, and then the cell viability, cytotoxicity, lipid reactive oxygen species (ROS), iron ion deposition, and iron-related markers of bronchial epithelial cells after CSE exposure were detected. The morphological changes of mitochondria in bronchial epithelial cells were observed by transmission electron microscopy. The expression levels of ACSL4 and GPX4 proteins in bronchial epithelial cells were detected by Western blotting.

Results: The expression of LTF is down-regulated in both lung tissue of the COPD mouse model and bronchial epithelial cells, and it plays a key role in ferroptosis of CSE-induced bronchial epithelial cells. In the LTF-interfered bronchial epithelial cells treated with CSE, ferroptosis-related markers (such as ROS and MDA) were significantly increased, GSH was significantly decreased, mitochondrial volume was reduced, cristae were decreased, the expression of ACSL4 protein was increased, while the expression of GPX4 protein was decreased. Meanwhile, overexpression of LTF can reverse the ferroptosis status of bronchial epithelial cells treated with CSE.

Conclusion: Under CSE induction, the decrease in LTF expression level will lead to the accumulation of ferrous ions in bronchial epithelial cells and induce the occurrence of ferroptosis.

Background: Cigarette smoking (CS), the major risk factor for chronic obstructive pulmonary disease (COPD), induces oxidative stress, mitophagy, and ferroptosis. Because FUN14 domain-containing protein 1 (FUNDC1), a mitophagy receptor, may drive the onset and progression of COPD, we investigated its role in CS-induced ferroptosis in COPD and to explore the underlying cellular signaling mechanisms.

Methods: Wild-type (C57BL/6J background) and FUNDC1-knockdown (KD) mice were exposed to CS for 12 weeks. FUNDC1-KD and FUNDC1-overexpressing (OE) alveolar epithelial A549 cells were exposed to CS extracts (CSE) in the presence and absence of the JNK inhibitor, SP6001 (10 mM). Oxidative stress, inflammation, mitochondrial function, and ferroptosis were measured.

Results: FUNDC1 expression was increased in lung tissues from COPD patients and CS-exposed mice. CS exposure induced airway inflammation, reduced lung function, and enhanced ferroptosis in mice. FUNDC1-KD prevented CS-induced lung injury in mice. Similarly, CSE exposure up-regulated FUNDC1 expression, promoted ferroptosis, inflammation, oxidative stress, lipid peroxidation, and mitochondrial damage in A549 cells. FUNDC1-KD prevented CSE-induced cellular damage. Transcriptomic data indicated that FUNDC1 mediated ferroptosis through the JNK pathway. These in vitro results were further confirmed by pretreatment with the JNK inhibitor SP6001.

Conclusion: FUNDC1 plays an important role in CS-exposed alveolar epithelial cells and in a mouse model of COPD through the JNK-ferroptosis pathway.

Introduction: Lactate has emerged as a multifunctional signaling molecule regulating various physiological and pathological processes. Furthermore, lactylation, a newly identified posttranslational modification triggered by lactate accumulation, plays significant roles in human health and diseases. This study aims to investigate the roles of lactate/lactylation in respiratory diseases.

Methods: Comprehensive literature analysis was conducted using PubMed database, utilizing a range of keywords including "lactate", "lactylation", "lung", "pulmonary", and "disease".

Results: Emerging evidence indicates that increased glycolytic flux, resultant lactate accumulation, and elevated lactylation levels play key roles in the pathogenesis of respiratory diseases, including lung cancer, idiopathic pulmonary fibrosis (IPF), acute lung injury/acute respiratory distress syndrome (ALI/ARDS), pulmonary hypertension (PH), and asthma. Under these conditions, the upregulation of glycolytic enzymes and increased lactate transport are observed. Elevated levels of lactate and lactylation profoundly influence multiple biological processes, such as inflammatory responses, immune cell activation, autophagy, ferroptosis, EMT, tumorigenesis, and fibrosis, and lactate/lactylation-targeted therapies have demonstrated therapeutic efficacy against diverse respiratory illnesses.

Conclusions: Elevated levels of lactate and lactylation play key roles in the pathogenesis of various respiratory diseases, and lactate/lactylation-targeted therapies appear to be potential therapeutic strategies for these respiratory diseases.

Introduction: Rhinovirus (RV) is the leading cause of exacerbations of lung disease. A sensory neuronal model, derived from human dental pulp stem cells and differentiated into peripheral neuronal equivalents (PNEs), was used to examine RV's effects on airway sensory nerves. We investigated whether RV can directly infect and alter PNEs or whether it exerts effects indirectly via the release of mediators from infected epithelial cells.

Methods: PNEs or primary bronchial epithelial cells (PBECs) were infected with the RV-A16 strain. Viral replication was confirmed by viral titration assays, immunofluorescence (IF) for the double-stranded RNA (dsRNA) replication intermediate and western blotting (WB). RNA sequencing was used to determine transcriptomic changes in PNEs, and inflammatory responses were assessed by inflammatory microarray. Calcium mobilisation assays were used to investigate the effect of interleukin-1β (IL-1β) on PNE transient receptor potential (TRP) A1 channel responses.

Results: Viral titrations, WB and IF confirm RV-A16 entry and replication in PNEs and PBECs. Gene signatures associated with antiviral immune responses, sensory neuropathies and N-Methyl-D-aspartic acid (NMDA) receptor activity were upregulated in RV infected PNEs. Several cytokines were increased from PNEs and PBECs following RV infection, most notably IL-1β. Treatment of PNEs with IL-1β resulted in heightened TRPA1 channel sensitivity.

Conclusion: We report the suitability of an airway neuronal model for the study of the direct effects of RV infection on nerves. RV-induced release of IL-1β from airway epithelium heightens neuronal TRPA1 responses suggesting a mechanism for virus-induced cough hypersensitivity.

Introduction: Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) are common viral etiologies of respiratory infections. Although co-infection with other respiratory pathogens is frequently observed, its clinical significance remains unclear.

Methods: We retrospectively analyzed 57,746 patients who underwent FILMARRAY®, a comprehensive multiplex polymerase chain reaction testing, between November 2020 and March 2023. Clinical features were compared between single infection and co-infection involving RSV or hMPV using χ² or Fisher's exact tests. Multiple logistic regression was performed to identify associations with bronchial asthma (BA) exacerbation, adjusting for age, sex, testing period, and RSV co-infection.

Results: Among RSV-positive patients, co-infection was associated with higher prevalence of BA history, wheeze, BA exacerbation, combined BA history and exacerbation, systemic steroid use, and age under 6 years compared to that with single infection. RSV co-infection with coronavirus, parainfluenza virus, adenovirus, and rhinovirus/enterovirus was particularly associated with BA exacerbation. Age under 6 years and RSV co-infection were identified as independent risk factors for BA exacerbation using multiple logistic regression. In contrast, no associations were observed in the hMPV co-infection.

Conclusion: RSV co-infection with other respiratory viruses increases the risk of BA exacerbation, especially in age under 6 years patients. Given the proven efficacy of RSV vaccine for adults and monoclonal antibody for high-risk children in preventing RSV-related lower respiratory tract disease, RSV-targeted prevention strategies for younger children appear effective in reducing respiratory disease burden.

Chronic Obstructive Pulmonary Disease (COPD) is a complex, heterogeneous condition characterized by diverse clinical phenotypes and underlying pathobiological mechanisms. Traditional "one-size-fits-all" management strategies have limited effectiveness in addressing this heterogeneity. The Treatable Traits (TTs) approach represents a precision medicine paradigm that targets specific, identifiable, and modifiable traits in individual patients, regardless of diagnostic labels. This paper explores the alignment between the TTs framework and emerging pharmacological therapies, with a particular focus on anti-inflammatory agents and bronchodilators currently under investigation. Each drug category is mapped to relevant TTs, such as eosinophilic or neutrophilic inflammation, corticosteroid resistance, chronic bronchitis, and frequent exacerbations. This review highlights the importance of biomarker-driven phenotyping and real-world data in designing TT-based clinical trials. It emphasizes challenges such as trait instability over time, comorbidity clustering, and trial design heterogeneity. Moreover, we advocate for incorporating digital health tools, long-term follow-up, and cost-effectiveness analyses to ensure translational relevance. In conclusion, integrating emerging therapies with the TTs approach holds substantial promise for personalizing COPD management, improving outcomes, and facilitating targeted drug development.

We evaluated relationships between changes in lung function and changes in patient-reported outcomes (PROs) in 736 patients with idiopathic pulmonary fibrosis (IPF) enrolled in the IPF-PRO Registry. Weak correlations were observed between changes in percent predicted values for forced vital capacity or diffusing capacity of the lungs (DLco) and changes in St George's Respiratory Questionnaire (SGRQ) total and activity scores and the 12-item Short Form Survey (SF-12) physical component summary score over 12-month periods. Patients who had a deterioration in SGRQ activity score or SF-12 PCS score of ≥ 5 units had numerically larger declines in lung function than other patients, but the differences were small. The weak relationships observed between changes in lung function and changes in PROs underscore the importance of evaluating both changes in lung function and changes in HRQL in clinical practice and clinical trials.

Introduction: Asthma is a heterogenous disease shaped by different inflammatory pathways. The aim is to investigate transcriptomic profiles in asthmatic patients and associate these with inflammation, airway damage and lung function.

Methods: Adult asthma patients attending the outpatient pneumology clinic in our tertiary center, underwent diagnostic sputum induction and upon consent remaining sputum RNA was used for bulk RNA-sequencing (n = 56) coupled with unsupervised clustering. A retrospective analysis of comorbidities was performed. Sputum cytokine mRNA levels were determined via qPCR. Airway damage markers were determined in sputum supernatant RESULTS: Unsupervised clustering subdivided all asthmatic patients in one of three clusters. Cluster 1 contained most of the pauci-granulocytic asthma patients in whom oxidative stress was upregulated and TLR-signalling and several cytokine pathways down-regulated. Cluster 2 had upregulated S100 family signalling pathway genes, was mostly associated to type 2 inflammation with elevated sputum eosinophils, epithelial damage, IL-4 mRNA levels and allergy. Asthma patients in cluster 3 had worse lung function, upregulated inflammatory genes, increased sputum neutrophils and calprotectin levels.

Conclusion: Three different asthma clusters could be identified bridging over the classical type 2/non-type 2 classification.

Clinical trial: ClinicalTrials.gov Identifier: NCT01224938 registered on 19 October 2010.

Background: Cytokeratin (CK)18 is present in the bronchi and alveolar epithelium of the lung, and its cleavage product, CK-18M30, serves as a biological marker of apoptosis. However, the specific roles of CK-18 and CK-18M30 in acute exacerbation of chronic obstructive pulmonary disease (AECOPD) remain unclear.

Methods: This study enrolled 289 patients with AECOPD who met the inclusion criteria. Demographic information and clinical characteristics of the patients were documented. A 3-year follow-up period was implemented to evaluate acute exacerbations and mortality. Serum CK-18 and CK-18M30 concentrations were measured using enzyme-linked immunosorbent assays.

Results: Serum concentrations of CK-18/CK-18M30 at admission in patients with AECOPD were higher than those in the control group. As severity increased, serum CK-18/CK-18M30 levels increased progressively in AECOPD patients. Pearson's correlation analysis revealed that serum CK-18/CK-18M30 concentrations were positively correlated with several clinical parameters. Linear and logistic regression models demonstrated positive correlations between serum CK-18 and CK-18M30 levels at admission and severity scores. Furthermore, higher serum CK-18/CK-18M30 levels at admission were associated with increased frequency of death and acute exacerbation in patients with AECOPD within 3 years.

Conclusion: Serum CK-18/CK-18M30 levels at admission were positively correlated with severity and poor prognosis in patients with AECOPD within 3 years. Therefore, serum CK-18 and CK-18M30 concentrations may serve as novel diagnostic and prognostic biomarkers for patients with AECOPD.