Lung最新文献

Purpose: The popularity of electronic cigarettes (e-cigarettes) has grown exponentially over the past few years, and teenagers now prefer them to tobacco cigarettes. We determined whether exposure to e-cigarette vapour (e-vapour) adversely affects ion transport using human airway epithelial cell lines 16HBE14o- and Calu-3 and well-differentiated primary human bronchial epithelial cells (HBEs).

Methods: We concurrently measured fluorescent signals and short-circuit current (I_SC), an indicator of electrogenic ion transport, in polarised epithelia. The P2Y receptor-mediated signalling pathway was used to induce an increase in intracellular calcium concentration ([Ca²⁺]_i) and I_SC. We used a single-polypeptide fluorescence resonance energy transfer reporter based on exchange proteins directly activated by cAMP (Epac) to measure forskolin-induced changes in cAMP and I_SC.

Results: We compared the effects of e-vapour to those of traditional cigarette smoke (CS) on the human airway cell models. In all three cell types, e-vapour, similar to CS, significantly reduced agonist-induced increases in Ca²⁺ or cAMP signalling and I_SC. However, reductions in the epithelial electrolyte transport activities did not correlate with any changes in the protein levels of various ion channels and transporters.

Conclusion: Our data suggest that e-vapour is not harmless and causes ion transport dysfunction similar to CS, thereby predisposing e-cigarette users to vaping-induced lung injury.

Histone deacetylases (HDACs), a class of enzymes involved in epigenetic modifications, play a pivotal role in modulating chromatin structure and gene expression. Among these, histone deacetylase 3 (HDAC3) has emerged as a key regulator in diverse cellular pathophysiological processes. The remarkable therapeutic potential of HDAC inhibitors in lung cancer has intensified research into the role of HDAC3 in pulmonary diseases. Through deacetylating histones and non-histone proteins, HDAC3 has been increasingly recognized for its critical involvement in regulating inflammatory responses, fibrotic processes, and oncogenic signaling pathways, positioning it as a compelling therapeutic target. This review systematically examines the structural and functional features of HDAC3 and discusses its multifaceted contributions to pulmonary pathologies, including lung injury, pulmonary fibrosis, and lung cancer. Additionally, we critically evaluate advances in HDAC inhibitor-based therapies for lung cancer, with emphasis on the development of HDAC3-targeted therapies. As a promising therapeutic target for pulmonary diseases, HDAC3 needs to be further investigated to elucidate its regulatory mechanisms and facilitate the development of selective inhibitors for clinical translation.

Background: Monoclonal antibody therapies targeting specific inflammatory pathways have shown potential in treating chronic obstructive pulmonary disease (COPD). However, the efficacy and safety of these treatments across different patient phenotypes remain uncertain.

Methods: This meta-analysis included 15 registered randomized controlled trials (RCTs) evaluating monoclonal antibodies targeting type 2 and non-type 2 inflammatory pathways in COPD. The primary outcomes assessed were rates of moderate to severe exacerbations, rates of severe exacerbations, lung function (pre- and post-bronchodilator FEV₁), St. George's Respiratory Questionnaire (SGRQ) scores, and safety-related events. Subgroup analyses were performed based on inflammatory phenotype, exacerbation frequency, and smoking status. Meta-regression was used to examine the influence of covariates, such as baseline FEV₁%pred and other demographic factors.

Results: Monoclonal antibody therapies significantly reduced the rates of moderate to severe exacerbations (RR 0.88, 95% CI 0.83-0.93) and severe exacerbations (RR 0.82, 95% CI 0.72-0.94). Subgroup analyses revealed more pronounced benefits in eosinophilic and frequent exacerbator phenotypes. Non-eosinophilic patients demonstrated a better response to IL-33-targeting therapies. Lung function and quality of life showed modest improvements across most therapies. Smoking status and baseline FEV₁ were significant modifiers of treatment efficacy. No significant increase in serious adverse events was noted.

Conclusions: Monoclonal antibody therapies, particularly those targeting type 2 inflammation, effectively reduce exacerbation rates in COPD, with greater benefits observed in patients with eosinophilic phenotypes and frequent exacerbations. Baseline lung function also influences treatment response. These findings underscore the importance of personalized, phenotype-driven treatment approaches and support the continued development of biologics for COPD management.

Introduction: Pneumonia is one of the most common complications in patients suffering multiple traumas and is associated with an exceptionally high mortality rate. MIP-3-alpha and MIP-3-beta are pro-inflammatory chemokines expressed in the pulmonary mucosa and are reported to play a crucial role in inflammation. Thus, the present study aimed to investigate whether there is an association between MIP-3-alpha- and MIP-3-beta expression and manifestation of pneumonia in patients suffering polytrauma.

Material and methods: This prospective outcome study was conducted at our level I trauma center, and 110 polytraumatized patients (Injury Severity Score ≥ 16, ≥ 2 body regions) were prospectively enrolled (median age, 39 years; median Injury Severity Score (ISS), 33; 70.9% male) over four years. Protein levels were assessed at admission (day 0) and subsequently on days 1, 3, 5, 7, and 10 during routine blood draws, utilizing one separation gel tube for each measurement. Furthermore, the correlation between MIP-3-alpha- and MIP-3-beta expression and the manifestation of pneumonia was calculated.

Results: We observed significantly higher levels of MIP-3-beta expression over the entire time course in the pneumonia cohort. MIP-3-alpha levels were elevated on days 3, 5, 7, and 10 post-trauma in patients suffering from pneumonia. In contrast, no comparable pattern was observed for other pro- and anti-inflammatory cytokines (e.g., IL-6 or TNF-alpha). A peak of serum level expression was documented on day 5 in both biomarkers (MIP-3-alpha 51.8 pg/mL; MIP-3-beta 328.0 pg/mL). ROC analysis provided a cut-off value of 19.3 pg/mL (sensitivity 0.87, specificity 0.33; AUC 0.757) for MIP-3-alpha, whereas a cut-off value of 209.5 pg/mL (sensitivity 0.78, specificity 0.34; AUC 0.757) was determined for MIP-3-beta on day 5.

Conclusion: The present study demonstrated elevated MIP-3-alpha and MIP-3-beta levels as sensitive pneumonia predictors in patients with multiple traumas. These biomarkers allow for identifying patients at high risk of developing pneumonia at an early stage.

Purpose: Toll-like receptor 4 (TLR4) is a transmembrane receptor promoting pro-inflammatory signalling, that is associated with the pathogenesis of pulmonary fibrosis. TLR4 is abundantly expressed on monocytes and the acceleration of TLR4 signalling induces the secretion of soluble TLR4 isoforms (sTLR4) in circulation. The aim of study was to evaluate the association of serum levels of sTLR4 with acute exacerbation (AE) and prognosis of patients with idiopathic pulmonary fibrosis (IPF).

Methods: This retrospective cohort study included 97 patients with IPF and 76 healthy participants. The association of serum sTLR4 levels with the onset of AE and the prognosis in 97 patients with IPF was analyzed.

Results: No significant difference in sTLR4 serum level was observed between the patients with IPF and healthy participants. Kaplan-Meier curves showed that patients with sTLR4 ≥ 2.2 ng/mL had a significantly higher incidence of AE-IPF and a significantly lower 5-year survival rate. Univariate and multivariate Cox hazard analyses demonstrated that sTLR4 ≥ 2.2 ng/mL was significantly associated with higher incidence of AE and poorer survival. In an exploratory analysis, a weak correlation was observed between sTLR4 levels and monocyte counts, and the incidence of AE-IPF was the highest in the patients with sTLR4 ≥ 2.2 ng/mL and monocyte counts ≥ 381/μL.

Conclusion: High sTLR4 level is associated with an increased incidence of AE-IPF and poor prognosis in patients with IPF. The combination of sTLR4 level and monocyte count might be used to stratify patients with IPF according to the risk for AE via reflecting monocyte activation.

Background: In severe asthma, intensive ("supratherapeutic") doses of inhaled corticosteroids (ICS) are often used. The prevalence of supratherapeutic ICS use and its impact on corticosteroid-related comorbidities is poorly understood. We aimed to describe the prevalence of supratherapeutic ICS use in severe asthma, its relation to corticosteroid-related comorbidities, and changes in prescribed and redeemed ICS dose after 12 months of biologic therapy.

Methods: Patients from the nationwide Danish Severe Asthma Register (DSAR) receiving biologic therapy > 12 months were included. Supratherapeutic doses were defined as > 1600 µg budesonide daily. Baseline characteristics, comorbidity burden, and change in ICS use after 12 months of biologic therapy was stratified according to ICS use at baseline.

Results: We included 652 patients in our analyses and 156 (24%) were supratherapeutic ICS users prior to initiation of biologic therapy. Supratherapeutic ICS users had a higher baseline prevalence of cataracts at 14 vs 8.1%; p = 0.025. No differences in other corticosteroid-related comorbidities were observed. No change in prevalence of prescribed supratherapeutic ICS was seen after 12 months of biologic therapy. However, a reduction in ICS adherence among supratherapeutic users was observed with 72% of patients demonstrating > 80% adherence at 12 months, compared to 83% at baseline (p < 0.001).

Conclusion: Supratherapeutic doses of ICS were used by almost one-fourth of the patients prior to initiation of biologic therapy and were associated with a higher prevalence of cataracts. Physician-driven ICS reduction was rare, yet supratherapeutic ICS users were found to self-regulate ICS therapy when treated with biologic therapy.

Purpose: Oxygen therapy is helpful for patients with breathing difficulties; however, sustained supplementation with high-concentration oxygen can cause hyperoxic acute lung injury. Sirtuin 2 (SIRT2), a nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylase, has been shown to be involved in pulmonary fibrosis, apoptosis, and inflammation. Here, we elucidated the role of SIRT2 in hyperoxic acute lung injury.

Methods: Wild-type (WT) mice and SIRT2-deficient (SIRT2^-/-) mice were exposed to room air or hyperoxia for 72 h. Thereafter, changes in hyperoxia-induced responses were evaluated in WT and SIRT2^-/- mice.

Results: SIRT2 expression was elevated in WT mice after hyperoxic exposure. We also observed that the levels of SIRT2 were higher in tracheal aspirates from newborns with bronchopulmonary dysplasia (BPD) than in those without BPD. Hyperoxia-induced inflammation and apoptosis were more considerably attenuated in SIRT2^-/- mice than in WT mice. We also observed an interaction between SIRT2 and forkhead box O3 (FOXO3), and that SIRT2 deficiency was associated with altered acetylation levels of FOXO3 and changes in the expression of its downstream targets. Further investigation of the therapeutic effect of SIRT2 showed that hyperoxic acute lung injury was alleviated when AGK2, a SIRT2 inhibitor, was administered.

Conclusion: Taken together, SIRT2 plays a critical role in the pathogenesis of hyperoxic acute lung injury by regulating apoptotic signaling. These findings indicated that SIRT2 is potentially a novel therapeutic strategy for hyperoxic acute lung injury.

Purpose: We used data from the IPF-PRO Registry of patients with idiopathic pulmonary fibrosis (IPF) to identify characteristics that predicted survival for a further > 5 years.

Methods: Participants had IPF that was diagnosed or confirmed at the enrolling center in the previous 6 months. Patients were followed prospectively. A Classification And Regression Tree (CART) was used to identify predictors of survival > 5 versus ≤ 5 years following enrollment. The following variables, assessed at enrollment, were considered: age; body mass index (BMI); former smoker; current smoker; time from first imaging evidence, symptoms, or diagnosis of IPF to enrollment; forced vital capacity (FVC) % predicted; diffusing capacity of the lungs for carbon monoxide (DLco) % predicted; antifibrotic drug use; supplemental oxygen use; history of cardiac disease; pulmonary hypertension; COPD/emphysema; and rural location.

Results: The analysis cohort comprised 819 patients, of whom 278 (33.9%) survived > 5 years. DLco % predicted, supplemental oxygen use and FVC % predicted were the most important variables for predicting survival > 5 versus ≤ 5 years after enrollment. The importance of these variables (scaled such that the most important had an importance of 100%) was 100%, 78.2% and 74.2%, respectively. The optimism-corrected area under the curve (AUC) of the CART was 0.72, with an accuracy of 0.72.

Conclusion: Among patients enrolled in the IPF-PRO Registry, a decision tree that included DLco % predicted, oxygen use and FVC % predicted facilitated the prediction of survival > 5 years. Understanding predictors of longer-term survival may facilitate conversations with patients about their prognosis and treatment.

Purpose: Pulmonary ischemia/reperfusion injury (IRI) causes endothelial barrier dysfunction and increased vascular permeability. Fibronectin leucine-rich transmembrane protein-3 (FLRT3) is known to regulate endothelial cell function, but its role in pulmonary IRI remains unexplored.

Methods: We established both a mouse lung I/R model and a hypoxia/reoxygenation (H/R) cell culture model using human pulmonary microvascular endothelial cells (HPMECs). The effects of FLRT3 manipulation were assessed through lentiviral-mediated overexpression and knockdown approaches. Lung injury was evaluated by histological analysis, immunohistochemistry, and lung injury scoring. Endothelial barrier function was assessed using transmission electron microscopy, Evans blue extravasation, and endothelial permeability assays.

Results: FLRT3 expression was predominantly localized in pulmonary endothelial cells and was downregulated following I/R injury. Lentiviral vectors overexpressing FLRT3 (LV-FLRT3, 1 × 10⁹ TU/ml) via tail vein injection before I/R surgery. FLRT3 overexpression effectively protected against lung injury by maintaining vascular integrity and reducing edema formation in I/R-challenged mice. In H/R-treated HPMECs, we identified that FLRT3 protein underwent autophagic-lysosomal degradation. Mechanistically, FLRT3 preserved endothelial barrier function through interaction with Rho family GTPase 3 (RND3), which prevented RhoA pathway-mediated cytoskeletal disruption. FLRT3 overexpression in HPMECs promoted cell migration, maintained cytoskeletal structure, and reduced endothelial hyperpermeability under H/R conditions. Importantly, RND3 knockdown in vivo significantly attenuated FLRT3's protective effects against I/R injury, as evidenced by increased lung injury scores, vascular permeability, and RhoA pathway activation.

Conclusions: Our findings reveal FLRT3, a critical regulator of endothelial barrier function during IRI through the RND3-RhoA pathway, is a potential therapeutic target for pulmonary IRI.