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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.

Purpose: Lung cancer is the leading cause of cancer death worldwide which includes two main types of carcinoma distinguished in non-small cell lung cancer (NSCLC) involving epithelial cells, and small cell lung cancer (SCLC) affecting neuronal cells and hormone secreting cells. Studies have shown a causal link between inflammation/innate immunity and onset of NSCLC. The present study aimed to evaluate the expression of Toll-like receptors (TLRs) 4 and TLR8 in peripheral blood mononuclear cells (PBMC) and in lung tissues of patients with NSCLC, useful for future prognostic tools for NSCLC.

Methods: Patients surgically treated for NSCLC with anatomical resections and patients with benign disease were enrolled. The expression levels of TLR4 and TLR8 were determined by real time PCR and by immunohistochemical analysis in PBMC and in lung tissues, respectively. A preliminary in silico analysis including 1194 arrays from healthy and cancer tissues were extracted by Genevestigator database. The association between TLRs gene expression and survival outcome was also investigated.

Results: Bioinformatics analysis revealed that downregulation of TLR4 and TLR8 positively impacts the survival in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). However, no significant differences in TLR4 and TLR8 gene expression between case and control groups were observed in PBMC. A positive correlation was found in their expression levels. Interestingly, immunohistochemical analysis showed that the levels of TLR4 and TLR8 were higher in the lung tissues of patients with NSCLC than in the control group in terms of staining intensity and positive cells.

Conclusion: Albeit the precise role of TLRs is not fully defined, this study identified the potential involvement of TLR4 and TLR8 in the pathogenesis of NSCLC. Our data led us to hypothesize their potential role in overall survival which deserves to be explored further to establish whether TLR4 and TLR8 can represent positive prognostic indicators of disease in NSCLC.

Background: Although blood eosinophil count (BEC) has been extensively studied as a biomarker in chronic obstructive pulmonary disease (COPD), there remain challenges and controversy in using a single reading. It has not been determined whether the difference in BEC between baseline and that during an acute exacerbation of COPD (AECOPD) has any role in predicting subsequent AECOPD.

Methods: A prospective study was conducted to investigate the possible role of differences in BEC from baseline to that during AECOPD to predict future AECOPD risk. The BEC difference was expressed as absolute eosinophil difference: BEC at index moderate-to-severe exacerbation (E_i) - baseline BEC (E₀).

Results: Among 348 Chinese patients with COPD, 158 who experienced an index moderate-to-severe AECOPD were analyzed. Using the cut-off of 105 cells/µL for absolute eosinophil difference as determined by receiver operating characteristic (ROC) analysis, patients with absolute eosinophil difference ≥ 105 cells/µL had a shorter time to subsequent AECOPD with adjusted hazard ratio (aHR) of 1.68 (95% CI = 1.02-2.74; p = 0.040). They also had a higher annual number of subsequent AECOPD (2.49 ± 2.84/year vs 1.58 ± 2.44/year, p = 0.023). Similar findings were shown in the subgroup with stable-state baseline BEC < 300 cells/µL.

Conclusion: Greater difference in BEC between baseline and upon moderate-to-severe AECOPD might be associated with shorter time to next AECOPD, as well as more episodes of subsequent AECOPD.

Purpose: Cigarette smoke (CS) has been demonstrated to mediate oxidative stress (OS) and epithelial-mesenchymal transition (EMT) in bronchial epithelial cells, thereby contributing to airway remodeling in chronic obstructive pulmonary disease (COPD). Studies have shown upregulation of Ubiquitin C-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme, in the airway epithelium of smokers. Many studies indicate that UCHL1's regulation of EMT and OS has a complex role in various cell types, including respiratory epithelium. Thus, we aimed to investigate UCHL1's regulation of EMT, OS, and related mechanisms in cigarette smoke-exposed airway epithelium.

Methods: Exposure to cigarette smoke (CS) or cigarette smoke extract (CSE) was employed to establish both animal and cellular models. Protein expression was analyzed using immunohistochemistry, immunofluorescence, and Western blotting. Lentiviral UCHL1 or GPX1-siRNA was used to modulate UCHL1 or GPX1 expression, respectively. Transwell assays were employed to evaluate cell migration and EMT-related alterations. Oxidative stress levels were assessed using specific assay kits.

Results: This study validated that exposure to CS induces UCHL1 expression in bronchial epithelial cells both in vitro and in vivo, a phenomenon positively correlated with increased OS and EMT in the airway. Notably, UCHL1 overexpression counteracted CSE's impact on EMT markers, cell migration, and oxidative stress in BEAS-2B cells, while UCHL1 knockdown exacerbated these effects. Furthermore, in BEAS-2B cells treated with CSE, upregulation of UCHL1 was found to enhance the expression of glutathione peroxidase 1 (GPX1), an antioxidant enzyme. The effect of UCHL1 overexpression on EMT-related protein markers and cell migration was reversed upon GPX1 silencing via siRNA.

Conclusions: These findings suggest that UCHL1-mediated regulation of GPX1 expression alleviates cigarette smoke-induced EMT-related protein markers change and cell migration in BEAS-2B cell.

Purpose: The natural history of IPF remains unpredictable despite antifibrotic treatment. In addition, some patients discontinue treatment due to the occurrence of adverse events. To date, no data exist on either the effect of long-term treatment or predictors of treatment response. In the present study, we aim to evaluate the functional trajectory of IPF patients treated with antifibrotics for at least three years and to establish predictors of treatment response.

Methods: This multicenter study enrolled long-term survivors IPF patients provided they had stopped treatment for no longer than one month during at least three-year study period. Based on the absolute decline of FVC%predicted (pred.) observed during the 3-year treatment and normalized per year, patients were defined as progressors (≥ 5%) or non-progressors (< 5%).

Results: We identify 172 IPF patients who completed three years of antifibrotic treatment with no interruption. The 27% of these IPF patients progressed despite complete adherence to treatment. Progressors were more likely to be non-smokers compared to non-progressors, with higher occurrence of diarrhea and with a more preserved lung function at diagnosis. FVC %pred. and liters at diagnosis, a greater FVC decline in the 1-st year of follow up, being non-smokers, and complaining of diarrhea over treatment are independent predictors of progression.

Conclusion: Almost one third of IPF patients adherent to three years of antifibrotics experience progression. A functional decline at first year of treatment despite preserved lung function at diagnosis, non-smoking status, and occurrence of diarrhea over treatment are independent predictors of disease progression.

Background: m6A RNA methylation is a critical epigenetic modification involved in the pathogenesis of pulmonary arterial hypertension (PAH). While macrophage-mediated inflammation plays a central role in PAH, the specific contributions of m6A regulators within macrophages are not yet fully understood. This study explores the role of METTL3 in macrophages, with particular emphasis on its contribution to the progression of PAH.

Methods: SU5416/Hypoxia (SuHx) PAH mouse models were treated daily with STM2457, a selective METTL3 antagonist, or vehicle for 10 days. Additionally, SuHx PAH was induced in Mettl3flox/floxlyz2cre + and Mettl3flox/flox mice using genetic approaches. Pulmonary acceleration time to pulmonary ejection time (PAAT/PAET) and right ventricular free wall (RVFWD) were measured by ultrasound. Hemodynamic parameters, including right ventricular systolic pressure (RVSP), were assessed. Pulmonary vascular and right heart remodeling were evaluated using HE staining, while vascular and right heart fibrosis were assessed by Masson's trichrome staining. The expression of fibrosis-associated genes was quantified by qPCR. Macrophage activation in tissues was determined via CD86 and CD206 immunofluorescence staining, and the expression of inflammatory cytokines and fibrosis-associated genes was quantified by qPCR.

Results: METTL3 expression was significantly upregulated in the lungs and macrophages of PAH models. Treatment with STM2457 reversed the progression of SuHx PAH, as evidenced by a reduction in RVSP, attenuation of pulmonary vascular and right heart remodeling, and decreased fibrosis in both the heart and lungs. Furthermore, the expression of fibrosis-associated genes in the right heart, including Col1a1, Col1a3, and α-SMA, was downregulated following STM2457 treatment and METTL3 depletion in macrophages. Both STM2457 treatment and METTL3 depletion resulted in a significant reduction in the number of CD86⁺ and CD206⁺ macrophages, accompanied by a suppression of pro-inflammatory cytokines such as IL-1β and iNOS, alongside an upregulation of anti-inflammatory cytokines, including IL-10 and Arg1.

Conclusion: STM2457 treatment and METTL3 depletion in macrophages effectively reversed SuHx PAH by modulating macrophage inflammatory responses and alleviating pulmonary vascular and right heart remodeling, as well as fibrosis. These findings underscore the role of METTL3 in PAH pathogenesis by regulating macrophage function and inflammation.

Aim: The important role of phosphodiesterase 4B (PDE4B) inhibition on lipopolysaccharide (LPS)-induced ALI has been reported. However, the corresponding mechanisms remain unclear. In the present study, the relationship between PDE4B and phosphorylation of p65 (Ser468) in LPS-induced injury by in vivo and in vitro models was investigated.

Methods and results: pde4b^+/+ mice, inflammation was significantly up-regulated after LPS stimulation, including the highest number of immune cells, especially neutrophils, and the level of pro-inflammatory cytokines measured by ELISA, while all those were blunted in pde4b^-/- mice. Moreover, pde4b^-/- mice improved the expression of PKA in lung tissues and down-regulated the IKKα/β-NF-κB p65 signaling determined by western blotting. In vitro experiments in MH-S cells revealed that siRNA-mediated specific silence of PDE4B expression resulted in a decrease of inflammatory markers and phosphorylation of p65 at Ser468 after LPS treatment, but overexpressing PDE4B increased the inflammation and phosphorylation of p65 at Ser468. In MH-S cells, luciferase analysis indicated that PDE4B acts as a positive regulator of p65 in inflammation. PKA inhibitor (H-89) increased pP65 and PDE4B expression, while PKA activator (6-BZ-cAMP) showed the opposite effect in macrophages. More importantly, the proteasome-mediated degradation of cAMP effector was negatively correlated with the phosphorylation of p65 (Ser468) and PDE4B expression in MH-S cells.

Conclusions: PDE4B plays a critical role in orchestrating LPS-induced acute lung inflammation by cAMP/PKA axis-mediated phosphorylation of p65.

Refractory chronic cough (RCC) remains a persistent clinical challenge, often resistant to traditional treatments. Emerging evidence now positions RCC as a disorder rooted in hypersensitivity, driven primarily by central neural processes rather than external physiological causes. Central to this understanding is the concept of interoception-the brain's ability to perceive and interpret internal bodily signals. Neuroimaging research has identified abnormalities in brain regions associated with interoception and inhibitory control among RCC patients. Interestingly, RCC shares neurophysiological characteristics with other disorders like overactive bladder and urinary urge incontinence (OAB/UUI), which also involve dysregulated interoceptive and inhibitory mechanisms. Behavioral treatments for OAB/UUI are highly effective and are regarded as the first-line treatment in many consensus guidelines. OAB/UUI behavioral treatments have been shown to induce central neuroplastic changes, further underscoring their efficacy and potential parallel for RCC interventions. Behavioral cough suppression therapy (BCST), an efficacious treatment for RCC, may leverage similar neuroplastic adaptations, enhancing interoceptive processing and inhibitory control. Given the multi-dimensional nature of interoception, which encompasses sensory perception shaped by learning, memory, and emotional context, BCST's engagement of multiple neural pathways offers an alternative therapeutic option compared to single-mechanism pharmacological treatments. Future research should prioritize exploring the mechanistic underpinnings of BCST and other interoception-based therapies for developing more comprehensive and effective treatment options. Such research holds promise for improving patient outcomes, alleviating the significant healthcare burden associated with RCC, and advancing our understanding of central hypersensitivity disorders.

Objective: This integrative review aims to evaluate the efficacy and safety of nebulized tranexamic acid (TXA) in managing hemoptysis, assessing its potential as a non-invasive alternative to traditional invasive procedures.

Methods: An integrative review was conducted in accordance with PRISMA guidelines and was registered on PROSPERO (CRD42024584812). The search included databases such as PubMed, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials, encompassing studies published up to August 7, 2024. The inclusion criteria focused on human studies that utilized nebulized TXA for hemoptysis, with reported outcomes on bleeding cessation, recurrence, and adverse effects. Extracted data included patient demographics, underlying conditions, TXA dosing, administration methods, clinical outcomes, and reported adverse events.

Results: Fourteen studies met the inclusion criteria: five original research studies, and nine case reports involving 13 patients. The majority of patients were older adults with underlying conditions such as chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), and infections. Nebulized TXA demonstrated high efficacy in controlling hemoptysis across studies, with most patients experiencing rapid cessation of bleeding. In a randomized controlled trial, 96% of patients receiving TXA achieved complete resolution of hemoptysis within five days, compared to 50% in the placebo group. TXA use was also associated with shorter hospital stays and a decreased need for invasive interventions. The safety profile of nebulized TXA was favorable. However, the long-term safety of nebulized TXA, remains unexplored.

Conclusion: Nebulized tranexamic acid appears to be an effective and safe non-invasive treatment option for hemoptysis, particularly in non-massive cases. It provides rapid control of bleeding and may reduce the requirement for invasive procedures. However, further large-scale randomized controlled trials are necessary to confirm these findings and to establish optimal dosing regimens.

Background: Guidelines specify steroids as therapy for acute exacerbation of chronic obstructive pulmonary disease (AECOPD). However, the duration of survival benefit associated with steroids and the optimal dosage of nebulized budesonide (NB) during hospitalization remain unclear.

Methods: We conducted a retrospective study of hospitalized AECOPD patients. The primary endpoint was all-cause mortality after discharge. Cox regression analysis was used to determine the impact of steroid therapy on survival.

Results: Wilcoxon analysis showed the positive impact of systemic corticosteroids (SCs) therapy on survival during the early stage of follow-up (P = 0.038). NB therapy was associated with a significantly reduced risk of death within six months after discharge (adjusted Hazard ratio (HR), 0.36; 95% confidence interval (CI) 0.15-0.88). Subgroup analysis suggested that fewer than two AEs in the previous year (adjusted HR 0.05; 95% CI 0.01-0.38), age >  = 65 years (adjusted HR 0.31; 95% CI 0.11-0.90), body mass index (BMI) < 25 kg/m² (adjusted HR 0.33; 95% CI 0.12-0.92), and smoking index > 40 packets/year (adjusted HR 0.17; 95% CI 0.04-0.79) were involved in this association. Finally, treatment with a total dose of NB <  = 60 mg during hospitalization reduced six-month mortality compared to treatment without steroids (adjusted HR 0.39; 95% CI 0.17-0.92), but not the total dose of NB > 60 mg.

Conclusions: NB therapy for hospitalized AECOPD patients significantly reduced six-month mortality. Subgroup analysis showed that certain populations benefited more from NB therapy, and <  = 60 mg NB might be suitable treatment for hospitalized AECOPD patients.