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Journal articleWang M, He Y, Hu H, et al., 2026,
Protective role of fatty acid oxidation against epithelial barrier dysfunction in allergic asthma.
, Redox Rep, Vol: 31BACKGROUND: Fatty acid oxidation (FAO) is implicated in lung diseases, but its role in bronchial asthma is not fully understood. We investigated its effect on airway epithelial barrier integrity. METHODS: Using a house dust mite (HDM)-induced murine asthma model and HDM, IL-4, IL-13, or TNF-α stimulated human primary bronchial epithelial cells (BECs) and bronchial epithelial (Beas-2b) cells, we modulated FAO with L-carnitine (agonist) and Etomoxir (inhibitor). BECs and Beas-2b cells were infected with lentivirus-mediated CPT1A shRNA prior to stimulation. Barrier function, mitochondrial oxidative stress, inflammation, and metabolism were assessed. RESULTS: FAO level in lungs negatively correlated with increased inflammation and tissue injury in HDM-induced asthmatic mice (all p < 0.05), while positively regulating tight junction protein expression. In BECs and Beas-2b cells, Etomoxir treatment and CPT1A knockdown exacerbated the impairment of FAO caused by various stimulants (all p < 0.05). Furthermore, FAO negatively regulated HDM/cytokine-induced epithelial barrier damage, hyperactive inflammatory response, and mitochondrial dysfunction in Beas-2b cells (all p < 0.05). In contrast, treatment with L-carnitine significantly alleviated these pathophysiological features in both in vivo and in vitro models. CONCLUSION: FAO plays a protective role in the occurrence and development of asthma by maintaining airway epithelial cell homeostasis and barrier function.
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Journal articleSathyapala A, Parthasarathy S, 2026,
Viewpoint: "Turning the Air Blue": Implementing sleep apnea care to improve Positive Airway Pressure adherence here and across the pond
, American Journal of Respiratory and Critical Care Medicine, ISSN: 1073-449XNo abstract as it is an invited opinion piece
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Journal articleSadatsafavi M, Miravitlles M, Quint JK, et al., 2026,
Development and validation of PRECISE-X model: predicting first severe exacerbation in COPD.
, Thorax, Vol: 81, Pages: 541-547OBJECTIVES: In patients with chronic obstructive pulmonary disease (COPD), severe exacerbations (ECOPDs) impose significant morbidity and mortality. Current guidelines emphasise using ECOPD history to inform preventive treatments but offer limited guidance for risk stratification for the first severe ECOPD. METHODS: We developed and validated PRECISE-X using a cohort of newly diagnosed COPD patients from the UK's Clinical Practice Research Datalink (2004-2022), to predict first severe ECOPD over 5 years (primary outcome) and 12 months (secondary outcome). Predictors were selected via clinical expertise and data-driven methods. Internal-external cross-validation was performed across practice regions to evaluate the model's out-of-sample performance in terms of discrimination (c-statistic), calibration and net benefit. RESULTS: The study included 2 19 015 patients (mean age 66.0; 42.4% female). Observed risk of first severe ECOPD was 29.5% at 5 years (4.2% at 1 year). The final model included four mandatory predictors (sex, age, Medical Research Council dyspnoea score and forced expiratory volume in 1 second) and 28 optional predictors. In internal-external cross-validation, the average out-of-sample c-statistic was 0.836 (95% CI 0.827 to 0.846) for 5-year prediction and 0.756 (95% CI 0.746 to 0.766) for 1-year prediction. Calibration across regions was robust, and the model showed positive NB across a wide range of risk thresholds. In a secondary validation assessment among those with available spirometry data with confirmed airflow obstruction, the model was well calibrated and had only a modest decline in discriminatory performance. CONCLUSIONS: PRECISE-X accurately predicts the first severe COPD exacerbation using routine clinical data, supporting earlier risk stratification and proactive disease management.
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Journal articlePhilip KEJ, Owles H, McVey S, et al., 2026,
An online singing-based breathing and wellbeing programme (ENO Breathe) in people with long COVID breathlessness in the UK: a cohort study
, The Lancet Digital Health, Pages: 10098-10098, ISSN: 2589-7500BackgroundPost-COVID-19 condition (also known as long COVID) breathlessness is a common, complex, and frequently debilitating problem for which few evidence-based interventions exist. A previous randomised trial found that participation in an online 6-week breathing and wellbeing programme (ENO Breathe), using singing techniques, was associated with improvements in health-related quality of life (HRQOL) and breathlessness. We aimed to assess the impact of this intervention outside a trial setting.MethodsIn this cohort study, participants were referred from 51 UK-based National Health Service (NHS) long COVID clinics, where they had been diagnosed with breathlessness due to long COVID. The eligibility criteria of ENO Breathe were age 18 years or older, having long COVID with associated breathlessness, diagnosis and referral from a specialist collaborating NHS long COVID clinic, and access and ability to engage with the online programme. We compared baseline and post-intervention data to assess the effect of the ENO Breathe programme on HRQOL assessed using the RAND-36 Mental and Physical Health Composite (MHC and PHC) primary outcome, with an estimated minimally clinically important difference of 3; breathlessness (assessed using Dyspnoea-12 scores and visual analogue scales [VAS] for breathlessness at rest, walking, using stairs, and running); anxiety (assessed using the Generalised Anxiety Disorder-7 questionnaire [GAD-7]); and respiratory symptoms (assessed using the COPD Assessment Test [CAT]).Findings1413 programme participants were included in this analysis (mean age 49 years [SD 11·9], BMI 28 kg/m2 [7·2]). 1130 (80%) participants were female, 273 (19%) were male, and ten (1%) did not disclose their gender. 1165 (82%) participants were White, 87 (6%) were Asian, 47 (3%) were Black, 48 (3%) were of mixed or multiple ethnic backgrounds, 31 (2%) reported their ethnicity or race as other (ie, not one of the categories specified), and 35 (2%) did not d
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Journal articleChae W, An J, Lee W, et al., 2026,
Circulating 1-Methylnicotinamide Predicts Dupilumab Response in Adult Asthma: A Prediction Model.
, Clin Exp Allergy -
Journal articleToumpanakis D, Usmani OS, Wells AU, et al., 2026,
Response.
, Chest, Vol: 169 -
Journal articleFu H, Sun P, Yuan X, et al., 2026,
Epithelial-Associated CD207+ DCs Link Allergen Sensing and IL-25-Driven Th2 Inflammation in Asthma.
, Allergy, Vol: 81, Pages: 1522-1535BACKGROUND: IL-25 is a key epithelial-derived alarmin associated with T2-high asthma, yet its downstream mechanisms remain poorly defined. CD207 (Langerin)+ dendritic cells (DCs) are localized at the airway epithelial interface. However, whether these cells respond to epithelial-derived cytokines and contribute to the Th2 immune response in asthma remains unclear. METHODS: Single-cell RNA-seq from healthy human lungs was analyzed to define the transcriptomic features of CD207+ DCs. Their function was validated in a house dust mite (HDM)-induced asthma model using Cd207-/- mice. Flow cytometry was performed on lung and mediastinal lymph nodes. DC-T cell co-cultures were used to assess Th2 polarization. Epithelial-DC interactions were evaluated using transwell co-culture with ALI-differentiated tracheal epithelial cells. Clinical relevance was examined in airway samples from asthma patients in the U-BIOPRED cohort. RESULTS: CD207+ DCs were enriched in intraepithelial compartments and exhibited increased MHC-II and Claudin-1 expression. In asthma, their abundance correlated with T2 signatures and Th2 markers (CRTH2, ST2). CD207 deletion reduced HDM uptake, Th2 cytokines, airway inflammation, and Th2 differentiation. IL-25 induced CD207+ DCs and enhanced their Th2-polarizing capacity in vitro. An IL-25-CD207 co-expression score correlated with IL-4/IL-5/IL-13 levels and was higher in steroid-naïve patients with severe asthma. CONCLUSION: Our study identifies CD207+ DCs as epithelial-associated antigen-presenting cells that bridge IL-25 signaling and Th2 polarization in allergic asthma. Targeting the IL-25-CD207 axis may offer therapeutic opportunities for T2-high asthma.
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Journal articleWilliams TJ, Kermani NZ, Gonzales-Huerta LE, et al., 2026,
A Role for Non-Canonical Caspases in Fungal Allergic Airway Disease.
, Clin Exp Allergy, Vol: 56, Pages: 576-578Inhibition of the murine ortholog caspase‐11 reduces neutrophilia and inflammatory cytokine levels. Wedelolactone or its derivatives offer a potential therapeutic approach for mixed or steroid‐resistant inflammation in allergic fungal airway disease.
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Journal articleDinh C-T, Lee Y-L, Chang L-T, et al., 2026,
Assessing the impact of air pollution on anemia: a comprehensive review and meta-analysis.
, Expert Rev Hematol, Vol: 19, Pages: 529-538INTRODUCTION: Air pollution and household fuel use may impair hematologic health through inflammation and oxidative stress. We synthesized evidence on associations of ambient/household air pollution with anemia risk and erythrocyte indices. METHODS: We searched PubMed, Embase, and Web of Science (inception-27 September 2025). Two reviewers independently screened and extracted data, and assessed risk of bias using Joanna Briggs Institute checklists. Random-effects meta-analyses pooled risk ratios (RRs) per 10 µg/m3 for particulate matter with aerodynamic diameter ≤10 µm (PM10), ≤2.5 µm (PM2.5), and nitrogen dioxide (NO2), and by household fuel type. RESULTS: Thirty-six studies were included. Each 10 µg/m3 increase in PM2.5 and NO2 was associated with higher anemia risk (RR 1.200, 95% CI 1.041-1.384, I2 98.2%; RR 1.127, 95% CI 1.025-1.241, I2 98.0%). Solid and biomass fuel increased anemia risk (RR 1.143, 95% CI 1.027-1.274, I2 82.9%; RR 1.271, 95% CI 1.050-1.539, I2 91.7%). PM10 was associated with lower hemoglobin (0.074 g/dL, 95% CI -0.124 to -0.023, I2 90.7%). Effects were generally stronger in males and in low- and middle-income countries. CONCLUSIONS: Ambient and household air pollution are associated with increased anemia risk and reductions in hemoglobin; high heterogeneity and observational designs limit causal inference.
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Journal articleKlimek L, Mullol J, Reitsma S, et al., 2026,
Correspondence: The First Biosimilar for Biologics in Allergy: CT-P39 (Omlyclo-Omalizumab-Igec) Is Available for Asthma, Chronic Spontaneous Urticaria, and Chronic Rhinosinusitis With Nasal Polyps.
, Allergy -
Journal articleInternational Consortium to Classify Ageing-Related Pathologies ICCARP respiratory working group members, Weight CM, Tatler AL, et al., 2026,
The crucial role of normative ageing in respiratory pathogenesis.
, Lancet Healthy LongevAlthough breathing seems like a simple action, many individuals encounter difficulties under ever-changing and complex circumstances, which can become increasingly problematic as the individuals age. In this Review, we comprehensively assess the ageing respiratory system. We begin with the physiological structural changes and their effect on lung function associated with ageing, before exploring the genetic and molecular factors that contribute to the loss of respiratory function with age. Defining how biological ageing manifests in the respiratory system and understanding disease-driven hallmarks of accelerated ageing conditions will enable the development of interventions to improve health across age groups, which will be crucial to address population health challenges over the coming decades.
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Journal articleLee B, Anpalagan H, Wong E, et al., 2026,
Hormone replacement therapy and the risk of asthma attacks: population-based cohort study
, ERJ Open Research, Pages: 01599-2025, ISSN: 2312-0541Background Women experience higher rates and greater severity of asthma after puberty, suggesting that sex hormones play a key role in airway disease. Hormone replacement therapy (HRT), which acutely alters circulating sex hormone levels, provides a useful model to examine their effects on asthma attacks. We sought to examine the association between HRT use and asthma attacks. Methods We obtained a cohort of women with asthma, aged 45 to 60 years, using nationwide U.K. primary care health records linked to hospital and mortality data, 2004-2020, to compare HRT-users to non-users. We applied inverse-probability of treatment weighting and Cox proportional hazards, accounting for demographics, asthma severity and comorbidities; stratifying by potential modifiers: body mass index (BMI), blood eosinophil count, smoking and HRT-type (oestrogen-only, progesterone-only and combined). Results 182,010 women were eligible for the study, of whom 9,663 were incident HRT users and 172,347 were non-users. Median age was 52 years (IQR: 50-55 years). HRT-users and non-users were broadly similar in terms of BMI, smoking history but non-users had slightly higher proportions residing in more deprived areas, with more comorbidities, higher reliever use and asthma attacks in the year before study entry, but lower use of preventer inhalers. After applying weighting, there was no association found between HRT use and asthma attacks (weighted-HR 0.97, 95% CI 0.90-1.04). There was no modification of that association by blood eosinophil level, BMI, smoking history or HRT-type. Conclusion Hormone replacement therapy use is not associated with asthma attacks in women with established asthma aged 45 to 60 years old.
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Journal articleLiao Z-A, Tsao P-N, Chen C-M, et al., 2026,
Hippo signaling pathway regulates branching morphogenesis of the fetal lung under hypoxia.
, Pediatr ResBACKGROUND: Hypoxia is known to disrupt embryonic organogenesis and increase the risk of neonatal respiratory disorders. The Hippo pathway is crucial in regulating organ development, size, and cell proliferation. However, the mechanism of how hypoxia affects lung development through this pathway remains unclear. METHODS: Fetal lungs were dissected from embryonic day 11.5 ICR mice and cultured ex vivo under normoxic (21% O₂) or hypoxic (1% O₂) conditions for 72 h, while human fetal lung fibroblasts (IMR-90) were exposed for 24 h. RNA sequencing analysis was performed on mouse fetal lungs. Biochemical analyses of lactate dehydrogenase and interleukin-6 were performed on supernatants. Expression levels of Hippo pathway-related proteins were determined by Western blot and immunofluorescence. RESULTS: Hypoxia markedly inhibited branching morphogenesis, reducing terminal bronchioles and total lung area (p < 0.05). Elevated LDH and IL-6 levels indicated cytotoxicity and inflammation. Western blot analysis revealed increased phosphorylation of YAP/TAZ, accompanied by decreased SOX2 expression (p < 0.05). Furthermore, genes related to cell differentiation and adhesion were also downregulated, indicating disrupted epithelial-mesenchymal coordination. CONCLUSION: These findings suggest that hypoxia may alter Hippo signaling in fetal lung fibroblasts, thereby impairing branching morphogenesis. Prenatal hypoxia exposure might contribute to abnormal lung development and increase susceptibility to neonatal pulmonary disorders. IMPACT: Prenatal hypoxia impairs fetal lung branching morphogenesis by modulating Hippo signaling and fibroblast-derived factors. Prenatal hypoxia enhances cytotoxicity and inflammatory cytokine production in fetal lungs and fibroblasts. This study provides new insights into the pathogenesis of hypoxia-related neonatal lung disorders and suggests Hippo signaling as a potential therapeutic target.
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Journal articleAndersson LI, Kupczyk M, Dahlén B, et al., 2026,
Adipokines in Obese Asthma: A Complex Relationship Influenced More by Sex, Weight, and Oral Steroid Treatment Than Disease Severity.
, AllergyBACKGROUND: Obesity-related asthma (OBA) is a distinct asthma phenotype, with increased severity. Adipokine release from excessive adipose tissue is suggested to be a key feature of OBA pathophysiology. However, it is unclear how the clinical characteristics of severe asthma associate with adipokine mediators. We examined systemic adipokine levels and evaluated relationships with disease severity, weight, sex, and steroid treatment in asthma. METHODS: A multiplex immunoassay for nine adipokines with proposed involvement in obesity-related inflammation (adiponectin, adipsin, BAFF, chemerin, FGF-21, leptin, lipocalin-2/NGAL, osteonectin and resistin) was designed. Plasma adipokines were measured in 127 patients with mild-to-moderate asthma (MMA) or severe asthma (SA) from the European BIOAIR cohort at baseline and after a controlled 2-week oral corticosteroid (OCS) intervention. RESULTS: Leptin and chemerin were significantly increased in patients with SA vs. MMA. Leptin, adiponectin, adipsin, and NGAL were affected by sex, whereas leptin and adipsin were strongly affected by weight. OCS increased leptin and adiponectin, decreased adipsin and BAFF, and did not affect osteonectin, resistin, or chemerin. No adipokines showed positive associations with exhaled NO, blood or sputum eosinophils, although certain correlations with serum CRP, blood, and sputum neutrophils were observed. CONCLUSIONS: Overall, we observe variable relationships between the nine adipokines, obesity and asthma severity. There were no relationships between adipokine levels and type-2 airway inflammation, yet associations with systemic neutrophilic inflammation were seen. Although one adipokine, chemerin, was independently associated with asthma severity, deciphering the role of adipokines in OBA is complex due to the influence of sex, BMI, and OCS.
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Journal articleKarp T, Merid SK, Kermani NZ, et al., 2026,
Nasal gene expression shows a distinct signature in type 2-high asthma but not in type 2-low disease.
, J Allergy Clin Immunol, Vol: 157, Pages: 879-889BACKGROUND: Type 2 (T2)-low asthma is defined by low levels of T2 inflammation and is associated with resistance to inhaled corticosteroids. Its molecular mechanisms are mostly unknown, and treatment options are limited. We previously showed that nasal brush transcriptomes differ between asthma and controls, reflecting disease-relevant biology. OBJECTIVE: We explored nasal gene expression related to T2-low asthma in the ATLANTIS cohort. METHODS: We compared nasal brush RNA sequencing data between 82 T2-low and 63 T2-high asthma patients and 57 controls. T2-low asthma was defined as blood eosinophil counts < 0.15 × 109/L and Feno < 25 ppb and T2-high as blood eosinophil counts > 0.3 × 109/L and Feno > 25 ppb. Weighted gene coexpression network analysis (WGCNA) was applied to identify gene modules associated with T2-low asthma. The BAMSE and U-BIOPRED cohorts were used for replication analyses. RESULTS: Although differentially expressed genes were found in patients with T2-high asthma across all 3 cohorts, no differentially expressed genes were observed in individuals with T2-low disease compared to controls in ATLANTIS, nor consistently across other cohorts. Our assessment of molecular heterogeneity could not attribute this result to greater intersample variability within the T2-low group. WGCNA in ATLANTIS identified "black" and "purple" gene modules linked to T2-low asthma, with genes enriched in T-cell immunity and ribosomal RNA biology pathways, respectively. The "black" module was replicated in U-BIOPRED and showed the same direction in BAMSE. CONCLUSION: T2-high asthma shows a distinct nasal gene expression signature compared to healthy controls, while patients with T2-low asthma exhibit no consistent changes. Future studies should explore T-cell immunity in T2-low asthma and integrate lower airway multiomics data.
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Journal articleDevulder JV, Fenwick PS, Kolosionek E, et al., 2026,
Clearance of Senescent Cells by <scp> BCL <sub>XL</sub> </scp> ‐ <scp>PROTAC</scp> : A Novel Approach to Treat <scp>COPD</scp> ?
, Aging Cell, Vol: 25, ISSN: 1474-9718<jats:title>ABSTRACT</jats:title> <jats:p> Ageing and cellular senescence significantly contribute to the progression of age‐related diseases, particularly chronic obstructive pulmonary disease (COPD). Cellular senescence refers to the cessation of cell division in response to stress and damage. While senescent cells remain metabolically active, they secrete pro‐inflammatory factors that drive disease progression. Senolytic therapies aim to selectively target and eliminate these senescent cells by inducing their apoptosis. This study examines the senolytic potential of BCL <jats:sub>XL</jats:sub> ‐PROTAC, a novel proteolysis‐targeting chimera designed to degrade BCL <jats:sub>XL</jats:sub> , in small airway epithelial cells and fibroblasts from patients with COPD. Treatment of COPD small airway epithelial cells and fibroblasts with BCL <jats:sub>XL</jats:sub> ‐PROTAC led to their apoptosis through the activation of caspase 3, along with a reduction in senescence markers such as p21 <jats:sup>CIP1</jats:sup> , p16 <jats:sup>INK4a</jats:sup> and senescence‐associated β‐galactosidase. The effects of BCL <jats:sub>XL</jats:sub> ‐PROTAC were selective for senescent cells and did not affect non‐COPD cells. The clearance of COPD small airway epithelial cells and fibroblasts by BCL <jats:sub>XL</jats:sub> ‐PROTAC was associated with an increase in the proliferation marker Ki67 and enhanced cell proliferation. Additionally, in precision‐cut lung slices obtained from COPD patients, BCL <jats:sub>XL</jats:sub> ‐PROTAC signific
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Journal articleFreeman A, Rink S, Bansal AT, et al., 2026,
Multimorbidity phenotypes and associated characteristics in severe asthma: an observational study of European severe asthma registries.
, Lancet Reg Health Eur, Vol: 63BACKGROUND: The phenotypic nature of multimorbidity in severe asthma is poorly understood. Our aims in this study were to define multimorbidity phenotypes and their characteristics in severe asthma across Europe by identifying and characterising co-aggregation of comorbidities. METHODS: Cross-sectional patient data were analysed from the pan-European Severe Heterogenous Asthma Research Collaboration: Patient Centred (SHARP) Central database of national severe asthma registries. Patients were grouped by four European regions (North, South, East, and West). Hierarchical clustering of comorbidities was applied to characterise the correlation structure of the ten commonest comorbidities within these geographical regions. Subsequent multimorbidity phenotypes (MMP) and their clinical features were then defined. FINDINGS: Data were available for 2690 severe asthma patients and 23 comorbidities from 11 countries. Three comorbidity clusters were consistently seen across the four European regions: 1) osteoporosis plus steroid-induced weight gain, 2) eczema plus rhinitis, and 3) chronic sinusitis plus nasal polyps. Four further comorbidities (obesity, bronchiectasis, gastro-oesophageal reflux disease, psychological factors) showed variable clustering. Multimorbidity was ubiquitous. Patients were assigned multimorbidity phenotypes (MMP) according to comorbidity cluster alignment. MMP sn (sinonasal-associated) and MMP u (no specific cluster alignment) were commonest. MMP ster (steroid-associated multimorbidity) had highest maintenance oral steroid (m-OCS) use, and Body Mass Index, plus worst lung function, asthma control, and asthma exacerbation frequency. MMP max (maximal multimorbidity) showed high prevalence of variably assigned comorbidities, higher m-OCS and biologic treatment needs. INTERPRETATION: Multimorbidity is common in severe asthma and can be classified into replicable novel phenotypes with characteristic clinical traits and outcomes. Recognising these phenotypes c
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Journal articleWawman RE, Shah PL, Boffito M, et al., 2026,
The relationship between plasma favipiravir concentrations and clinical outcomes in COVID-19
, ERJ Open Research, ISSN: 2312-0541Question addressed by the studyFavipiravir has shown efficacy against SARS-CoV-2 in patients under 60, but data linking plasma concentrations to clinical outcomes are limited. This study investigated whether favipiravir plasma concentrations influence clinical efficacy and outcomes in hospitalised COVID-19 patients and asked: how can antiviral dosing strategies be optimised to improve pandemic preparedness and treatment efficacy?Materials/patients and methodsAdult participants were drawn from the PIONEER trial, in which patients received oral favipiravir (1800 mg twice daily on day 1, then 800 mg twice daily for nine days) plus standard care. This analysis included patients with confirmed COVID-19 and ≥75% study adherence. Samples were collected between days 5–10 post-treatment initiation. The primary outcome was time to clinical improvement. Secondary outcomes included achievement of clinical improvement and mortality risk.ResultsOf 140 patients (50% male; mean age 59.5 [sd 14.8]), 29 (21%) reached target plasma concentrations. Mean time to improvement was 7.7 [5.9] vs 9.1 [7.2] days for target achievers vs non-achievers (p=0.26). Target was more often achieved in females (34%) than males (7%) (p=0.0002). Plasma concentration inversely correlated with BMI (r=–0.4; p<0.0001), with lower BMI in achievers (26.0 [5.1] vs 30.5 [6.9]; p=0.003). ALP and ALT levels were also lower in achievers (p=0.004 and p=0.02, respectively).Answer to the questionMost patients did not reach target favipiravir levels. Concentrations were influenced by sex, BMI, and liver function, confirming the need for pharmacokinetically guided dosing and therapeutic monitoring to optimise antiviral efficacy in future pandemic responses.
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Journal articleDevulder J, Fenwick P, Kolosionek E, et al., 2026,
Clearance of senescent cells by BCLXL-PROTAC: a novel approach to treat COPD?
, Aging Cell, ISSN: 1474-9718Aging and cellular senescence significantly contribute to the progression of age-related diseases, particularly chronic obstructive pulmonary disease (COPD). Cellular senescence refers to the cessation of cell division in response to stress and damage. While senescent cells remain metabolically active, they secrete pro-inflammatory factors that drive disease progression. Senolytic therapies aim to selectively target and eliminate these senescent cells by inducing their apoptosis. This study examines the senolytic potential of BCLXL-PROTAC, a novel proteolysis-targeting chimera designed to degrade BCLXL, in small airway epithelial cells and fibroblasts from patients with COPD. Treatment of COPD small airway epithelial cells and fibroblasts with BCLXL-PROTAC led to their apoptosis through the activation of caspase 3, along with a reduction in senescence markers such as p21CIP1, p16INK4a, and senescence-associated β galactosidase. The effects of BCLXL-PROTAC were selective for senescent cells and did not affect non-COPD cells. The clearance of COPD small airway epithelial cells and fibroblasts by BCLXL-PROTAC was associated with an increase in the proliferation marker Ki67 and enhanced cell proliferation. Additionally, in precision-cut lung slices obtained from COPD patients, BCLXL-PROTAC significantly reduced p21CIP1 expression in the airway epithelium, validating its effectiveness in a more complex tissue environment. These findings demonstrate that BCLXL-PROTAC is a potent and selective senolytic agent that may promote lung cell rejuvenation, supporting its potential as a novel therapeutic strategy for age-related diseases, including COPD.
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Journal articleXie M, Chang Q, Li C, et al., 2026,
TRPA1 mediates ozone-induced murine model of COPD through the Wnt5a/GSK-3β/β-catenin pathway.
, Environ Pollut, Vol: 393Ambient ozone (O3), a ubiquitous oxidant gas and key component of photochemical smog, damages the airway epithelium, provokes oxidative stress, and sustains chronic inflammation, which favors the onset and advancement of chronic obstructive pulmonary disease (COPD). Yet the molecular sensors linking long-term ozone exposure to COPD remain incompletely defined. We examined whether the oxidant-sensitive channel Transient receptor potential ankyrin 1 (TRPA1) mediates ozone-driven murine model of COPD through the Wnt5a/GSK3β/β-catenin pathway. C57BL/6J or TRPA1-deficient mice underwent ozone exposure (2.5 ppm, 3 h/session) every 3 days for 2 months, following administration of either the TRPA1 antagonist A967079 or the Wnt5a/GSK3β/β-catenin inhibitor XAV-939. Similarly, BEAS-2B cells treated with A967079 or XAV-939 or TRPA1-silenced cells were subjected to ozone (1 ppm, 3 h/day) for 4 consecutive days. Oxidative stress, inflammatory responses, emphysematous changes, mitochondrial dysfunction, and airway remodeling were assessed. In addition, gene set variation analysis (GSVA) was used to quantify Reactome Wnt5a/GSK3β/β-catenin pathway activity through public COPD transcriptomic cohorts. Pharmacological inhibition or genetic deficiency of TRPA1 significantly attenuated ozone-induced lung function impairment, and ozone-triggered oxidative stress, emphysematous changes, mitochondrial dysfunction, and airway remodeling. Notably, pharmacological suppression of the Wnt5a/GSK3β/β-catenin pathway using XAV-939 produced comparable protective effects to TRPA1 blockade in both ozone-exposed murine models and BEAS-2B cells. GSVA demonstrated tissue-specific associations between TRPA1 and Wnt5a/GSK3β/β-catenin pathway in COPD patients. TRPA1 mediates crucially ozone-induced COPD through modulation of the Wnt5a/GSK-3β/β-catenin signaling. Therapeutic targeting of both TRPA1 and Wnt5a/GSK3β/β-cat
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