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Epidemiological studies show cigarette smoking enhances corneal endothelial dysfunction, but mechanisms remain unclear. Our study reveals that prolonged smoke exposure activates the aryl hydrocarbon receptor (AhR), increasing CYP1B1 expression and accelerating senescence and fibrosis in corneal endothelium, potentially reflecting adaptive responses to maintain corneal resilience. Although these molecular modifications indicate early endothelial dysfunction, no pathological changes were observed. The findings indicate that while chronic cigarette smoke exposure triggers initial molecular alterations and endothelial dysfunction, the progression to Fuchs endothelial corneal dystrophy likely requires additional environmental or genetic factors beyond smoke exposure alone., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Previous randomized controlled trials had established the efficacy of dupilumab among patients with chronic obstructive pulmonary disease (COPD) treated with triple therapy over 52 weeks of follow-up., Objective: This population-based cohort study aimed to explore the long-term clinical effectiveness of dupilumab in COPD patients., Methods: This population-based cohort study included U.S. patients with COPD between April 2017 and August 2024. Patients initiating dupilumab and therapies that incorporated long-acting β2-agonists (LABA) inhalers were included. Patients with asthma or lung cancer were excluded. The risk of outcomes after the initiation of dupilumab versus LABA-containing therapies was measured. For detailed Methods, please see the Methods section in this article's Online Repository at www.jacionline.org., Results: A total of 1,521 dupilumab initiators and 1,521 propensity score-matched patients receiving LABA-based therapies were included. Dupilumab recipients were associated with lower all-cause mortality (HR:0.53, 95% CI:0.43-0.65), emergency visits (HR:0.78, 95% CI:0.69-0.89), and acute exacerbation (AE) rates (HR:0.59, 95% CI:0.53-0.65). Dupilumab was also associated with reductions in the requirement of short-acting β2-agonists (HR:0.48, 95% CI:0.43-0.52), short-acting muscarinic antagonists (HR:0.43, 95% CI:0.37-0.49) for symptoms control. Additionally, dupilumab decreased subsequent pneumonia (HR:0.65, 95% CI:0.50-0.86), and COPD-relevant comorbidities including new-onset heart failure (HR:0.69, 95% CI:0.53-0.90) and new-onset anxiety (HR:0.70, 95% CI:0.53-0.93)., Conclusions: Dupilumab was associated with a lower rate of mortality, emergency visits, reduced risk of AEs, respiratory symptoms, and respiratory infections in COPD patients. More studies are required to validate the effectiveness of dupilumab among patients with COPD across various severities., (Copyright © 2024. Published by Elsevier Inc.)

Nasal sprays for pre-exposure prophylaxis against respiratory infections show limited protection (20-70%), largely due to their single mechanism of action-either neutralizing pathogens or blocking their entry at the nasal lining, and a failure to maximize the capture of respiratory droplets, allowing them to potentially rebound and reach deeper airways. This report introduces the Pathogen Capture and Neutralizing Spray (PCANS), which utilizes a multi-modal approach to enhance efficacy. PCANS coats the nasal cavity, capturing large respiratory droplets from the air, and serving as a physical barrier against a broad spectrum of viruses and bacteria, while rapidly neutralizing them with over 99.99% effectiveness. The formulation consists of excipients identified from the FDA's Inactive Ingredient Database and Generally Recognized as Safe list to maximize efficacy for each step in the multi-modal approach. PCANS demonstrates nasal retention for up to 8 hours in mice. In a severe Influenza A mouse model, a single pre-exposure dose of PCANS leads to a >99.99% reduction in lung viral titer and ensures 100% survival, compared to 0% in the control group. PCANS suppresses pathological manifestations and offers protection for at least 4 hours. This data suggest PCANS as a promising daily-use prophylactic against respiratory infections., (© 2024 Wiley‐VCH GmbH.)

Protein biomarkers are associated with mortality in cardiovascular disease, but their effect on predicting respiratory and all-cause mortality is not clear. We tested whether a protein risk score (protRS) can improve prediction of all-cause mortality over clinical risk factors in smokers. We utilized smoking-enriched (COPDGene, LSC, SPIROMICS) and general population-based (MESA) cohorts with SomaScan proteomic and mortality data. We split COPDGene into training and testing sets (50:50) and developed a protRS based on respiratory mortality effect size and parsimony. We tested multivariable associations of the protRS with all-cause, respiratory, and cardiovascular mortality, and performed meta-analysis, area-under-the-curve (AUC), and network analyses. We included 2232 participants. In COPDGene, a penalized regression-based protRS was most highly associated with respiratory mortality (OR 9.2) and parsimonious (15 proteins). This protRS was associated with all-cause mortality (random effects HR 1.79 [95% CI 1.31-2.43]). Adding the protRS to clinical covariates improved all-cause mortality prediction in COPDGene (AUC 0.87 vs 0.82) and SPIROMICS (0.74 vs 0.6), but not in LSC and MESA. Protein-protein interaction network analyses implicate cytokine signaling, innate immune responses, and extracellular matrix turnover. A blood-based protein risk score predicts all-cause and respiratory mortality, identifies potential drivers of mortality, and demonstrates heterogeneity in effects amongst cohorts., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Airflow limitation is a hallmark of chronic obstructive pulmonary disease, which can develop through different lung function trajectories across the life span. There is a need for longitudinal studies aimed at identifying circulating biomarkers of airflow limitation across different stages of life., Objectives: This study sought to identify a signature of serum proteins associated with airflow limitation and evaluate their relation to lung function longitudinally in adults and children., Methods: This study used data from 3 adult cohorts (TESAOD [Tucson Epidemiological Study of Airway Obstructive Disease], SAPALDIA [Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults], LSC [Lovelace Smoker Cohort]) and 1 birth cohort (TCRS [Tucson Children's Respiratory Study]) (N = 1940). In TESAOD, among 46 circulating proteins, we identified those associated with FEV 1 /forced vital capacity (FVC) percent (%) predicted levels and generated a score based on the sum of their z-scores. Cross-sectional analyses were used to test the score for association with concomitant lung function. Longitudinal analyses were used to test the score for association with subsequent lung function growth in childhood and decline in adult life., Results: After false discovery rate adjustment, serum levels of 5 proteins (HP, carcinoembryonic antigen, ICAM1, CRP, TIMP1) were associated with percent predicted levels of FEV 1 /FVC and FEV 1 in TESAOD. In cross-sectional multivariate analyses the 5-biomarker score was associated with FEV 1 % predicted in all adult cohorts (meta-analyzed FEV 1 decrease for 1-SD score increase: -2.9%; 95% CI: -3.9%, -1.9%; P = 2.4 × 10 -16 ). In multivariate longitudinal analyses, the biomarker score at 6 years of age was inversely associated with FEV 1 and FEV 1 /FVC levels attained by young adult life (P = .02 and .005, respectively). In adults, persistently high levels of the biomarker score were associated with subsequent accelerated decline of FEV 1 and FEV 1 /FVC (P = .01 and .001)., Conclusions: A signature of 5 circulating biomarkers of airflow limitation was associated with both impaired lung function growth in childhood and accelerated lung function decline in adult life, indicating that these proteins may be involved in multiple lung function trajectories leading to chronic obstructive pulmonary disease., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Chronic obstructive pulmonary disease (COPD) is caused by cigarette smoke (CS) exposure but can often be progressive even in former smokers. Exposure of mice to CS for 22 wk causes emphysema, but whether emphysema persists after cessation of CS exposure is not clear. The purpose of this study was to determine whether emphysema persists in mice following a recovery period of 22 wk and whether a susceptibility factor, such as deficiency in the Bcl-2-interacting killer (Bik), is required for this persistence. Therefore, bik +/+ and bik -/- mice at 6-10 wk of age were exposed to 250 mg/m 3 total particulate matter of CS or filtered air (FA) for 3 or 22 wk and were kept in FA for an additional 22 wk. Lungs were lavaged to quantify inflammatory cells, and sections were stained with hematoxylin and eosin to assess severity of emphysema. Exposure to CS for 3 wk increased the number of inflammatory cells in bik -/- mice compared with bik +/+ mice but not at 22 wk of exposure. At 22 wk of CS exposure, extent of emphysema was similar in bik +/+ and bik -/- mice. However, when mice were exposed to CS over the first 22 wk and were kept in FA for an additional 22 wk, emphysema remained similar in bik +/+ mice but was enhanced in bik -/- mice. These findings link increased inflammation with persistent emphysematous changes even after smoking cessation and demonstrate that a preexisting susceptibility condition is required to sustain enhanced emphysema that was initiated by long-term CS exposure. NEW & NOTEWORTHY Exposure of mice to cigarette smoke (CS) for 22 wk causes emphysema, but whether emphysema persists after an additional period of 6 mo after cessation of CS exposure has not been reported. In addition, the role of preexisting susceptibility in enhancing the persistence of CS-induced emphysema after exposure to CS has stopped has not been shown. The present study shows that a preexisting susceptibility must be present to enhance CS-induced emphysema after cessation of CS exposure.