American journal of respiratory and critical care medicine
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Am. J. Respir. Crit. Care Med. · Apr 2024
Long-Term Exposure to Low-Level Ambient Benzene and Mortality in a National English Cohort.
Background: Benzene affects human health through environmental exposure in addition to occupational contact. However, few studies have examined the associations between long-term exposure to low concentrations of ambient benzene and mortality risks in nonoccupational settings. Methods: This prospective cohort study consists of 393,042 participants without stroke, myocardial infarction, or cancer at baseline from the UK Biobank. ⋯ Furthermore, the effect of benzene exposure on mortality persisted across different subgroups and was somewhat stronger in younger and White people (P for interaction < 0.05). Conclusions: Long-term exposure to low concentrations of ambient benzene significantly increases mortality risk in the general population. Ambient benzene represents a potential threat to public health, and further investigations are needed to support timely pollution regulation and health protection.
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Am. J. Respir. Crit. Care Med. · Apr 2024
17q21 Variants Disturb Mucosal Host Defense in Childhood Asthma.
Rationale: The strongest genetic risk factor for childhood-onset asthma, the 17q21 locus, is associated with increased viral susceptibility and disease-promoting processes. Objectives: To identify biological targets underlying the escalated viral susceptibility associated with the clinical phenotype mediated by the 17q21 locus. Methods: Genome-wide transcriptome analysis of nasal brush samples from 261 children (78 healthy, 79 with wheezing at preschool age, 104 asthmatic) within the ALLIANCE (All-Age-Asthma) cohort, with a median age of 10.0 (range, 1.0-20.0) years, was conducted to explore the impact of their 17q21 genotype (SNP rs72163891). ⋯ Increased mucosal GSDMB expression is associated with a cell-lytic immune response coupled with compromised airway immunocompetence. These findings suggest that GSDMB-related airway cell death and perturbations in the mucosal IFN signature account for the increased vulnerability of 17q21 risk allele carriers to respiratory viral infections during early life, opening new options for future biological interventions. The All-Age-Asthma (ALLIANCE) cohort is registered at www.clinicaltrials.gov (pediatric arm, NCT02496468).
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Am. J. Respir. Crit. Care Med. · Apr 2024
Senolytic-facilitated Reversal of End-Organ Dysfunction in a Murine Model of Obstructive Sleep Apnea.
Rationale: Obstructive sleep apnea (OSA) is a highly prevalent condition that is associated with accelerated biological aging and multiple end-organ morbidities. Current treatments, such as continuous positive airway pressure (CPAP), have shown limited cognitive, metabolic, and cardiovascular beneficial outcomes despite adherence. Thus, adjunct therapies aiming to reduce OSA burden, such as senolytics, could improve OSA outcomes. ⋯ Methods: We compared the effects of 6 weeks of therapy with either partial normoxic recovery alone or combined with the senolytic navitoclax after 16 weeks of intermittent hypoxia exposures, a hallmark of OSA, on multiphenotypic cardiometabolic and neurocognitive parameters. Measurements and Main Results: Our findings indicate that only when combined with navitoclax, partial normoxic recovery significantly improved sleepiness (sleep in the dark phase: 34% ± 4% vs. 26% ± 3%; P < 0.01), cognition (preference score: 51% ± 19% vs. 70% ± 11%; P = 0.048), coronary artery function (response to acetylcholine [vasodilation]: 56% ± 13% vs. 72% ± 10%; P < 0.001), glucose, and lipid metabolism and reduced intestinal permeability and senescence in multiple organs. Conclusions: These findings indicate that the reversibility of end-organ morbidities induced by OSA is not only contingent on restoration of normal oxygenation patterns but can be further enhanced by targeting other OSA-mediated detrimental cellular processes, such as accelerated senescence.