Divay Chandra

Single-cell transcriptomic profiling of chronic obstructive pulmonary disease (COPD) lungs identified QKI, an RNA-binding protein, as a candidate emphysema-associated gene, but its epithelial role in COPD pathobiology remains unclear. We show that QKI expression is reduced in human COPD lungs and that alveolar type 2 epithelial (AT2) cell QKI protein levels correlate strongly with spirometric indices and diffusing capacity (DL _CO ). Lung epithelium-specific QKI knockout mice (QKI ^Δ/Δ ) developed spontaneous airspace enlargement with emphysema-like mechanics, and QKI-deficient AT2 cells showed impaired spheroid colony formation and increased apoptosis. Integrated transcriptomic and proteomic analyses of primary AT2 cells revealed a selective reduction in functional mitochondrial (respiratory-chain and metabolic) protein abundance despite relatively preserved transcript levels, consistent with mitochondrial transcriptome-proteome discordance. QKI loss increased mtDNA abundance and TOMM20 staining but decreased ATP5A, indicating accumulation of structurally increased but functionally dysfunctional mitochondria. In human epithelial cells, CRISPR-mediated QKI deficiency reduced oxidative respiration, increased glycolytic reliance, elevated mitochondrial ROS and membrane potential, and increased apoptosis; these phenotypes were partially rescued by QKI re-expression. These findings identify epithelial QKI as a regulator of mitochondrial integrity and stress tolerance in COPD.

The COVID-19 pandemic disrupted many aspects of academic research, particularly for early career investigators striving for independence. This study examines geographic heterogeneity in the pandemic’s impact on the publication productivity of recipients of National Heart, Lung, and Blood Institute K01, K08, and K23 awards within Departments of Medicine across different states in the US using data from the National Institutes of Health RePORTER and the Centers for Disease Control and Prevention COVID data tracker from 2015 to 2022. Findings indicate that while publication productivity increased steadily until 2020, it plateaued soon after. K-awardees in states with an early peak in COVID-19-related deaths maintained relatively stable productivity levels post-2020, whereas those in states with a late peak experienced a decline. The observed geographic differences may stem from variations in pandemic response measures, resource availability, and institutional support. These findings highlight the need for careful consideration of geographic heterogeneity when designing targeted interventions, such as funding support and tenure extensions, to mitigate the pandemic’s impact on early career investigators. Addressing additional factors, including career stage, personal responsibilities, and institutional environments, is essential for a comprehensive understanding of disparities in publication productivity.

Rationale Emphysema is defined by progressive alveolar destruction and impaired tissue repair, with diminished Wnt/β-catenin signaling implicated in its pathogenesis. Preclinical studies suggest that lithium, a pharmacologic activator of Wnt/β-catenin signaling, may attenuate emphysema. However, its effects in humans remain unknown. Objectives To investigate whether individuals using lithium for neuropsychiatric conditions have reduced susceptibility to emphysema compared to users of other neuropsychiatric medications. Methods We analyzed cross-sectional data from two large cohorts - the UK Biobank and COPDGene - comprising over 800 individuals using oral lithium. Lithium users were compared to individuals using other neuropsychiatric medications. In the UK Biobank, outcomes included spirometry and self-reported physician-diagnosed emphysema. In COPDGene, outcomes included spirometry and quantitative CT measures of emphysema. Multivariable regression and propensity score matching accounted for demographics, smoking history, and psychiatric diagnoses. Measurements and Main Results In the UK Biobank, lithium use was associated with higher FEV₁ and FVC (% predicted) and ∼50% lower adjusted odds of emphysema diagnosis. In COPDGene, lithium users exhibited significantly higher FEV₁, FVC, and FEV₁/FVC ratios, lower CT-measured emphysema (%LAA-950), and higher lung density. These associations persisted after multivariable adjustment and across sensitivity analyses. Conclusions Lithium use is associated with less emphysema in two independent cohorts. These findings align with preclinical evidence supporting Wnt/β-catenin activation as a protective mechanism and warrant further investigation of lithium and related agents as potential therapies for emphysema.

Forkhead Box Protein P1 (FoxP1) is a crucial transcriptional repressor essential for the development of the brain and heart. In adults, FoxP1 protein levels are dysregulated in a variety of disorders, including chronic obstructive pulmonary disease (COPD), atherosclerosis, and heart failure, where they causally contribute to disease pathogenesis. Although independent investigators have reported that FoxP1 protein is ubiquitinated, and E3 ligases have been identified for other FoxP family proteins, the identity of the E3 ligase that controls FoxP1 protein stability has remained unknown. Here, we identify FBXO24, a subunit of the Skp-Cullin-F-box (SCF) ubiquitin E3 ligase complex, as the regulator of FoxP1 ubiquitination and stability. Specifically, FBXO24 regulates K48 and K63 ubiquitination, complexes with, and co-localizes to the nucleus with FoxP1 protein in lung epithelial cells. Depleting FBXO24 reverses the unfolded protein response and cell death triggered by loss of FoxP1 protein in lung epithelium, suggesting a protective role. Additionally, FBXO24 knockout mice exhibit elevated FoxP1 levels in the lung and heart and reduced unfolded protein response activity after short-term cigarette smoke exposure. Intriguingly, we also uncovered bidirectional regulation, whereby FoxP1 protein binds to the FBXO24 promoter to suppress FBXO24 transcription. To our knowledge, this is the first evidence that a substrate for an E3 ligase can also regulate the E3 ligase and, therefore, control levels of other substrates, revealing new regulatory networks. Targeting FBXO24 may offer a therapeutic strategy for COPD, atherosclerosis, and heart failure by stabilizing FoxP1 levels in the heart and lungs and mitigating harmful downstream effects.

Electronic cigarette (e-cigarette) use continues to rise globally. E-cigarettes have been presented as safer alternatives to combustion cigarettes that can mitigate the harm associated with tobacco products; however, the degree to which e-cigarette use itself can lead to morbidity and mortality is not fully defined. Herein we describe how e-cigarettes function; discuss the current knowledge of the effects of e-cigarette aerosol on lung cell cytotoxicity, inflammation, antipathogen immune response, mucociliary clearance, oxidative stress, DNA damage, carcinogenesis, matrix remodelling and airway hyperresponsiveness; and summarise the impact on lung diseases, including COPD, respiratory infection, lung cancer and asthma. We highlight how the inclusion of nicotine or flavouring compounds in e-liquids can impact lung toxicity. Finally, we consider the paradox of the safer cigarette: the toxicities of e-cigarettes that can mitigate their potential to serve as a harm reduction tool in the fight against traditional cigarettes, and we summarise the research needed in this underinvestigated area.

Chord length is an indirect measure of alveolar size and a critical endpoint in animal models of chronic obstructive pulmonary disease (COPD). In assessing chord length, the lumens of nonalveolar structures are eliminated from measurement by various methods, including manual masking. However, manual masking is resource intensive and can introduce variability and bias. We created a fully automated deep learning–based tool to mask murine lung images and assess chord length to facilitate mechanistic and therapeutic discovery in COPD called Deep-Masker (available at http://47.93.0.75:8110/login). We trained the deep learning algorithm for Deep-Masker using 1,217 images from 137 mice from 12 strains exposed to room air or cigarette smoke for 6 months. We validated this algorithm against manual masking. Deep-Masker demonstrated high accuracy with an average difference in chord length compared with manual masking of −0.3 ± 1.4% (rs = 0.99) for room-air–exposed mice and 0.7 ± 1.9% (rs = 0.99) for cigarette-smoke–exposed mice. The difference between Deep-Masker and manually masked images for change in chord length because of cigarette smoke exposure was 6.0 ± 9.2% (rs = 0.95). These values exceed published estimates for interobserver variability for manual masking (rs = 0.65) and the accuracy of published algorithms by a significant margin. We validated the performance of Deep-Masker using an independent set of images. Deep-Masker can be an accurate, precise, fully automated method to standardize chord length measurement in murine models of lung disease.