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PubMed2026

Inhaled vitamin A mitigates hyperoxia-induced acute and chronic lung damage in a neonatal rat model of bronchopulmonary dysplasia.

RATIONALE: Prevention of bronchopulmonary dysplasia (BPD) remains a critical unmet need. OBJECTIVES: We continued evaluating aerosolized vitamin A in a neonatal rat hyperoxia-injury model of BPD, testing whether lung-targeted inhalation yields superior outcomes compared to enteral or intramuscular (IM) delivery. METHODS: Rat pups were exposed to continuous 95% hyperoxia for seven days to induce lung damage. Vitamin A was administered from post-natal day (PD) 1-7 by inhalation, enteral or IM dosing. Persisting effectiveness of inhaled vitamin A was examined at PD 21, dwelling in normoxia after all interventions were discontinued at PD 7. MEASUREMENTS AND MAIN RESULTS: Comprehensive analyses include alveolar morphometrics, in vivo pulmonary function testing, assessment of hepatic vitamin A level, and quantitating gene and protein expression of relevant biomarkers of lung maturation, inflammation and damage/repair, employing singlex and multiplexed assays and whole-genome gene expression. CONCLUSIONS: Inhaled vitamin A suppressed hyperoxia-induced lung damage, with key hallmarks of BPD, including lung morphometrics and biomarkers associated with lung damage and inflammation, being effectively indistinguishable from healthy controls at both PD 7 and 21, Natural reparative processes were enhanced, with normal alveolarization and pulmonary function at PD 21. Despite raising hepatic vitamin A levels, enteral dosing was ineffective in restoring alveolar morphology at PD 7. Consistent with previous reporting, IM dosing yielded modest effect at PD 7 but with little evidence of benefit to pulmonary function at PD 21. Observation of dose-dependent effects with aerosolized vitamin A strengthens the evidence of the benefits of lung-targeted delivery, supporting further development of inhaled vitamin A as a BPD preventive strategy.

Journal Article↗

PubMed2026

Deep learning-assisted, pathogenesis-informed lung histopathology scoring in preclinical mouse models of SARS-CoV-2 and influenza A infection.

INTRODUCTION: SARS-CoV-2 and influenza A virus (IAV) cause viral pneumonia, yet their lung lesions evolve with distinct spatial organization and resolution-phase architecture. In preclinical murine studies, H&E histopathology is a primary endpoint, but burden-focused semiquantitative scoring can miss pathogen- and phase-specific differences in lesion topology, compartmental involvement, inflammatory organization, and repair. We aimed to define virus- and phase-specific morphologic signatures and translate them into a practical, pathogenesis-informed scoring guide, supported by whole-slide convolutional neural network (CNN) analysis with class activation mapping (CAM). METHODS: Mice were infected under standardized conditions and evaluated during the early, peak-injury, and late phases of infection, corresponding to 2~3, 5~8, and 14 days post-infection (dpi), respectively. Lungs were assessed by H&E with semiquantitative scoring and by immunostaining to map viral antigen distribution and epithelial tropism. Whole-slide CNN models were trained for virus- and phase-specific classification, and CAM localized discriminative regions. RESULTS: Dose titration established reproducible lethal and sublethal infection conditions for both viruses. Viral antigen kinetics diverged, with SARS-CoV-2 peaking early and declining toward clearance by the resolution phase, whereas IAV peaked later and declined by the resolution phase, paralleling distinct injury-repair trajectories. CNN/CAM analysis distinguished virus- and phase-specific histologic patterns across the early, peak-injury, and resolution phases of infection and highlighted spatial signatures consistent with expert review. At the peak-injury phase, SARS-CoV-2 lungs showed broad alveolar/interstitial involvement, whereas IAV exhibited bronchocentric inflammatory organization. During the resolution phase, IAV showed prominent epithelial regeneration with remodeling-forward architecture, while SARS-CoV-2 more often retained localized residual inflammatory foci. Across both infections, tissue inflammatory composition shifted over time, with higher neutrophil representation during the peak-injury phase and a relative increase in lymphocytic representation during the resolution phase. Integrating lesion topology/distribution, edema, epithelial injury-regeneration, remodeling features, and lymphocyte predominance, we proposed a pathogen-resolved, phase-informed histopathology scoring guide with recommended evaluation windows for each model. CONCLUSION: Together, these findings define virus- and phase-specific morphologic programs that inform respiratory virus pathogenesis in mice and can be translated into practical scoring criteria for preclinical respiratory virus studies.

Animals↗

PubMed2017

Smoking and Lung Cancer: A Geo-Regional Perspective.

Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) represents the most frequently diagnosed subtype of this morbid malignancy. NSCLC is causally linked to tobacco consumption with more than 500 million smokers worldwide at high risk for this fatal malignancy. We are currently lagging in our knowledge of the early molecular (e.g., genomic) effects of smoking in NSCLC pathogenesis that would constitute ideal markers for early detection. This limitation is further amplified when considering the variable etiologic factors in NSCLC pathogenesis among different regions around the globe. In this review, we present our current knowledge of genomic alterations arising during early stages of smoking-induced lung cancer initiation and progression, including discussing the premalignant airway field of injury induced by smoking. The review also underscores the wider spectra and higher age-adjusted rates of tobacco (e.g., water-pipe smoke) consumption, along with elevated environmental carcinogenic exposures and relatively poorer socioeconomic status, in low-middle income countries (LMICs), with Lebanon as an exemplar. This "cocktail" of carcinogenic exposures warrants the pressing need to understand the complex etiology of lung malignancies developing in LMICs such as Lebanon.

early detection↗

PubMed2026

Gut microbiota dynamics and metabolic pathways associated with bleomycin-induced pulmonary fibrosis progression.

BACKGROUND: Pulmonary fibrosis (PF) is a progressive respiratory disease characterized by epithelial injury, aberrant repair and excessive extracellular matrix deposition. Although the gut-lung axis is increasingly implicated in respiratory disorders, stage-resolved characterization of gut microbiota taxonomic and functional potential during PF development is limited. METHODS: We established a bleomycin-induced murine PF model and performed cross-sectional shotgun metagenomic sequencing of fecal samples from separate cohorts at three defined stages: baseline (control), day 7 (early fibrosis; M7), and day 14 (established fibrosis; M14). Microbial taxonomy, alpha/beta diversity, and predicted functional capacity were inferred using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Carbohydrate-Active enZymes (CAZy) annotations; associations were assessed using Procrustes and Spearman correlation analyses. RESULTS: Histopathology and immunohistochemistry confirmed progressive fibrogenesis with increased TGF-β1 and α-SMA expression. Compared with baseline, bleomycin-treated groups exhibited stage-specific shifts in gut microbial composition, including depletion of mucin-associated taxa (e.g., Prevotella, Akkermansia muciniphila) and expansion of Muribaculaceae- and Clostridiaceae-affiliated taxa. Alpha and beta diversity metrics differed across groups. KEGG/CAZy-based annotations revealed predicted, stage-dependent changes in microbial metabolic potential, including early reductions in pathways related to amino acid and glycan metabolism (M7) and later increases in predicted starch/sucrose catabolism, phosphotransferase system (PTS) representation, and secondary bile acid biosynthesis (M14). Correlation analyses linked compositional shifts to these predicted functional changes. CONCLUSION: In a stage-resolved, cross-sectional study, bleomycin-associated pulmonary fibrosis was accompanied by compositional and predicted functional alterations in the gut microbiota. These data identify candidate taxa and predicted pathways for follow-up mechanistic testing, but functional (metabolomic) and causality experiments are required to confirm whether and how microbial changes contribute to PF pathogenesis.

Animals↗

PubMed2026

Respiratory manifestations as clues to inherited metabolic disorders in children: a phenotype-driven diagnostic approach.

UNLABELLED: Inherited metabolic disorders (IMDs) are uncommon but clinically important causes of respiratory morbidity in children. Respiratory involvement may be the first or dominant manifestation, although it may precede, accompany, or follow systemic involvement. Because cough, dyspnea, hypoxemia, recurrent infection, abnormal chest imaging, and ventilatory failure are non-specific, affected children may initially be managed for common respiratory conditions, such as infection, asthma, aspiration, immunodeficiency, or non-metabolic diffuse lung disease, before the underlying IMD is recognized. This narrative mini-review presents a phenotype-driven approach to recognizing IMDs in pediatric respiratory practice. Rather than cataloguing rare disorders by metabolic pathway, it organizes respiratory involvement into practical clinical entry points: diffuse lung disease, pulmonary alveolar proteinosis-like disease, pulmonary vascular disease, recurrent infection or bronchiectasis, upper-airway or thoracic restriction, and neuromuscular respiratory failure and aspiration. For each pattern, we highlight extrapulmonary red flags and first-line biochemical, enzymatic, and genetic tests that may guide early etiological diagnosis. CONCLUSION: Careful recognition of respiratory phenotypes, combined with targeted metabolic and genomic evaluation, may shorten diagnostic delay and allow disease-specific treatment before irreversible pulmonary or neurological injury occurs. WHAT IS KNOWN: • IMDs can involve the respiratory system and may mimic common pediatric respiratory disorders or non-metabolic forms of childhood diffuse lung disease. • Respiratory manifestations may precede, accompany, or follow classical systemic features, and their temporal pattern varies among individual IMDs. WHAT IS NEW: • This mini-review organizes IMD-related respiratory involvement by presenting respiratory phenotype rather than by metabolic pathway. • It links respiratory entry points with extrapulmonary red flags and targeted biochemical, enzymatic, and genetic testing to support earlier diagnosis.

Humans↗

PubMed2026

The KEAP1-NFE2L2/NRF2 Axis in Non-Small Cell Lung Cancer Radioresistance: Redox Homeostasis and Emerging DNA Damage Response Mechanisms.

Radioresistance and local recurrence remain major barriers to effective radiotherapy in non-small cell lung cancer (NSCLC). Loss-of-function KEAP1 alterations or activating NFE2L2 alterations can stabilize NRF2, but do not alone establish sustained transcriptional activity or functional dependency. This focused narrative review evaluates clinical radiotherapy studies and mechanistically informative preclinical studies linking the KEAP1-NFE2L2/NRF2 axis to NSCLC radioresistance. We prioritized clinical studies reporting radiotherapy-specific outcomes and preclinical studies coupling NRF2-related molecular status or perturbation with radiation-response endpoints; contextual studies informed metabolic, DNA damage response (DDR), immune and normal-lung effects. Evidence most consistently supports NRF2-mediated redox protection through glutathione-dependent defense, cellular reducing capacity and antioxidant enzymes, limiting radiation-induced reactive oxygen species (ROS) accumulation and oxidative injury. Limited studies further suggest that NRF2 may affect DNA-damage signaling, checkpoint control and repair. The detailed RPA32-TOPBP1-ATR-CHK1 model is therefore considered proposed rather than established in NRF2-active NSCLC. Retrospective clinical studies associate pathogenic KEAP1/NFE2L2 alterations with impaired local control in some radiotherapy-treated cohorts, but do not justify treating genomic status, protein abundance, transcriptional activity and functional dependency as equivalent measures or demonstrate treatment-predictive value. NRF2-mediated normal-lung protection also constrains systemic inhibition. Prospective studies integrating molecular classification, radiation-response endpoints, local control and normal-tissue toxicity are required before biomarker-guided radiosensitization can be considered.

DNA damage response↗

PubMed2026

Dosimetric Parameters of the Heart and Its Substructures in Predicting Cardiac Events or Survival in Patients With Lung Cancer After Radiation Therapy: A Systematic Review and Meta-analysis.

The predictive value of radiation dose to the whole heart (WH) and cardiac substructures (CS) for cardiac events (CEs) and survival in patients with lung cancer remains uncertain. The goal of this study was to conduct a systematic review and meta-analysis to provide an evidence-based estimate of the relationship between these associations. A systematic meta-analysis was performed following PRISMA guidelines. Risk of bias was assessed using the JBI Critical Appraisal Checklist for Case Series. Outcomes were classified into major adverse cardiac events (MACE), arrhythmias, pericardial effusion, and survival. Depending on heterogeneity, random- or fixed-effects models were applied to calculate pooled hazard ratios (HRs) for univariable and multivariable analyses. A total of 80 studies, including 21,645 patients, were analyzed. Of these, 25 studies reported CEs, and 69 reported survival outcomes. Among 91 WH and 215 CS parameters evaluated, several showed significant associations. Key findings from our meta-analysis include: (1) left anterior descending (LAD) V15 was significantly associated with MACE. The mean heart dose (MHD), as well as ventricle and LAD doses, were significantly associated with ischemic events. (2) Multiple CS parameters were associated with different arrhythmia subtypes. (3) MHD, heart V5/V35/V55 and pericardial doses were significantly associated with pericardial effusion. (4) MHD was significantly associated with survival; CS parameters also showed predictive value, and especially, heart base dose being the most significant. (5) We also identified several thresholds with potential predictive values, such as LAD V15 <10% for MACE, left pulmonary vein (LPV) V55 <2%, and right pulmonary vein (RPV) V10 <54% for atrial fibrillation (AF), right atrium (RA) V60 <0.03 cc for non-AF supraventricular tachyarrhythmia, and left main artery (LMA) V10 ≥1 cc for bradyarrhythmia. This study identified 130 WH and CS dosimetric parameters associated with CEs and 131 with survival outcomes. These findings enhance our understanding of radiation-induced heart injury mechanisms and provide guidance for potential protective and intervention strategies.

Humans↗

PubMed2025

Dynamic Molecular Changes in Brain, Lung, and Heart of Hamsters Infected With SARS-CoV-2: Insights From a Severe and Recovery Phase Model.

The Global pandemic of coronavirus disease 2019 was initiated by the emergence of severe acute respiratory syndrome coronavirus 2. In addition to conventional pulmonary lesions, a range of neurological injury symptoms have been identified in clinical practice, but the aetiology of neurological disorders linked to SARS-CoV-2 infection remains poorly understood. Syrian hamsters, which are highly susceptible to SARS-CoV-2 infection, exhibit a disease phenotype similar to that observed in human COVID-19 patients. In this study, a hamster model of COVID-19 infection was used to analyze molecular changes in different tissues at various time points post infection with distinct strains using proteomic and phosphoproteomic approaches. Multi-omics analysis showed that SARS-COV-2 infection triggers sustained downregulation of the abundance and phosphorylation levels of neuronal and synapse-associated proteins in the brain, suggesting that neuronal damage persists even during the recovery period. Additionally, infections with SARS-CoV-2 may contribute to the onset of long-term symptoms of COVID-19 by impacting energy metabolism, neurotransmitter release, and synaptic transmission pathways. This study provides a comprehensive molecular profile of hamsters infected with different SARS-CoV-2 strains in different tissues, offering foundational insights into the pathogenic mechanisms of COVID-19.

Animals↗

PubMed2025

Multi-omics analysis reveals distinct spatial compartmentalization of lung repair niches in pediatric ARDS.

BACKGROUND: Pediatric acute respiratory distress syndrome (PARDS), often triggered by viral infections, is a life-threatening condition. Despite its severity, children demonstrate significantly better survival rates and superior lung repair compared to adults. However, the mechanisms underlying this age-specific advantage remain incompletely understood. PATIENTS AND METHODS: We conducted a pilot multi-omics study of influenza-associated PARDS integrating single-cell RNA sequencing (scRNA-seq) of pediatric lung tissue and bronchoalveolar lavage fluid (BALF), spatial transcriptomics, and plasma proteomics. Analyses were harmonized with the Human Lung Cell Atlas (HLCA) reference, reanalysis of public pediatric PARDS airway scRNA-seq, and contextual comparisons to adult lethal COVID-19 lung. RESULTS: Tissue scRNA-seq and spatial data indicated outcome-linked divergence in PARDS. Survivor showed spatially restricted repair with preserved alveolar type II (AT2) cells, AT2-to-alveolar type I (AT1) differentiation signatures, and higher KRT17, whereas fatal case and adults exhibited diffuse immune activation with pro-fibrotic and pro-apoptotic signaling. In BALF, KRT17-positive airway stress–repair epithelial cells (hillock-like) increased from the acute to recovery phase, and plasma proteomics showed higher circulating KRT17 in survivors. HLCA-based label transfer strengthened cell-type definitions and enabled pediatric–adult comparisons suggesting biological and developmental differences; the adult lethal COVID-19 atlas provided a benchmark with attenuated epithelial repair and prominent collagen CTHRC1-pathologic fibroblasts. Fibroblast programs were regionally compartmentalized, with injury-enriched CTHRC1+ states versus alveolar fibroblasts in preserved areas, and showed stronger injury–homeostasis anti-correlation in fatalities. Myeloid remodeling included BALF transitions from FCN1-high inflammatory states toward FABP4-positive resident-like states, consistent with public pediatric datasets showing reduced inflammatory and interferon-stimulated gene (ISG) modules and severity-linked increases in aged neutrophils. CONCLUSIONS: This pilot multi-omics case series outlines putative pediatric lung repair niches in influenza-associated PARDS. KRT17-positive transitional epithelium, preserved AT2 differentiation, and restoration of resident-like macrophages may align with recovery, whereas diffuse immune activation and CTHRC1-enriched fibroblast programs may accompany worse outcomes. HLCA-guided annotations and adult benchmarks indicate possible age-related differences, warranting validation in larger multi-center cohorts.

Humans↗

PubMed2025

Acute Changes in Rat Tissue Gene Expression Following Exposure to Flight Relevant Hypobaria.

Aeromedical evacuation (AE) is an invaluable tool for the transport of critically injured patients to care facilities. There is increasing evidence obtained from animal models and human patients that exposure to AE-relevant hypobaria within a few days of injury can worsen outcomes. The cause of this secondary injury is not well understood but it may be related to changes in gene expression induced by exposure to evacuation-relevant conditions. In order to explore the causes of secondary injury, gene expression induced by AE-relevant flight conditions was analyzed. Adult male rats were exposed to flight cabin-relevant hypobaria (8000 or 4000 ft equivalents) and/or different oxygen concentrations (21% or 100%) for 5 or 10 hr. At the end of the exposures, RNA was isolated from lung, blood, heart, and brain (hippocampus), levels of gene expression were measured via microarray analysis, and canonical pathway analysis identified the primary gene pathways enriched by the exposures. This information should be useful to not only optimize the health status of trauma patients undergoing aeromedical evacuation but also help determine which gene expression pathways could be modulated to optimize the therapeutic efficacy of the body's endogenous protection and repair mechanisms.

Animals↗

PubMed2026

KLF5-driven G6PD protects lung squamous cell carcinoma from ferroptosis by sustaining mitochondrial homeostasis and SLC7A11-dependent cystine uptake.

AIMS: Lung squamous cell carcinoma (LUSC) is a highly aggressive malignancy with limited therapeutic options. Ferroptosis has emerged as a promising antitumor strategy. However, the metabolic determinants governing ferroptotic vulnerability in LUSC remain incompletely understood. We investigated glucose-6-phosphate dehydrogenase (G6PD) in this context. MATERIALS AND METHODS: In vitro models using small interfering RNA (siRNA)-mediated G6PD depletion, together with pharmacological studies using 6-aminonicotinamide (6-AN) and LUSC xenograft models, were employed to investigate the underlying mechanisms. KEY FINDINGS: G6PD was markedly upregulated in LUSC, and analysis of the Cancer Genome Atlas lung squamous cell carcinoma (TCGA-LUSC) cohort showed that elevated G6PD expression was associated with advanced clinicopathological features and poorer overall survival. While ferroptosis inducers (erastin and RSL3) did not alter G6PD mRNA, they robustly increased G6PD protein during ferroptotic stress. Genetic or pharmacological inhibition of G6PD significantly sensitized LUSC cells to RSL3-induced ferroptosis, evidenced by enhanced lipid peroxidation, glutathione depletion, and ferrostatin-1-reversible cell death. Mechanistically, G6PD inhibition led to mitochondrial ferrous iron accumulation, elevated reactive oxygen species, impaired respiration, and activation of PINK1/Parkin-dependent mitophagy, which further exacerbated ferroptotic injury. In vivo, combined treatment with 6-aminonicotinamide and RSL3 markedly suppressed LUSC xenograft growth and enhanced biochemical markers of ferroptotic stress. Furthermore, G6PD protects cells by positively regulating the cystine/glutamate antiporter SLC7A11 to maintain redox homeostasis. Upstream, the oncogenic factor Krüppel-like factor 5 (KLF5) directly activates G6PD transcription. SIGNIFICANCE: Our findings identify a KLF5-G6PD-SLC7A11 axis as a critical metabolic safeguard against ferroptosis in LUSC. Targeting G6PD disrupts mitochondrial homeostasis, enhances mitophagy-dependent oxidative stress, and sensitizes tumors to ferroptotic therapy, highlighting a promising therapeutic strategy for LUSC.

Ferroptosis↗

PubMed2026

Revisiting endothelial tropism of SARS-CoV-2 using a cell-specific hACE2 mouse model.

UNLABELLED: Severe COVID-19 is frequently associated with vascular complications, raising ongoing debate about whether SARS-CoV-2 can directly infect endothelial cells and thereby contribute to disease pathogenesis. Although endothelial cells express angiotensin-converting enzyme 2 (ACE2), the in vivo relevance of endothelial-restricted viral tropism remains unclear. To directly assess the consequences of endothelial-restricted SARS-CoV-2 tropism in vivo, we generated a transgenic mouse model expressing human ACE2 under control of the endothelial-specific Cdh5 promoter (Cdh5-hACE2). Despite confirmed pulmonary endothelial expression and protein presence of hACE2, SARS-CoV-2 infection of Cdh5-hACE2 mice did not induce clinical illness, detectable viral replication, immune cell influx in the lung, or histopathological abnormalities in the lung or brain. These findings indicate that endothelial-restricted SARS-CoV-2 tropism alone is insufficient to drive productive infection and clinical disease in vivo, suggesting that endothelial involvement in COVID-19 likely arises in the context of broader cellular infection or systemic host responses rather than from primary endothelial infection. IMPORTANCE: Although SARS-CoV-2 primarily infects the upper and lower airways, COVID-19 was quickly recognized as a multi-organ disease, in which vascular complications are a recurring feature. This has raised the possibility that direct infection of endothelial cells contributes to disease pathogenesis. However, whether vascular injury arises from productive endothelial infection or instead represents a secondary consequence of systemic inflammation remains unresolved. To directly disentangle these possibilities and define the in vivo consequences of endothelial-restricted viral tropism, we generated a transgenic mouse model expressing human ACE2 under the control of the endothelial-specific Cdh5 promoter (Cdh5-hACE2).

Animals↗