Citations

Iron is an important metal element regulating biological processes such as gene expression, electron transport, cell proliferation, differentiation and division, and cellular respiration. Regulation of iron levels is therefore critical, with excess iron accumulation leading to iron-dependent lipid peroxidation and cell death (ferroptosis). Factors such as aging and environmental exposures (e.g., high/low oxygen, particulate iron) can disrupt iron homeostasis. Iron-dependent processes influence downstream pathways such as inflammation, mitochondrial energetics, and remodeling (proliferation, fibrosis), pathways involved in lung diseases particularly at the extremes of age, from hyperoxic lung injury in neonates to chronic diseases such as asthma, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis (PF) that increase with age. Although these diseases involve structural and functional changes in bronchial versus alveolar compartments, including airway hyperreactivity, altered mucus production, cell proliferation and migration, increased extracellular matrix (ECM) remodeling, senescence, and metabolic dysregulation, the casual or consequential links between iron dysregulation and disease pathology, particularly with aging, are still being investigated. The aim of this topical review is to 1) highlight current knowledge regarding iron regulation in normal lung versus lung diseases, 2) identify known roles of iron in lung homeostasis and the contribution of iron dysregulation in lung diseases with aging, and 3) explore the potential benefit of targeting iron regulation and/or ferroptosis in lung diseases.

Abstract Introduction Pulmonary fibrosis is characterized by excessive fibroblast activation and alveolar remodeling, leading to progressive lung dysfunction. Osteoglycin (OGN), a small leucine-rich proteoglycan, and its functional fragment MC002 have been identified as regulators of alveolar epithelial regeneration, a process that is impaired in fibrotic lung disease. This study investigates the effects of OGN and MC002 on TGF-β-induced fibrotic responses in lung fibroblasts, organoids, and an in vivo fibrosis model. Methods Human lung fibroblasts (MRC5) were treated with OGN or MC002 for 48 hours, with or without transforming growth factor-beta (TGF-β; 2 ng/mL). Expression of the myofibroblast marker α-smooth muscle actin (ACTA2) and matrix markers collagen 1a1 (COL1A1) and fibronectin (FN1) was assessed by RT-PCR and Western blotting. Global transcriptomic changes were analyzed by RNA sequencing. Myofibroblast differentiation was evaluated by phalloidin staining and quantified using the phalloidin/DAPI ratio. Murine lung organoids were generated by co-culturing epithelial progenitor cells with fibroblasts and treated with TGF-β (2 ng/mL) in the presence or absence of OGN or MC002. Organoid number, size, and alveolar differentiation were quantified after 14 days. In vivo, pulmonary fibrosis was induced in mice using intratracheal bleomycin. MC002 was administered at different doses (6.75 µg or 20.25 µg) every other day starting from day 7 post-bleomycin, and lung weight and pressure-volume (PV) loops were assessed to evaluate fibrotic burden and lung mechanics. Osteoglycin expression in human lung tissue from 13 non-smokers, 11 ex-smokers, and 12 IPF patients was analyzed by immunostaining. Results TGF-β induced pro-fibrotic gene expression in fibroblasts, while OGN and MC002 alone had no pro-fibrotic effects. MC002 fully reversed TGF-β-induced ACTA2, COL1A1, and FN1 expression, whereas OGN selectively attenuated COL1A1. RNA-sequencing revealed broad suppression of fibrosis- and ECM-associated gene programs by MC002. At the protein level, TGF-β-induced ACTA2 expression was reversed by MC002 but not by OGN. Both compounds reduced TGF-β-induced stress fiber formation. In lung organoids, TGF-β impaired organoid formation and alveolar differentiation, effects that were restored by OGN and MC002 in a concentration-dependent manner. In the bleomycin model, MC002 significantly reduced lung weight and improved PV loop profiles, indicating attenuation of fibrotic stiffening and improved lung compliance. Osteoglycin protein expression was significantly diminished in IPF whole lung tissue and parenchyma compared to controls. Conclusion OGN, and particularly MC002, counteract TGF-β-driven fibroblast activation and myofibroblast differentiation while promoting alveolar preservation. The superior efficacy of MC002 supports its potential as a therapeutic candidate for pulmonary fibrosis. This abstract is funded by: Lung Foundation Netherlands 10.1.23.021PPS

Abstract Senescent cells accumulate with age and contribute to tissue dysfunction, yet their identification in tissues is challenging due to low abundance, heterogeneous phenotypes, and the lack of specific markers. Senescence-associated features span multiple subcellular compartments, including nuclear DNA damage foci, cytosolic protein changes, and perinuclear alterations, each requiring tailored detection strategies. To overcome these challenges, we developed SenoQuant ( https://github.com/HaamsRee/senoquant ), a versatile software designed for comprehensive, accurate, and unbiased spatial quantification and prediction of senescence markers across diverse tissue contexts. Utilizing AI models, SenoQuant enables precise nuclear and cytoplasmic segmentation and detection of senescence markers across low- and high-plex imaging modalities, applicable to cultured cells and tissue sections from mice and humans. The platform also supports custom AI models; for example, we built SenCeption, a proof-of-concept predictor of single-cell p21 status from DAPI-stained nuclei in human skin. Available as a free napari plugin, SenoQuant is widely accessible to researchers. By providing a unified approach to senescence analysis and prediction, SenoQuant opens new opportunities for exploring the complex biology of senescence and its impacts on aging and disease.

Recognizing that antioxidant systems are impaired in the airways of premature infants, we used human fetal airway cells to explore the impact of oxygen on iron regulation and iron-mediated cell death (ferroptosis). We find moderate hyperoxia impairs antioxidant systems that prevent ferroptosis and dysregulates iron metabolism, while severe hyperoxia has a negative effect on mechanisms driving the early onset of ferroptosis. Inhibitors of ferroptosis decrease iron and lipid peroxidation, demonstrating links between oxygen and iron regulation in developing airways.

Abstract As an intrinsically mechanosensitive organ, the lung experiences a range of mechanical forces. Chronic obstructive pulmonary disease (COPD) involves abnormal macroscopic cellular and extracellular matrix (ECM) changes that impact mechanical properties of the lung. Mechanosensitive Piezo1/2 channels are expressed in the lung including on airway smooth muscle cells (ASM) that mediate cellular responses to stretch and ECM biomechanics. The expression and roles of Piezos in COPD lung ASM are not known. We hypothesized that Piezo expression and activation are altered in COPD lung ASM influencing ECM regulation. Distribution of Piezo proteins in ASM and epithelium of small airways of COPD stage II and IV vs. non-COPD controls was assessed using immunohistochemistry and ImageJ (n=10-17/group). Isolated ASM cells from control (n=6) vs. COPD stage II and IV patients (n=3 each stage) were exposed to stretch or the Piezo1 agonist Yoda1 followed by measurement of ECM gene and protein expression. Less Piezo2 staining was observed in COPD IV patients compared to controls, with lesser area and intensity of staining in the epithelial layer, and lower intensity of staining in ASM and small airways as a whole. Fura-2-based imaging of ASM Ca 2+ showed lower influx after Yoda1 exposure in COPD II compared to control and COPD IV. Gene expression of Piezo1 increased upon stretching in controls but not in COPD ASM, while Piezo2 protein expression decreased with stretching in all groups. Yoda1 treatment resulted in decreased collagen1 , fibulin1 and periostin gene and collagen 1 and periostin protein expression in ASM. Overall, these results support a role for Piezo activation in abnormal ECM-ASM cell crosstalk in COPD.

Background With improved cardiac surgical outcomes, attention has shifted to patient-centred outcomes, including cosmetic appearances of surgical scars. Minimally invasive cardiac surgery (MICS) is often promoted for its cosmetic benefits, yet empirical evidence remains limited. This study aimed to systematically evaluate scar-specific outcomes comparing MICS to conventional full median sternotomy (FMS) in adult cardiac surgery. Methods A systematic review and meta-analysis was conducted following PRISMA guidelines. PubMed, Embase, Central, and Scopus were searched from inception to August 2025. Studies comparing MICS to FMS, reporting scar-related patient-reported outcomes, wound complications, or cosmetic satisfaction, were included. The primary outcome was scar assessment using validated instruments. Random-effects models calculated standardised mean differences (SMD) and risk ratios (RR) with 95% confidence intervals. Results Twenty-two studies comprising 3131 patients (1459 MICS, 1672 FMS) met inclusion criteria. MICS demonstrated significantly better scar assessment scores (SMD −0.74, 95% CI −1.27 to −0.22; p < 0.01; I 2 = 88%, six studies), higher patient satisfaction rates (RR 1.42, 95% CI 1.21–1.66; p < 0.001; I 2 = 84%, 12 studies), and reduced wound complications (RR 0.31, 95% CI 0.20–0.47; p < 0.001; I 2 = 0%, nine studies). Only six studies reported validated scar assessment scores, highlighting limited integration of these measures. Substantial heterogeneity was observed due to diverse assessment tools and surgical techniques. Conclusions MICS can offer significant advantages in scar-specific outcomes compared to FMS in carefully selected patient populations. Cosmetic outcomes should be interpreted within the context of overall effectiveness and may support shared decision making only when clinical outcomes between surgical approaches are comparable. The lack of standardised scar assessment protocols and limited reporting of cosmetic outcomes represent critical gaps. Future research should prioritise standardised scar evaluation tools and expand cosmetic outcome reporting across all cardiac surgical procedures.

Abstract The lung, one the largest branching organs in our body and vital for survival at first breath, is commonly known as the gas-exchange organ. Recent novel findings on lung sensing cells, molecules, and lung-brain crosstalk in the emerging discipline of interoception have highlighted the consideration of the lung as a sensory organ. Acknowledging the central importance of lung sensing to human health and disease, NHLBI convened a workshop to synthesize the past, current, and future of lung sensing research, with in-person presentations by ∼20 interdisciplinary experts and a large virtual audience. Here, we highlight the key topics discussed and summarize a blueprint for the future in this important field.

Abstract For implantable closed loop neuromodulation systems, real-time neural sensing, biomarker detection, and targeted stimulation are essential components for delivering personalized therapy. Current limitations in sampling rate and the number of available recording channels in implantable systems may pose significant challenges, especially in epilepsy research where high-frequency biomarkers and multi-site monitoring are essential. The Brain Interchange (BIC) system of CorTec is an externally powered, wireless implantable system that enables sensing and stimulation up to 32 channels at 1 kHz addressing the current limitations in the field. In this study, we present a modular closed loop neuromodulation environment developed for the BIC, enabling real-time data streaming, event detection, and flexible stimulation control. The framework integrates a Simulink-based processing pipeline, real-time communication, and a graphical user interface supporting both open and closed loop paradigms. System performance was evaluated through impedance measurement, latency assessment across three stimulation modes, and real-time closed loop stimulation using electrocardiogram (ECG) for in-lab demonstration. This modular environment provides a flexible platform for developing and validating neuromodulation algorithms and can be extended to incorporate advanced biomarker detection and multi-channel neural interfaces for future clinical research.