Daily Respiratory Research Analysis

Radiation-induced lung injury (RILI) is a dose-limiting factor in thoracic radiotherapy, and effective treatments are currently lacking. Ionizing radiation (IR) induced senescence of lung epithelial cells is considered a central process in the development and progression of RILI. Ferroptosis, a form of regulated cell death characterized by iron dependency, has been implicated in various IR-induced injuries, including RILI. However, whether ferroptosis participates in the pathological process of cellular senescence remains unreported. In this study, we investigated the potential association between ferroptosis and senescence in lung epithelial cells during RILI, as well as the upstream regulatory mechanisms. Our research found that IR induces mitochondrial dysfunction and senescence in lung epithelial cells and promotes the release of the senescence-associated secretory phenotype (SASP). These effects can be effectively inhibited by the ferroptosis inhibitor Ferrostatin-1 (Fer-1). Further study revealed that IR-induced iron overload and ferroptosis are closely associated with ferritin degradation. Inhibition of autophagy with 3-methyladenine (3-MA) reduced ferritin heavy chain (FTH) degradation, thereby alleviating IR-induced ferroptosis and cellular senescence, suggesting that ferritinophagy is involved in these processes. Additionally, in vivo and in vitro experiments demonstrated that IR activates nuclear receptor coactivator 4 (NCOA4). Knockdown of NCOA4 in vitro suppressed iron overload and ferroptosis in lung epithelial cells and ameliorated cellular senescence. In vivo administration of compound 9a disrupts the NCOA4-FTH interaction, thereby inhibiting NCOA4-mediated ferritinophagy. This inhibition reduced intracellular iron levels and ferroptosis, improved mitochondrial function and epithelial cell senescence, and ultimately mitigated RILI. These findings indicate ferroptosis as a key regulator of IR-induced senescence in lung epithelial cells and highlight the critical role of NCOA4-mediated ferritinophagy in the pathogenesis of RILI.

Nucleic acid amplification tests (NAATs) were performed selectively as an initial diagnostic test for pulmonary tuberculosis (TB) in Taiwan. We assessed whether expanded use of Xpert MTB/RIF assay as an initial diagnostic test made positive contribution to the management of TB. Patients who had NAATs as an initial diagnostic test requested by clinician were classified as group A. Those who did not were randomized in a 1:1 ratio into group B who had an immediate Xpert test by intervention and group C who had usual care. 6835 patients were enrolled. Comparing group B and group C, the proportion of patients diagnosed with active TB (3.1% vs 2.7%, p = 0.336), the proportion of patients died before anti-TB treatment (2.3% vs 5.1%. p = 0.318), the median interval between submitting sputum and initiation of anti-TB treatment (7.0 days, interquartile range 3.0-25.0 vs 6.0 days, interquartile range 2.0-23.0, p = 0.589), and the proportion of TB patients with treatment success (73.8% vs 81.8%, p = 0.657) were not significantly different. There is no evidence that expanded use of Xpert MTB/RIF test as an initial diagnostic test for pulmonary TB among cases with a relatively low pretest probability of TB has positive influence on TB control in Taiwan.Trial Registration: ClinicalTrials.gov. Number NCT04433195 (date: 16/06/2020).

Airway mucus presents a significant barrier to inhaled drug delivery, particularly for nanoparticle-based interventions, with this barrier exacerbated in chronic respiratory diseases (CRDs) due to hyperviscous secretions and persistent inflammation. In this study, a dual-functional lipid-polymer hybrid nanoparticle was developed to combine rapid mucolysis with sustained anti-inflammatory activity, and its performance was evaluated using both conventional in vitro assays and a physiologically relevant lung-on-a-chip model. Dipalmitoylphosphatidylcholine (DPPC)-coated PLGA nanoparticles (hydrodynamic diameter 378.1 ± 23.0 nm; 58-61 wt% lipid; ζ ≈ +3 mV) encapsulated N-acetylcysteine (NAC) within the lipid shell for rapid release and all-trans retinoic acid (ATRA) within the core for sustained delivery. NAC exhibited a burst release of 44.2-52.5% within 6 h and significantly reduced the viscosity of cystic fibrosis-mimetic mucus, enabling a 26.5-fold higher penetration across a ∼ 0.6 mm mucus plug compared to NAC-free controls. The formulation was well tolerated by pulmonary epithelial and fibroblast cells and demonstrated high cellular uptake driven by the DPPC coating. To assess efficacy under physiologically relevant airway conditions, a human lung-on-a-chip model incorporating air-liquid interface, flow, and cyclic stretch was employed. In this model, repeated dosing of NAC + ATRA nanoparticles resulted in a 2.6-fold reduction in IL-6 and a 2.3-fold reduction in IL-8 levels compared to diseased controls at 72 h, outperforming NAC-free nanoparticles at early timepoints and maintaining suppression over 9 days. These findings demonstrate the therapeutic promise of dual-functional mucopenetrative nanoparticles and establish the utility of lung disease-on-chip platforms for evaluating inhaled nanotherapeutics under physiologically relevant conditions.