Ciclesonide

Subglottic stenosis (SGS) coexists with bronchopulmonary disease, complicating topical therapy given the distinct anatomical targets. Optimizing inhaled medication delivery to both regions remain a therapeutic challenge. This study evaluates the ability of orally inhaled aerosol particles to achieve dual‑site deposition in SGS and bronchopulmonary regions.

Computational modeling of orally inhaled drug particle delivery.

Academic Medical Center.

Digitally modified airways simulating 8 SGS variants, combining McCaffrey Stage I (5 mm) and II (15 mm) subglottic lengths with Cotton‑Myer Grade I (10%, 30%), Grade II (60%), and Grade III (90%) luminal constrictions. Oral inhalation at 15 L/min and particle transport were simulated for fluticasone propionate (FP; mean aerosol velocity 9.19 m/s, particle size range 1‐8 μm) and ciclesonide (CIC; mean aerosol velocity 4.26 m/s, particle size range 1‐4 μm) inhaler characteristics, and 6 particle‑size distributions M 1 (1‐5 μm), M 2 (6‐10 μm), M 3 (1‐10 μm) while maintaining the respective parent (CIC and FP) mean aerosol velocity.

In the normal airway, CIC and FP inhalers achieved >80% bronchial deposition but ≤0.02% subglottic delivery. Among modified devices, M 2 CIC optimized dual targeting, providing the highest subglottic deposition (0.09%) with preserved bronchial efficiency (69.46%). In SGS models, M 2 CIC and M 2 FP consistently achieved the most balanced delivery, with maximum deposition of M 2 CIC = 8.4% and M 2 FP = 7.86% at subglottic region, and M 2 CIC = 69.89% and M 2 FP = 61.02% at bronchial site. M 3 variants offered intermediate dual deposition at advanced and Grade III stenosis stages.

M 2 CIC and M 2 FP inhaler modifications optimized dual‐site supporting tailored device strategies for SGS with coexisting bronchopulmonary disease.

Cytokine storm, a life-threatening hyperinflammatory response seen in severe infections like COVID-19, autoimmune diseases, and certain therapies, remains difficult to treat due to limited approved therapeutics. To support preclinical drug development and repurposing in line with 3R principles, we present a novel in vitro model for screening of cytokine-modulating compounds. Herein, we demonstrate that lymphoblastoid cell lines (LCL cells), derived from healthy donors, provide a translationally relevant and phenotypically diverse platform for cytokine profiling and drug screening. Upon stimulation with PMA/ionomycin, LCL cells exhibited a robust secretion of pro-inflammatory (IL-6, IL-8, TNF-α) and anti-inflammatory (IL-10) cytokines, closely mirroring the cytokine profile of activated whole blood. Compared to established immune cell lines THP-1 and Jurkat, LCL cells showed broader cytokine responses and retained interindividual variability. We validated the model for cytokine-modulating drug screening using two well-established immunosuppressants, dexamethasone and cyclosporin A. Dexamethasone reduced IL-6 by 21 %, IL-8 by 71 %, IL-12 by 68 %, TNF-α by 83 %, and increased IL-10 by 51 %. Cyclosporin A lowered IL-6 by 34 %, IL-8 by 69 %, IL-10 by 48 %, and TNF-α by 41 %. Subsequently, we tested a panel of clinically investigated COVID-19 therapies, selected based on a comprehensive literature review. Ciclesonide and acalabrutinib showed strong suppression of all measured cytokines by more than 60 %, while baricitinib, which has become a standard of care for severe COVID-19, reduced IL-6 by 70 %, IL-12 by 68 %, and TNF-α by 47 %, but had minimal effect on IL-8. Notably, LCL cells retained interindividual variability, as demonstrated by diverse cytokine as well as divergent NF-κB nuclear translocation responses, supporting the model's capacity to reveal real-world patient heterogeneity. Collectively, our findings establish LCL cells as a reproducible, immunologically responsive, and patient-representative platform for cytokine storm research and high-content drug testing, providing both mechanistic insight and translational relevance.