Curcumin nanoparticles alleviate bronchial epithelial atrophy and ER stress in a novel mouse model of Concomitant hypoxia and simulated microgravity

Background: The lung is susceptible to damage due to hypoxia and hindlimb unloading (HU) in mice. However, relevant interventions remain elusive. Curcumin-loaded nanoparticles (Cur-NP) offer anti-inflammatory benefits. We investigated the therapeutic efficacy of Cur-NP on the respiratory epithelium and relevant molecular mechanisms. Methods: Cur PLGA NP were synthesized by an emulsion solvent-evaporation method and characterized for their physicochemical properties. We used male, 4-month-old male c57BL/6j HU mice for two weeks in normoxic (21 % oxygen) or hypoxic (15 % oxygen) conditions. The mice were divided into placebo, free Cur, or Cur-NP treatment groups. After treatment, mice were euthanized for the investigation of lung histology and the molecular markers of endoplasmic reticulum (ER) stress, necroptosis, and apoptosis. Results: Cur-NP resulted in spherical 478.7 ± 21.0 nm particles with 0.35 ± 0.06 PDI, −15.9 ± 1.1 mV ZP, 18.5 ± 0.8 % drug load, and 92.6 ± 4.1 % encapsulation efficiency. HU and hypoxia were associated with bronchial epithelial atrophy and upregulated ER stress. Cur-NP exhibited a sustained release of Cur, with 18.7 % of the drug released over 24 h compared to 64.5 % for free Cur. The Cur-NP increased bronchial epithelial thickness by 16 %, upregulated RIPK1, a necroptosis marker, by 37 %, and reduced ER stress markers, total and spliced XBP-1, by 33 % and 48 %, respectively. However, these effects were not observed in mice treated with free Cur. Conclusion: Nanonization significantly enhanced the therapeutic efficacy of Cur in treating lung pathology associated with hypoxia and HU. However, further research is warranted to rigorously characterize how Cur-NP affects ER stress, its downstream regulators, and cell death pathways.