Although asthma, a chronic inflammatory airway disease, is relatively well-managed by inhaled corticosteroids, the side effects associated with the long-term use of these agents precipitate the need for alternative therapeutic options based on differing modes of action. Bilirubin, a potent endogenous antioxidant, and anti-inflammatory molecule have been shown to ameliorate asthmatic symptoms; however, its clinical translation has been limited owing to its water insolubility and associated potential toxicity. Here we report the first application of water-dispersible bilirubin-based nanoparticles (BRNPs) with a diameter of ~100 nm, composed of PEGylated bilirubin, as a nanomedicine for the treatment of allergic lung inflammatory disease. In the present study, the anti-asthmatic effects of BRNPs were assessed in a mouse model of allergen-induced asthma. Because allergen-specific type 2 T-helper (Th2) cells play a key role in the pathogenesis and progression of allergic asthma, the effects of BRNPs on Th2 immune responses were investigated both in vivo and in vitro. Compared with unconjugated bilirubin (UCB), treatment with BRNPs in vivo showed much higher serum concentration and a longer circulation time of bilirubin, and suppressed the symptoms of experimental allergic asthma and dramatically ameliorated Th2-related allergic lung inflammation. Consistent with these results, BRNPs caused a reduction of Th2 cell populations and the expression of related cytokines by antibody-stimulated CD4+ T cells in vitro. Therefore, our results establish BRNPs as an important immunomodulatory agent that may be useful as a therapeutic for allergic lung inflammatory disease and other immune-mediated disorders.
KEYWORDS: antioxidant · anti-inflammation therapy · asthma · bilirubin · bilirubin nanoparticles · Th2 immune responses