Biomedical Science and Engineering Interdisciplinary Program, KAIST Institute for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, South Korea; Graduate School of Medical Science and Engineering, Biomedical Research Center, KAIST Institute for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, South Korea.
Department of Biological Sciences, KAIST Institute for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, South Korea.
Biomaterials. 2017 Sep;140:37-44. doi: 10.1016/j.biomaterials.2017.06.014. Epub 2017 Jun 12.
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 bilirubin-based nanoparticles (BRNPs) as a nanomedicine for the treatment of allergic lung inflammatory disease. BRNPs were prepared directly from self-assembly of PEGylated bilirubin in aqueous solution and had a hydrodynamic diameter of ∼100 nm. 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. BRNPs after intravenous injection (i.v.) showed much higher serum concentration and a longer circulation time of bilirubin than the intraperitoneal injection (i.p.) of BRNPs or unconjugated bilirubin (UCB). The anti-asthmatic effects of BRNPs were assessed in a mouse model of allergen-induced asthma. Compared with UCB, treatment with BRNPs 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.
尽管吸入性皮质类固醇可相对较好地控制哮喘（一种慢性炎症性气道疾病），但这些药物长期使用的副作用促使人们需要寻求基于不同作用机制的替代治疗方案。胆红素作为一种有效的内源性抗氧化剂和抗炎分子，已被证明可改善哮喘症状；然而，由于其水溶性差和潜在毒性，其临床应用受到限制。在此，我们首次报道了基于胆红素的纳米颗粒（BRNPs）作为一种治疗过敏性肺部炎症疾病的纳米药物的应用。BRNPs 是通过 PEG 化胆红素在水溶液中的自组装直接制备而成，其水动力学直径约为 100nm。由于过敏原特异性 2 型辅助性 T 细胞（Th2 细胞）在过敏性哮喘的发病机制和进展中发挥着关键作用，因此研究了 BRNPs 对 Th2 免疫反应的影响，包括体内和体外研究。与 BRNPs 的腹腔注射（i.p.）或 unconjugated bilirubin（UCB）相比，静脉注射（i.v.）BRNPs 后血清中胆红素的浓度更高，循环时间更长。我们在过敏原诱导的哮喘小鼠模型中评估了 BRNPs 的抗哮喘作用。与 UCB 相比，BRNPs 治疗可抑制实验性过敏性哮喘的症状，并显著改善与 Th2 相关的过敏性肺部炎症。与这些结果一致，BRNPs 在体外通过抗体刺激 CD4 T 细胞引起 Th2 细胞群和相关细胞因子表达的减少。因此，我们的结果确立了 BRNPs 作为一种重要的免疫调节药物，可作为治疗过敏性肺部炎症疾病和其他免疫介导性疾病的一种有前途的治疗方法。
