Adaptive bilirubin nanoscavenger alleviates pulmonary oxidative stress and inflammation for acute lung injury therapy,Journal of Advanced Research

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Adaptive bilirubin nanoscavenger alleviates pulmonary oxidative stress and inflammation for acute lung injury therapy
Journal of Advanced Research ( IF 11.4 ) Pub Date : 2025-03-17 , DOI: 10.1016/j.jare.2025.03.027
Longfa Kou ₁ , Yitianhe Xu ₂ , Shize Li ₂ , Zhinan He ₁ , Di Huang ₃ , Zhanzheng Ye ₁ , Yixuan Zhu ₁ , Yunzhi Wang ₁ , Xinyu Di ₁ , Yuqi Yan ₁ , Yinhao Lin ₁ , Wanling Zhu ₄ , Xianbao Shi ₄ , Hailin Zhang ₅ , Ruijie Chen ₂

Affiliation

Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou 325027, China; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou 325027, China.
Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
Department of Pharmacy, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, China.
Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou 325027, China; Department of Children's Respiration Disease, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China.

Introduction

Acute lung injury (ALI) is a life-threatening condition characterized by rapidly progressing respiratory distress and hypoxemia. Oxidative stress-induced inflammation in lung tissue plays a crucial role in the progression of ALI. Excessive generation of reactive oxygen species (ROS) in the pulmonary microenvironment activates inflammatory signaling pathways, enhancing the transcription of pro-inflammatory factors and ultimately leading to tissue necrosis.

Objectives

Bilirubin (BR), an exceptional endogenous antioxidant, possesses the ability to counteract elevated levels of reactive oxygen species (ROS) through direct reactions or by inducing antioxidant systems such as Nrf2/HO-1 signaling. However, its limited solubility poses a hindrance to further applications. Hence, it is imperative to develop a suitable bilirubin-based system for biological utilization.

Methods

In this study, we developed a bilirubin-based ROS-sensitive adaptive nanoscavenger (GP@BR) by co-assembling bilirubin-conjugated glycol chitosan (GC-BR) and bilirubin-conjugated polyethylene glycol (PEG-BR), aiming to alleviate oxidative stress for ALI treatment.

Results

The different conjugations endowed the bilirubin derivatives with varying sensitivity towards reacting with ROS, enabling GP@BR to exert antioxidative properties specifically in oxidative environments on demand. Besides its excellent antioxidant properties, GP@BR also demonstrated the ability to absorb excess inflammatory cytokines. Moreover, our optimized nanoscavenger facilitated bilirubin transport across the mucosal layer on pulmonary epithelial cells. In vivo studies confirmed that GP@BR significantly improved ALI symptoms and suppressed pulmonary fibrosis.

Conclusion

This study highlighted the potential of ROS-sensitive adaptive properties and multiple actions of this nanoscavenger in the treatment of ALI.

中文翻译：

适应性胆红素纳米清除剂减轻急性肺损伤治疗的肺氧化应激和炎症

介绍

急性肺损伤（ALI）是一种危及生命的疾病，其特征是呼吸窘迫和低氧血症迅速发展。氧化应激诱导的肺组织炎症在 ALI 的进展中起着至关重要的作用。肺部微环境中活性氧（ROS）的过量产生会激活炎症信号通路，增强促炎因子的转录，最终导致组织坏死。

目标

胆红素（BR）是一种特殊的内源性抗氧化剂，具有通过直接反应或通过诱导抗氧化系统（如 Nrf2/HO-1 信号传导）抵消升高的活性氧（ROS）水平的能力。然而，其有限的溶解度对进一步的应用构成了障碍。因此，必须开发一种合适的基于胆红素的系统进行生物利用。

方法

在这项研究中，我们通过共组装胆红素共轭的乙二醇壳聚糖（GC-BR）和胆红素共轭的聚乙二醇（PEG-BR）开发了一种基于胆红素的 ROS 敏感自适应纳米清除剂（GP@BR），旨在减轻 ALI 治疗的氧化应激。

结果

不同的偶联物赋予胆红素衍生物对与 ROS 反应的不同敏感性，使GP@BR能够根据需要在氧化环境中发挥抗氧化特性。除了出色的抗氧化特性外，GP@BR还显示出吸收过量炎性细胞因子的能力。此外，我们优化的纳米清除剂促进了胆红素穿过肺上皮细胞粘膜层的运输。体内研究证实，GP@BR 显著改善了 ALI 症状并抑制了肺纤维化。