Jia XiaoXiao, Shi Ming, Wang Qifei, Hui Jessica, Shofaro Joshua Hui, Erkhembayar Ryenchindorj, Hui Mizhou, Gao Chenzhe, Gantumur Munkh-Amgalan
College of Life Science, Northeast Agricultural University, Harbin, People's Republic of China.
College of Veterinary Medicine, Qingdao Agricultural University, Qingdao, People's Republic of China.
J Inflamm Res. 2023 Jan 13;16:209-224. doi: 10.2147/JIR.S393495. eCollection 2023.
Hyaluronic acid (HA) and HA fragments interact with a variety of human body receptors and are involved in the regulation of various physiological functions and leukocyte trafficking in the body. Accordingly, the development of an injectable HA fragment with good tissue permeability, the identification of its indications, and molecular mechanisms are of great significance for its clinical application. The previous studies showed that the clinical effects of injectable 35kDa B-HA result from B-HA binding to multiple receptors in different cells, tissues, and organs. This study lays the foundation for further studies on the comprehensive clinical effects of injectable B-HA.
We elaborated on the production process, bioactivity assay, efficacy analyses, and safety evaluation of an injectable novel HA fragment with an average molecular weight of 35 kDa (35 kDa B-HA), produced by recombinant human hyaluronidase PH20 digestion.
The results showed that 35 kDa B-HA induced human erythrocyte aggregation (rouleaux formation) and accelerated erythrocyte sedimentation rates through the CD44 receptor. B-HA application and injection treatment significantly promoted the removal of mononuclear cells from the site of inflammation and into the lymphatic circulation. At a low concentration, 35 kDa B-HA inhibited production of reactive oxygen species and tumor necrosis factor by neutrophils; at a higher concentration, 35 kDa B-HA promoted the migration of monocytes. Furthermore, 35 kDa B-HA significantly inhibited the migration of neutrophils with or without lipopolysaccharide treatment, suggesting that in local tissues, higher concentrations of 35 kDa B-HA have antiinflammatory effects. After Tc radiolabeled 35 kDa B-HA was intravenously injected into mice, it quickly entered into the spleen, liver, lungs, kidneys and other organs through the blood circulation.
This study demonstrated that the HA fragment B-HA has good tissue permeability and antiinflammatory effects, laying a theoretical foundation for further clinical studies.
透明质酸（HA）及其片段可与多种人体受体相互作用，并参与体内多种生理功能的调节以及白细胞的运输。因此，开发一种具有良好组织渗透性的可注射HA片段、明确其适应症及分子机制对其临床应用具有重要意义。先前的研究表明，可注射的35kDa B-HA的临床效果源于B-HA与不同细胞、组织和器官中的多种受体结合。本研究为进一步研究可注射B-HA的综合临床效果奠定了基础。
我们详细阐述了通过重组人透明质酸酶PH20消化产生的平均分子量为35kDa的新型可注射HA片段（35kDa B-HA）的生产过程、生物活性测定、疗效分析和安全性评估。
结果表明，35kDa B-HA通过CD44受体诱导人红细胞聚集（缗钱状形成）并加速红细胞沉降率。B-HA的应用和注射治疗显著促进了单核细胞从炎症部位清除并进入淋巴循环。在低浓度下，35kDa B-HA抑制中性粒细胞产生活性氧和肿瘤坏死因子；在较高浓度下，35kDa B-HA促进单核细胞迁移。此外，35kDa B-HA显著抑制中性粒细胞在有或无脂多糖处理情况下的迁移，这表明在局部组织中，较高浓度的35kDa B-HA具有抗炎作用。将经锝放射性标记的35kDa B-HA静脉注射到小鼠体内后，它通过血液循环迅速进入脾脏、肝脏、肺、肾脏等器官。
本研究表明，HA片段B-HA具有良好的组织渗透性和抗炎作用，为进一步的临床研究奠定了理论基础。
