Anti-Inflammatory Effects of the 35kDa Hyaluronic Acid Fragment (B-HA/HA35)

Abstract

Background

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.

Methods

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.

Results

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 ^99mTc 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.

Conclusion

This study demonstrated that the HA fragment B-HA has good tissue permeability and antiinflammatory effects, laying a theoretical foundation for further clinical studies.

Keywords:

• hyaluronic acid
• 35kDa hyaluronic acid fragment
• B-HA/HA35
• molecular weight
• inflammation
• inflammatory cells
• reactive oxygen species
• injection safety

Acknowledgment

We would like to thank Harrison Barrett and Professor Lars Furenlid of the University of Arizona for their technical support. iQID dynamic imaging of the whole-body distribution of ^99mTc-B-HA in mice was conducted at the Center for Gamma-Ray Imaging, University of Arizona, USA. This center is supported by the research grant NIH/NIBIB P41-EB002035 (USA).

Disclosure

The authors report no conflicts of interest in this work.