Fibrotic disease is a major cause of mortality worldwide, with fibrosis arising from prolonged inflammation and aberrant extracellular matrix dynamics. Compromised cellular and tissue repair processes following injury, infection, metabolic dysfunction, autoimmune conditions and vascular diseases leave tissues susceptible to unresolved inflammation, fibrogenesis, loss of function and scarring. There has been limited clinical success with therapies for inflammatory and fibrotic diseases such that there remains a large unmet therapeutic need to restore normal tissue homoeostasis without detrimental side effects. We investigated the effects of a newly formulated low molecular weight dextran sulfate (LMW-DS), termed ILB®, to resolve inflammation and activate matrix remodelling in rodent and human disease models. We demonstrated modulation of the expression of multiple pro-inflammatory cytokines and chemokines in vitro together with scar resolution and improved matrix remodelling in vivo. Of particular relevance, we demonstrated that ILB® acts, in part, by downregulating transforming growth factor (TGF)β signalling genes and by altering gene expression relating to extracellular matrix dynamics, leading to tissue remodelling, reduced fibrosis and functional tissue regeneration. These observations indicate the potential of ILB® to alleviate fibrotic diseases.
Bibliographical noteFunding Information:
This study was funded by Tikomed AB with some contribution from the Queen Elizabeth Hospital Birmingham Charity. Some of the analyses were performed by Neuregenix Ltd., Birmingham, UK and Eurofins DiscoverX Corporation, Freemont, CA, USA, which had no commercial interest in the study outcomes. We are extremely grateful to Dr. Zsuzsanna Nagy (University of Birmingham) for her useful interpretation and comments on the gene expression data, the mechanism of action of ILB®, and the manuscript text.
© 2021, The Author(s).
ASJC Scopus subject areas
- Biomedical Engineering
- Cell Biology
- Developmental Biology
- Medicine (miscellaneous)