TGFβ is an important component of the inflammatory signaling of senescent cells, and cellular senescence is involved in the progression of numerous fibrotic and age-related conditions. Chronic inflammation causes tissue maintenance processes to run awry, and fibrosis, the inappropriate deposition of scar-like collagen structures that disrupt tissue function, is one of the possible outcomes. Here, researchers use an established class of compound to target this form of inflammatory signaling, finding that the treatment has a positive impact on fibrotic disease in animal models. This is consistent with other studies that have found that TGFβ is a useful target, in that suppressing TGFβ signaling can limit the harms done by senescent cells.
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.