Abstract
With regard to identifying the effective components of LMWH drugs curing hepatic fibrosis disease, we carried out a comparative study on the efficacy of enzymatically depolymerized LMWHs on CCl4 induced mouse liver fibrosis. The results showed that the controlled enzymatic depolymerization conditions resulted in LMWHs with significantly different activities. The LMWH product depolymerized by Heparinase I (I-11) with a Mw of 7160, exhibited a significant advantage in reducing the liver inflammation by suppressing TNF-α and IL-1β secretion, and minimizing hepatic fibrogenesis. The products prepared by only Heparinase II (II-11), and combined Heparinase III and II (III-II-5) showed limited positive effect on hepatic inflammation and fibrosis. On the contrary, the products by combined Heparinase III and I (III-I-9, III-I-5) showed no effect or stimulation effect on the hepatic fibrogenesis. Our results provided the basis for structure-activity relationship insight for inhibition of liver fibrosis activities of LMWHs, which might have significant implications for generic anti-fibrosis disease drug development.
Highlights
Tissue fibrosis represents a conserved pathological process, during which iterative injury in any organ triggers excess extra cellular matrix deposition (Rockey et al, 2015)
III-II-9 group decreased the liver index, whereas other low molecular weight heparins (LMWHs) appeared to have no impact (Figure 1A); I-11, and III-II-5 treatment significantly counteracted the increase of the spleen index, whereas other LMWH groups showed no reduction compared with the negative control (NC) group (Figure 1B)
Our results revealed that I-11, III-I-5, III-I-9, and III-II-9 all decreased the ratios, indicating all the tested LMWHs alleviated the edema (Figure 1C)
Summary
Tissue fibrosis represents a conserved pathological process, during which iterative injury in any organ triggers excess extra cellular matrix deposition (Rockey et al, 2015). Liver fibrosis is a key step to cirrhosis, liver failure, portal hypertension, and a high risk of developing hepatocellular carcinoma. This pathological process contributed to around 1.5 million deaths per year (Hernandez-Gea and Friedman, 2011), and become a significant health problem worldwide (Fagone et al, 2016). Only Pirfenidone and Nintedanib have been approved as antifibrosis drugs, not specific for liver fibrosis. The effective pharmacotherapy targeting liver fibrosis is extremely urgent
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