Combination therapy of Ulinastatin with Thrombomodulin alleviates endotoxin (LPS) - induced liver and kidney injury via inhibiting apoptosis, oxidative stress and HMGB1/TLR4/NF-κB pathway

Abstract

ABSTRACT Sepsis is a type of systemic inflammation response syndrome that leads to organ function disorders. Currently, there is no specific medicine for sepsis in clinical practice. Lipopolysaccharide (LPS) is an important endotoxin that causes sepsis. Here, we report an effective two-drug combination therapy to treat LPS-induced liver and kidney injury in endotoxic rats. Ulinastatin (UTI) and Thrombomodulin (TM) are biological macromolecules extracted from urine. In our study, combination therapy significantly improved LPS-induced liver and kidney pathological structure and functional injury, and significantly improved the survival rate of endotoxic rats. Results of TUNEL staining and Western blot showed that UTI combined with TM inhibited the excessive apoptosis of liver and kidney cells caused by LPS. The drug combination also promoted the proliferation of liver and kidney cells, reduced the levels of pro-inflammatory factors interleukin (IL)-6, IL-1β, tumor or necrosis factor (TNF)-α and nitric oxide, and down-regulated the expression of High Mobility Group Box 1 (HMGB1), Toll-like receptor (TLR) 4 and Nuclear Factor (NF)-κB phosphorylation to inhibit inflammation. In addition, the combination of UTI and TM also promoted the production of a variety of antioxidant enzymes in the tissues and inhibited the production of lipid peroxidation malondialdehyde (MDA) to enhance antioxidant defenses. Our experiments also proved that UTI combined with TM did not reduce the anticoagulant effect of TM. These results suggested that UTI combined with TM can improve endotoxin-induced liver and kidney damage and mortality by inhibiting liver and kidney cell apoptosis, promoting proliferation, and inhibiting inflammation and oxidative injury.