Amelioration of Coagulation Disorders and Inflammation by Hydrogen-Rich Solution Reduces Intestinal Ischemia/Reperfusion Injury in Rats through NF-κB/NLRP3 Pathway

Abstract

Intestinal ischemia/reperfusion (I/R) injury often causes inflammatory responses and coagulation disorders, which is further promoting the deterioration of the disease. Hydrogen has anti-inflammatory, antioxidative, and antiapoptotic properties against various diseases. However, the effect of hydrogen on coagulation dysfunction after intestinal I/R and the underlying mechanism remains unclear. The purpose of this study was to explore whether hydrogen-rich solution (HRS) could attenuate coagulation disorders and inflammation to improve intestinal injury and poor survival following intestinal I/R. The rat model of intestinal I/R injury was established by clamping the superior mesenteric artery for 90 min and reperfusion for 2 h. HRS (10 or 20 mL/kg) or 20 mL/kg 0.9% normal saline was intravenously injected at 10 min before reperfusion, respectively. The samples were harvested at 2 h after reperfusion for further analyses. Moreover, the survival rate was observed for 24 h. The results showed that HRS improved the survival rate and alleviated serum diamine oxidase activities, intestinal injury, edema, and apoptosis. Interestingly, HRS markedly improved intestinal I/R-mediated coagulation disorders as evidenced by abnormal conventional indicators of coagulation and thromboelastography. Additionally, HRS attenuated inflammatory responses and the elevated tissue factor (TF) and inhibited nuclear factor kappa beta (NF-κB) and nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation in peripheral blood mononuclear cells. Moreover, inflammatory factors and myeloperoxidase were closely associated with TF level. This study thus emphasized upon the amelioration of coagulation disorders and inflammation by HRS as a mechanism to improve intestinal I/R-induced intestinal injury and poor survival, which might be partially related to inhibition of NF-κB/NLRP3 pathway.

Potential Therapeutic Applications of Hydrogen in Chronic Inflammatory Diseases: Possible Inhibiting Role on Mitochondrial Stress

“…However, excessive inflammation driven by the inflammasome and IL-1β signaling pathways promotes breast cancer, fibrosarcoma, gastric cancer, and lung metastasis in a context-dependent manner [ 48 ]. Some literature has shown that H 2 can be involved in various models of inflammation based on mechanisms of mitochondrial oxidation inhibition and NLRP3 inflammasome activation ( Table 1 ) [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ].…”

“…H 2 exhibits anti-inflammatory, antioxidant, and anti-apoptotic effects, but its efficacy on intestinal I/R has been unclear. Yang et al investigated the effects of intravenous administration of H 2 -rich saline on intestinal I/R in an experiment on rats [ 17 ]. They reported that the administration of H 2 -rich saline improved the survival rate of the rats and ameliorated intestinal damage, edema, and apoptosis.…”

“…In addition, in this paper, they reported that the administration of H 2 -rich saline improved inflammatory response and also markedly ameliorated I/R-mediated coagulopathy in the intestine. They also reported that H 2 -rich saline inhibited the activation of NF- κ B and NLRP3 inflammasomes in peripheral blood mononuclear cells [ 17 ]. They suggested that the improvement of coagulopathy and inflammation by administration of H 2 -rich saline was partly due to the NF- κ B/NLRP3 pathway.…”

“…that can permeate the cell membrane, only H 2 is able to scavenge ·OH, which is always generated inside of mitochondria [ 13 , 14 ]. It has been shown by literature that H 2 in various animal models of inflammation may be based on mechanisms to inhibit mitochondrial oxidation and NLRP3 inflammasome activation [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. However, the ability for H 2 to inhibit mitochondrial oxidation and NLRP3 inflammasome activation is poorly understood.…”

Molecular and Cellular Mechanisms Associated with Effects of Molecular Hydrogen in Cardiovascular and Central Nervous Systems

“…Molecular hydrogen is currently recognized as an emerging therapeutic, as its supplemental application exerts protective effects in cardiovascular diseases [ 1 , 2 ], neurodegenerative diseases [ 3 ], inflammatory diseases [ 4 ], neuromuscular disorders [ 5 ], metabolic syndrome [ 6 ] diabetes [ 7 , 8 ], kidney disorders [ 9 , 10 ], and cancer [ 11 ]. The protective effects of molecular hydrogen are largely related to its antiapoptotic, anti-inflammatory, and antioxidative actions ( Figure 1 ).…”