Mesenchymal Stem Cells Ameliorate Hepatic Ischemia/Reperfusion Injury via Inhibition of Neutrophil Recruitment

Abstract

Ischemia/reperfusion injury (IRI) remains a major problem in organ transplantation, which represents the main cause of graft dysfunction posttransplantation. Hepatic IRI is characterized by an excessive inflammatory response within the liver. Mesenchymal stem cells (MSCs) have been shown to be immunomodulatory cells and have the therapeutic action on IRI in several organs. However, the mechanism of regulatory effect of MSCs on IRI remains unclear. In the present study, we examined the impact of MSCs on hepatic inflammatory response such as neutrophil influx and liver damage in a rat model of 70% hepatic IRI. Treatment with MSCs protected rat against hepatic IRI, with significantly decreased serum levels of liver enzymes, attenuated hepatic neutrophil infiltration, reduced expression of apoptosis-associated proteins, and ameliorated liver pathological injury. MSCs also significantly enhanced the intracellular activation of p38 MAPK phosphorylation, which led to decreased expression of CXCR2 on the surface of neutrophils. In addition, MSCs significantly diminished neutrophil chemoattractant CXCL2 production by inhibiting NF-κB p65 phosphorylation in macrophages. These results demonstrate that MSCs significantly ameliorate hepatic IRI predominantly through its inhibitory effect on hepatic neutrophil migration and infiltration.

Enhanced Effect of IL-1β-Activated Adipose-Derived MSCs (ADMSCs) on Repair of Intestinal Ischemia-Reperfusion Injury via COX-2-PGE2 Signaling

“…GO analysis of differentially expressed mRNAs revealed that processes falling in the categories of neutrophil chemotaxis, inflammatory response, and chemokine activity were involved in the healing of intestinal IR injury in the group treated with activated ADMSCs. Inhibition of neutrophil recruitment has been shown to be an important way for MSCs to ameliorate hepatic IR injury [32], while repression of the inflammatory response has been shown to be critical for the ability of MSCs to treat sepsis-induced organ injury [7], in line with our findings. Furthermore, KEGG pathway Figure 7: GO enrichment analysis and KEGG pathway analysis were used to explore the possible mechanism of activated ADMSC for treatment of intestinal IR injury.…”

“…In the present study, activated ADMSCs were the most effective for the treatment of IR injury, reflected by the lowest severity of IR injury and the lowest levels of apoptosis and inflammation, whereas activated ADMSCs/shCOX-2 displayed the worst efficacy. Li et al reported that MSCs significantly protected rats against hepatic IR injury and were associated with lower serum levels of liver enzymes and reduced neutrophil infiltration and expression of apoptosis-related genes [32]. Another study reported that pretreatment with TNF-α, IL-1β, and nitric oxide enhanced the paracrine functions of MSCs and that conditioned medium obtained from pretreated MSCs reduced the inflammatory reaction to radiation-induced intestinal injury and enhanced epithelial…”

Maresin 1, a Proresolving Lipid Mediator, Ameliorates Liver Ischemia-Reperfusion Injury and Stimulates Hepatocyte Proliferation in Sprague-Dawley Rats

“…MaR1 increased the mitotic and Ki-67 labeling index, which suggests that this treatment promoted the cell cycle and cell proliferation. It is important to consider that MaR1 is a derivative from DHA, an omega-3 fatty acid [12][13][14]. Omega-3 fatty acids can play a protective role in liver function after partial hepatectomy (PH), with improvement in liver regeneration and functional recovery following PH in experimental models [15].…”

Acetate protects against intestinal ischemia‐reperfusion injury independent of its cognate free fatty acid 2 receptor

“…10 Increasing evidence supports a mechanistic role for neutrophils in exacerbating damage after reperfusion and propagating systemic inflammatory events that contribute to multiple organ failure and systemic inflammatory response syndrome in several organs. [11][12][13][14] Traditionally neutrophils were solely regarded as proinflammatory, but it is now recognized that neutrophils are complex cells with a multitude of phenotypically distinct functions that modulate the activity of neighboring cells and contribute to the resolution of inflammation. [15][16][17] Neutrophils abundantly express free fatty acid 2 receptor (FFA2) a G-protein coupled receptor (GPCR).…”