Abstract
BackgroundPPAR-gamma (γ) is highly expressed in macrophages and its activation affects their polarization. The effect of PPAR-γ activation on Kupffer cells (KCs) and liver ischemia-reperfusion injury (IRI) has not yet been evaluated. We investigated the effect of PPAR-γ activation on KC-polarization and IRI.Materials and methodsSeventy percent (70%) liver ischemia was induced for 60mins. PPAR-γ-agonist or vehicle was administrated before reperfusion. PPAR-γ-antagonist was used to block PPAR-γ activation. Liver injury, necrosis, and apoptosis were assessed post-reperfusion. Flow-cytometry determined KC-phenotypes (pro-inflammatory Nitric Oxide +, anti-inflammatory CD206+ and anti-inflammatory IL-10+).ResultsLiver injury assessed by serum AST was significantly decreased in PPAR-γ-agonist versus control group at all time points post reperfusion (1hr: 3092±105 vs 4469±551; p = 0.042; 6hr: 7041±1160 vs 12193±1143; p = 0.015; 12hr: 5746±328 vs 8608±1259; p = 0.049). Furthermore, liver apoptosis measured by TUNEL-staining was significantly reduced in PPAR-γ-agonist versus control group post reperfusion (1hr:2.46±0.49 vs 6.90±0.85%;p = 0.001; 6hr:26.40±2.93 vs 50.13±8.29%; p = 0.048). H&E staining demonstrated less necrosis in PPAR-γ-agonist versus control group (24hr:26.66±4.78 vs 45.62±4.57%; p = 0.032). The percentage of pro-inflammatory NO+ KCs was significantly lower at all post reperfusion time points in the PPAR-γ-agonist versus control group (1hr:28.49±4.99 vs 53.54±9.15%; p = 0.040; 6hr:5.51±0.54 vs 31.12±9.58%; p = 0.009; 24hr:4.15±1.50 vs 17.10±4.77%; p = 0.043). In contrast, percentage of anti-inflammatory CD206+ KCs was significantly higher in PPAR-γ-agonist versus control group prior to IRI (8.62±0.96 vs 4.88 ±0.50%; p = 0.04). Administration of PPAR-γ-antagonist reversed the beneficial effects on AST, apoptosis, and pro-inflammatory NO+ KCs.ConclusionPPAR-γ activation reduces IRI and decreases the pro-inflammatory NO+ Kupffer cells. PPAR-γ activation can become an important tool to improve outcomes in liver surgery through decreasing the pro-inflammatory phenotype of KCs and IRI.
Highlights
Ischemia and reperfusion injury (IRI) is an important problem during solid organ transplantation, trauma, hypovolemic shock, and elective liver resection when inflow occlusion or total vascular exclusion is used to minimize blood loss
Percentage of anti-inflammatory CD206+ Kupffer cells (KCs) was significantly higher in peroxisome proliferator-activated receptor-γ (PPAR-γ)-agonist versus control group prior to ischemia-reperfusion injury (IRI) (8.62±0.96 vs 4.88 ±0.50%; p = 0.04)
Administration of PPAR-γ-antagonist reversed the beneficial effects on Aspartate aminotransferase (AST), apoptosis, and pro-inflammatory nitric oxide (NO)+ KCs
Summary
Ischemia and reperfusion injury (IRI) is an important problem during solid organ transplantation, trauma, hypovolemic shock, and elective liver resection when inflow occlusion or total vascular exclusion is used to minimize blood loss. The activation of KCs is thought to initiate hepatic IRI, and it is followed by the release of a series of pro-inflammatory cytokines such as tumor necrosis factor α (TNF-α) and interleukin (IL-1β), the expression of cell adhesion factors, the production of reactive oxygen species, prostanoids and nitric oxide (NO) [7, 8]. Due to the array of distinct types of liver cells in close proximity to each other allowing for cell-cell interactions, the KCs are intimately involved in liver response to stress and endogenous ligands released from injured or necrotic hepatocytes which are recognized by KCs through surface receptors, initiating the signaling cascade resulting in inflammation and organ damage at the early phase of the IRI event [12], [13], [14]. We investigated the effect of PPAR-γ activation on KC-polarization and IRI
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
