In vivo and In vitro PPAR-y Activation Decreases M1-Macrophage Polarization and Improves Liver Ischemia Reperfusion Injury

2018 ◽  
Vol 102 ◽  
pp. S708
Author(s):  
Ivan Linares ◽  
Agata Bartczak ◽  
Kaveh Farrokhi ◽  
Dagmar Kollmann ◽  
Moritz Kaths ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Macrophage Polarization ◽  
Liver Ischemia ◽  
M1 Macrophage

Liver kinase B1 attenuates liver ischemia/reperfusion injury via inhibiting the NLRP3 inflammasome

2021 ◽  
Vol 53 (5) ◽  
pp. 601-611
Author(s):  
Jiangwen Dai ◽  
Qingsong Chen ◽  
Weifeng Huang ◽  
Kun Shi ◽  
Yuke Zhang ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Nlrp3 Inflammasome ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Nuclear Factor Κb ◽  
Liver Ischemia ◽  
Iri Model ◽  
Liver Kinase B1

Abstract Liver ischemia/reperfusion injury (IRI), a serious inflammatory response driven by innate immunity, occurs in liver surgeries such as liver resection and liver transplantation, leading to liver dysfunction, liver failure, and even rejection after transplantation. Liver kinase B1 (LKB1) plays a pivotal anti-inflammatory role in IRI. One of the most important factors involved in liver IRI is the aberrant activation of the nucleotide binding oligomerization domain like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) inflammasome in Kupffer cells. However, the mechanisms underlying the effect of LKB1 on the NLRP3 inflammasome in liver IRI remain elusive. In this study, we found that the expression of LKB1 was decreased in liver IRI, while the NLRP3 inflammasome level was increased as shown, as revealed by RT-qPCR and western blot analysis. Furthermore, upregulation of LKB1 abrogated the expression of the NLRP3 inflammasome, which improved liver function and liver pathology in the liver IRI model in vivo. In vitro, overexpression of LKB1 inhibited the activation of NLRP3 inflammasome and nuclear factor-κB, while the inhibitory effect was reversed by silencing the expression of the forkhead box protein O1 in the RAW264.7 macrophage hypoxia/reoxygenation model. In conclusion, our results suggest that LKB1 exerts a protective effect against liver IRI by downregulating the NLRP3 inflammasome.

scholarly journals N6-methyladenosine demethylase FTO impairs hepatic ischemia–reperfusion injury via inhibiting Drp1-mediated mitochondrial fragmentation

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Ying Dong Du ◽  
Wen Yuan Guo ◽  
Cong Hui Han ◽  
Ying Wang ◽  
Xiao Song Chen ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fragmentation ◽  
Hepatic Ischemia ◽  
Adeno Associated Virus ◽  
Downstream Target ◽  
Hepatic Ischemia Reperfusion

AbstractDespite N6-methyladenosine (m6A) is functionally important in various biological processes, its role and the underlying regulatory mechanism in the liver remain largely unexplored. In the present study, we showed that fat mass and obesity-associated protein (FTO, an m6A demethylase) was involved in mitochondrial function during hepatic ischemia–reperfusion injury (HIRI). We found that the expression of m6A demethylase FTO was decreased during HIRI. In contrast, the level of m6A methylated RNA was enhanced. Adeno-associated virus-mediated liver-specific overexpression of FTO (AAV8-TBG-FTO) ameliorated the HIRI, repressed the elevated level of m6A methylated RNA, and alleviated liver oxidative stress and mitochondrial fragmentation in vivo and in vitro. Moreover, dynamin-related protein 1 (Drp1) was a downstream target of FTO in the progression of HIRI. FTO contributed to the hepatic protective effect via demethylating the mRNA of Drp1 and impairing the Drp1-mediated mitochondrial fragmentation. Collectively, our findings demonstrated the functional importance of FTO-dependent hepatic m6A methylation during HIRI and provided valuable insights into the therapeutic mechanisms of FTO.

scholarly journals Poly-IC Preconditioning Protects against Cerebral and Renal Ischemia-Reperfusion Injury

2011 ◽  
Vol 32 (2) ◽  
pp. 242-247 ◽  
Author(s):  
Amy E B Packard ◽  
Jason C Hedges ◽  
Frances R Bahjat ◽  
Susan L Stevens ◽  
Michael J Conlin ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Renal Ischemia ◽  
Cortical Cells ◽  
Polycytidylic Acid ◽  
Populations At Risk

Preconditioning induces ischemic tolerance, which confers robust protection against ischemic damage. We show marked protection with polyinosinic polycytidylic acid (poly-IC) preconditioning in three models of murine ischemia-reperfusion injury. Poly-IC preconditioning induced protection against ischemia modeled in vitro in brain cortical cells and in vivo in models of brain ischemia and renal ischemia. Further, unlike other Toll-like receptor (TLR) ligands, which generally induce significant inflammatory responses, poly-IC elicits only modest systemic inflammation. Results show that poly-IC is a new powerful prophylactic treatment that offers promise as a clinical therapeutic strategy to minimize damage in patient populations at risk of ischemic injury.

scholarly journals ZnPP reduces autophagy and induces apoptosis, thus aggravating liver ischemia/reperfusion injury in vitro

2014 ◽  
Vol 34 (6) ◽  
pp. 1555-1564 ◽  
Author(s):  
YUN WANG ◽  
XUANXUAN XIONG ◽  
HAO GUO ◽  
MINGBO WU ◽  
XIANGCHENG LI ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Liver Ischemia

scholarly journals Transplantation-Induced Ischemia-Reperfusion Injury Modulates Antigen Presentation by Donor Renal CD11c+F4/80+ Macrophages through IL-1R8 Regulation

2020 ◽  
Vol 31 (3) ◽  
pp. 517-531 ◽  
Author(s):  
Sistiana Aiello ◽  
Manuel Alfredo Podestà ◽  
Pamela Y. Rodriguez-Ordonez ◽  
Francesca Pezzuto ◽  
Nadia Azzollini ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Antigen Presentation ◽  
Kidney Transplant ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cold Ischemia ◽  
Reversible Ischemia ◽  
Antigen Presenting

BackgroundIn donor kidneys subjected to ischemia-reperfusion injury during kidney transplant, phagocytes coexpressing the F4/80 and CD11c molecules mediate proinflammatory responses and trigger adaptive immunity in transplantation through antigen presentation. After injury, however, resident renal macrophages coexpressing these surface markers acquire a proreparative phenotype, which is pivotal in controlling inflammation and fibrosis. No data are currently available regarding the effects of transplant-induced ischemia-reperfusion injury on the ability of donor-derived resident renal macrophages to act as professional antigen-presenting cells.MethodsWe evaluated the phenotype and function of intragraft CD11c+F4/80+ renal macrophages after cold ischemia. We also assessed the modifications of donor renal macrophages after reversible ischemia-reperfusion injury in a mouse model of congeneic renal transplantation. To investigate the role played by IL-1R8, we conducted in vitro and in vivo studies comparing cells and grafts from wild-type and IL-R8–deficient donors.ResultsCold ischemia and reversible ischemia-reperfusion injury dampened antigen presentation by renal macrophages, skewed their polarization toward the M2 phenotype, and increased surface expression of IL-1R8, diminishing activation mediated by toll-like receptor 4. Ischemic IL-1R8–deficient donor renal macrophages acquired an M1 phenotype, effectively induced IFNγ and IL-17 responses, and failed to orchestrate tissue repair, resulting in severe graft fibrosis and aberrant humoral immune responses.ConclusionsIL-1R8 is a key regulator of donor renal macrophage functions after ischemia-reperfusion injury, crucial to guiding the phenotype and antigen-presenting role of these cells. It may therefore represent an intriguing pathway to explore with respect to modulating responses against autoantigens and alloantigens after kidney transplant.

scholarly journals Inhibition of BRD4 Reduces Neutrophil Activation and Adhesion to the Vascular Endothelium Following Ischemia Reperfusion Injury

2020 ◽  
Vol 21 (24) ◽  
pp. 9620
Author(s):  
Shelby Reid ◽  
Noah Fine ◽  
Vikrant K. Bhosle ◽  
Joyce Zhou ◽  
Rohan John ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Neutrophil Adhesion ◽  
Neutrophil Accumulation ◽  
Iri Model ◽  
Brd4 Inhibition

Renal ischemia reperfusion injury (IRI) is associated with inflammation, including neutrophil infiltration that exacerbates the initial ischemic insult. The molecular pathways involved are poorly characterized and there is currently no treatment. We performed an in silico analysis demonstrating changes in NFκB-mediated gene expression in early renal IRI. We then evaluated NFκB-blockade with a BRD4 inhibitor on neutrophil adhesion to endothelial cells in vitro, and tested BRD4 inhibition in an in vivo IRI model. BRD4 inhibition attenuated neutrophil adhesion to activated endothelial cells. In vivo, IRI led to increased expression of cytokines and adhesion molecules at 6 h post-IRI with sustained up-regulated expression to 48 h post-IRI. These effects were attenuated, in part, with BRD4 inhibition. Absolute neutrophil counts increased significantly in the bone marrow, blood, and kidney 24 h post-IRI. Activated neutrophils increased in the blood and kidney at 6 h post-IRI and remained elevated in the kidney until 48 h post-IRI. BRD4 inhibition reduced both total and activated neutrophil counts in the kidney. IRI-induced tubular injury correlated with neutrophil accumulation and was reduced by BRD4 inhibition. In summary, BRD4 inhibition has important systemic and renal effects on neutrophils, and these effects are associated with reduced renal injury.

scholarly journals Endothelial Dysfunction of Bypass Graft: Direct Comparison of In Vitro and In Vivo Models of Ischemia-Reperfusion Injury

PLoS ONE ◽  
2015 ◽  
Vol 10 (4) ◽  
pp. e0124025 ◽  
Author(s):  
Gábor Veres ◽  
Péter Hegedűs ◽  
Enikő Barnucz ◽  
Raphael Zöller ◽  
Stephanie Klein ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Bypass Graft ◽  
In Vivo Models

scholarly journals Transplantation of autologously derived mitochondria protects the heart from ischemia-reperfusion injury

2013 ◽  
Vol 304 (7) ◽  
pp. H966-H982 ◽  
Author(s):  
Akihiro Masuzawa ◽  
Kendra M. Black ◽  
Christina A. Pacak ◽  
Maria Ericsson ◽  
Reanne J. Barnett ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Reperfusion Injury ◽  
Troponin I ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
High Energy ◽  
Creatine Kinase Mb ◽  
Myocardial Energetics

Mitochondrial damage and dysfunction occur during ischemia and modulate cardiac function and cell survival significantly during reperfusion. We hypothesized that transplantation of autologously derived mitochondria immediately prior to reperfusion would ameliorate these effects. New Zealand White rabbits were used for regional ischemia (RI), which was achieved by temporarily snaring the left anterior descending artery for 30 min. Following 29 min of RI, autologously derived mitochondria (RI-mitochondria; 9.7 ± 1.7 × 106/ml) or vehicle alone (RI-vehicle) were injected directly into the RI zone, and the hearts were allowed to recover for 4 wk. Mitochondrial transplantation decreased ( P < 0.05) creatine kinase MB, cardiac troponin-I, and apoptosis significantly in the RI zone. Infarct size following 4 wk of recovery was decreased significantly in RI-mitochondria (7.9 ± 2.9%) compared with RI-vehicle (34.2 ± 3.3%, P < 0.05). Serial echocardiograms showed that RI-mitochondria hearts returned to normal contraction within 10 min after reperfusion was started; however, RI-vehicle hearts showed persistent hypokinesia in the RI zone at 4 wk of recovery. Electrocardiogram and optical mapping studies showed that no arrhythmia was associated with autologously derived mitochondrial transplantation. In vivo and in vitro studies show that the transplanted mitochondria are evident in the interstitial spaces and are internalized by cardiomyocytes 2–8 h after transplantation. The transplanted mitochondria enhanced oxygen consumption, high-energy phosphate synthesis, and the induction of cytokine mediators and proteomic pathways that are important in preserving myocardial energetics, cell viability, and enhanced post-infarct cardiac function. Transplantation of autologously derived mitochondria provides a novel technique to protect the heart from ischemia-reperfusion injury.

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