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The protective effects of fibroblast growth factor 10 against hepatic ischemia-reperfusion injury in mice.

ABSTRACT: Hepatic ischemia-reperfusion injury (IRI) is a major complication of liver surgery and transplantation. IRI leads to hepatic parenchymal cell death, resulting in liver failure, and lacks effective therapeutic approaches. Fibroblast growth factor 10 (FGF10) is a paracrine factor which is well-characterized with respect to its pro-proliferative effects during embryonic liver development and liver regeneration, but its role in hepatic IRI remains unknown. In this study, we investigated the role of FGF10 in liver IRI and identified signaling pathways regulated by FGF10. In a mouse model of warm liver IRI, FGF10 was highly expressed during the reperfusion phase. In vitro experiments demonstrated that FGF10 was primarily secreted by hepatic stellate cells and acted on hepatocytes. The role of FGF10 in liver IRI was further examined using adeno-associated virus-mediated gene silencing and overexpression. Overexpression of FGF10 alleviated liver dysfunction, reduced necrosis and inflammation, and protected hepatocytes from apoptosis in the early acute injury phase of IRI. Furthermore, in the late phase of IRI, FGF10 overexpression also promoted hepatocyte proliferation. Meanwhile, gene silencing of FGF10 had the opposite effect. Further studies revealed that overexpression of FGF10 activated nuclear factor-erythroid 2-related factor 2 (NRF2) and decreased oxidative stress, mainly through activation of the phosphatidylinositol-3-kinase/AKT pathway, and the protective effects of FGF10 overexpression were largely abrogated in NRF2 knockout mice. These results demonstrate the protective effects of FGF10 in liver IRI, and reveal the important role of NRF2 in FGF10-mediated hepatic protection during IRI.

SUBMITTER: Li S

PROVIDER: S-EPMC7806526 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Ischemic stroke is one of the most common causes of mortality worldwide and is a primary cause of disability and mortality in adults. There is an unmet need for drugs that can effectively treat ischemic stroke. Hence, the present study explored the neuroprotective effects of andrographolide (Andro) in a mouse model of bilateral common carotid artery occlusion, and systematically evaluated the potential mechanisms underlying its effects. The effects of Andro on mouse brain tissue following cerebral ischemia‑reperfusion injury (CIRI) were evaluated by histopathological (H&E and Nissl) and immunofluorescence [glial fibrillary acidic protein (GFAP) and neuronal nuclei (NeuN)] staining. A traditional Chinese medicine‑based network pharmacology method was performed to establish and analyze compound‑target‑disease and function‑pathway networks in order to elucidate the possible mechanisms responsible for the protective role of Andrographis paniculata in CIRI. In addition, western blot analysis and RT‑qPCR was performed to evaluate the expression and activation of signaling proteins predicted to be involved in this mechanism. The amelioration of histopathological alterations was observed in mice pre‑treated with Andro. Immunofluorescence staining revealed that Andro decreased the expression of GFAP and increased the expression of NeuN, and significantly decreased the levels of pro‑inflammatory cytokines (IL‑1β, IL‑6 and TNF‑α). Network pharmacology analysis revealed that neuroinflammatory response and apoptosis were associated with the effects of Andrographis paniculata on CIRI. Western blot analysis revealed that the mice pre‑treated with Andro exhibited an upregulated protein expression of tropomyosin receptor kinase B (TrkB), p‑PI3K and p‑Akt, as well as a decrease in the expression of GFAP and an increase in the expression of NeuN. In addition, the data of RT‑qPCR indicated that the mice pre‑treated with Andro exhibited a significantly decreased expression of encoding IL‑1β mRNA, IL‑6 mRNA and TNF‑α mRNA in the brain compared to the untreated mice following CIRI. On the whole, the findings of the present study suggest that pre‑treatment with Andro exerts a protective effect against CIRI, which may be partly related to its potential to reduce neuroinflammatory response and apoptosis in patients with stroke.

Project description:ObjectivesRenal ischemia-reperfusion injury causes acute renal failure, and the hallmarks of renal ischemia-reperfusion injury are inflammation, apoptosis, necrosis, and capillary dysfunction. Milk fat globule-epidermal growth factor-factor VIII (MFG-E8), a membrane-associated secretory glycoprotein, is produced by immune cells and reported to participate in multiple physiologic processes associated with tissue remodeling. We have recently shown that MFG-E8 treatment attenuates organ injury, inflammatory responses, and survival after sepsis through the enhancement of phagocytosis of apoptotic cells. The purpose of this study was to determine whether administration of MFG-E8 attenuates renal ischemia-reperfusion injury.DesignProspective, controlled, and randomized animal study.Setting: A research institute laboratory.SubjectsMale C57BL/6J mice (20-25 g).Interventions: Renal ischemia-reperfusion injury with bilateral renal pedicle clamping for 45 mins, followed by reperfusion. A recombinant murine MFG-E8 (0.4 μg/20 g) was given intraperitoneally at the beginning of reperfusion.Measurements and main resultsMFG-E8 levels, organ injury variables, inflammatory responses, histology, apoptosis, and capillary functions were assessed at 1.5 and 20 hrs after reperfusion. A 60-hr survival study was conducted in MFG-E8 and recombinant murine MFG-E8-treated wild-type mice. After renal ischemia-reperfusion injury, MFG-E8 mRNA and protein expressions were significantly decreased in the kidneys and spleen. Treatment with recombinant murine MFG-E8 recovered renal dysfunction, significantly suppressed inflammatory responses, apoptosis, necrosis, and improved capillary functions in the kidneys. In the survival study, MFG-E8 mice showed a significant deterioration and, in contrast, recombinant murine MFG-E8-treated wild-type mice showed a significant improvement of survival compared with vehicle-treated wild-type mice.ConclusionsMFG-E8 can be developed as novel treatment for renal ischemia-reperfusion injury. This protective effect appears to be mediated through the enhancement of apoptotic cell clearance and improvement of capillary functions in the kidneys.

Project description:BackgroundMyocardial injury is a major cause of myocardial remodeling. Macrophages are important in cardiac repair as a result of their interactions with fibroblasts. As regulatory macrophages, M2b macrophages modulate inflammatory immune responses without participating in wound healing and could have enhanced protective effects on myocardial remodeling. Therefore, we tested the hypothesis that M2b macrophages could improve cardiac function and ameliorate myocardial fibrosis after the myocardial ischemia/reperfusion injury (MI/RI).MethodsIn vivo, MI/RI models were established with Sprague-Dawley (SD) rats and either M2b macrophages (MT group) or the same volume of vehicle (CK group) was injected into the ischemic zone. Two weeks after the operation, cardiac function and diameters were determined by echocardiography examination. Level of myocardial fibrosis was measured by Sirius red staining and the expression of fibrosis-related factors. In vitro, cardiac fibroblasts (CFs) were co-cultured with M2b macrophages or cultured with M2b macrophage supernatant. Expression of α-smooth muscle actin (α-SMA) and connective tissue growth factor (CCN2/CTGF) in the CFs were measured by western blotting and immunofluorescence staining. In addition, the expression of platelet-derived growth factors (PDGFs), the expression of platelet-derived growth factor receptors (PDGFRs) and the phosphorylation of PDGFRs was detected by western blotting.ResultsA significantly higher rat survival rate, improved left ventricular (LV) systolic function, decreased diameter of the LV and alleviated myocardial fibrosis were observed in the MT group than in the CK group. In vitro, the activation of CFs was significantly reduced by the M2b macrophages treatments, relative to the blank control. In addition, the kinase activation of PDGFRs was decreased by M2b macrophage treatments both in vivo and in vitro.ConclusionsOur study demonstrated that the administration of M2b macrophages could attenuate myocardial remodeling after MI/RI. The regulation of the activation of PDGFRs in CFs is an important part of the protective mechanism.

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The protective effects of fibroblast growth factor 10 against hepatic ischemia-reperfusion injury in mice.

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