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Neutrophils are important for the development of pro-reparative macrophages after irreversible electroporation of the liver in mice.

ABSTRACT: Irreversible electroporation (IRE) is a non-thermal tissue ablative technology that has emerging applications in surgical oncology and regenerative surgery. To advance its therapeutic usefulness, it is important to understand the mechanisms through which IRE induces cell death and the role of the innate immune system in mediating subsequent regenerative repair. Through intravital imaging of the liver in mice, we show that IRE produces distinctive tissue injury features, including delayed yet robust recruitment of neutrophils, consistent with programmed necrosis. IRE treatment converts the monocyte/macrophage balance from pro-inflammatory to pro-reparative populations, and depletion of neutrophils inhibits this conversion. Reduced generation of pro-reparative Ly6C^loF4/80^hi macrophages correlates with lower numbers of SOX9⁺ hepatic progenitor cells in areas of macrophage clusters within the IRE injury zone. Our findings suggest that neutrophils play an important role in promoting the development of pro-reparative Ly6C^lo monocytes/macrophages at the site of IRE injury, thus establishing conditions of regenerative repair.

SUBMITTER: Lopez-Ichikawa M

PROVIDER: S-EPMC8298444 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Neutrophils are important for the development of pro-reparative macrophages after irreversible electroporation of the liver in mice.

Lopez-Ichikawa Maya M Vu Ngan K NK Nijagal Amar A Rubinsky Boris B Chang Tammy T TT

Scientific reports 20210722 1

Irreversible electroporation (IRE) is a non-thermal tissue ablative technology that has emerging applications in surgical oncology and regenerative surgery. To advance its therapeutic usefulness, it is important to understand the mechanisms through which IRE induces cell death and the role of the innate immune system in mediating subsequent regenerative repair. Through intravital imaging of the liver in mice, we show that IRE produces distinctive tissue injury features, including delayed yet rob ...[more]

PMID: 34294763

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Project description:BackgroundHigh-frequency irreversible electroporation (H-FIRE) is a novel, next-generation nanoknife technology with the advantage of relieving irreversible electroporation (IRE)-induced muscle contractions. However, the difference between IRE and H-FIRE with distinct ablation parameters was not clearly defined. This study aimed to compare the efficacy of the two treatments in vivo.MethodsTen Bama miniature swine were divided into two group: five in the 1-day group and five in the 7-day group. The efficacy of IRE and H-FIRE ablation was compared by volume transfer constant (Krans), rate constant (Kep) and extravascular extracellular volume fraction (Ve) value of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), size of the ablation zone, and histologic analysis. Each animal underwent the IRE and H-FIRE. Temperatures of the electrodes were measured during ablation. DCE-MRI images were obtained 1, 4, and 7 days after ablation in the 7-day group. All animals in the two groups were euthanized 1 day or 7 days after ablation, and subsequently, IRE and H-FIRE treated liver tissues were collected for histological examination. Student's t test or Mann-Whitney U test was applied for comparing any two groups. One-way analysis of variance (ANOVA) test and Welch's ANOVA test followed by Holm-Sidak's multiple comparisons test, one-way ANOVA with repeated measures followed by Bonferroni test, or Kruskal-Wallis H test followed by Dunn's multiple comparison test was used for multiple group comparisons and post hoc analyses. Pearson correlation coefficient test was conducted to analyze the relationship between two variables.ResultsHigher Ve was seen in IRE zone than in H-FIRE zone (0.14 ± 0.02 vs. 0.08 ± 0.05, t = 2.408, P = 0.043) on day 4, but no significant difference was seen in Ktrans or Kep between IRE and H-FIRE zones at all time points (all P > 0.05). For IRE zone, the greatest Ktrans was seen on day 7, which was significantly higher than that on day 1 (P = 0.033). The ablation zone size of H-FIRE was significantly larger than IRE 1 day (4.74 ± 0.88 cm2vs. 3.20 ± 0.77 cm2, t = 3.241, P = 0.009) and 4 days (2.22 ± 0.83 cm2vs. 1.30 ± 0.50 cm2, t = 2.343, P = 0.041) after treatment. Apoptotic index (0.05 ± 0.02 vs. 0.73 ± 0.06 vs. 0.68 ± 0.07, F = 241.300, P < 0.001) and heat shock protein 70 (HSP70) (0.03 ± 0.01 vs. 0.46 ± 0.09 vs. and 0.42 ± 0.07, F = 64.490, P < 0.001) were significantly different between the untreated, IRE and H-FIRE zones, but no significant difference was seen in apoptotic index or HSP70 between IRE and H-FIRE zone (both P > 0.05). Electrode temperature variations were not significantly different between the two zones (18.00 ± 3.77°C vs. 16.20 ± 7.45°C, t = 0.682, P = 0.504). The Ktrans value (r = 0.940, P = 0.017) and the Kep value (r = 0.895, P = 0.040) of the H-FIRE zone were positively correlated with the number of hepatocytes in the ablation zone.ConclusionsH-FIRE showed a comparable ablation effect to IRE. DCE-MRI has the potential to monitor the changes of H-FIRE ablation zone.

Project description:BackgroundIrreversible electroporation (IRE) is a non-thermal form of ablation based on the delivery of pulsed electrical fields. It has been used to treat liver lesions, particularly those in proximity to major hepatic vasculature. The role of this technique in the portfolio of treatments for colorectal hepatic metastases has not been clearly defined. This study undertakes a systematic review of IRE for treatment of colorectal hepatic metastases.MethodsThe study protocol was registered with the PROSPERO register of systematic reviews (CRD42022332866) and reports in compliance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA). The Ovid MEDLINE®, EMBASE, Web of Science and Cochrane databases were queried in April 2022. The search terms 'irreversible electroporation', 'colon cancer', 'rectum cancer' and 'liver metastases' were used in combinations. Studies were included if they provided information on the use of IRE for patients with colorectal hepatic metastases and reported procedure and disease-specific outcomes. The searches returned 647 unique articles and the exclusions left a total of eight articles. These were assessed for bias using the methodological index for nonrandomized studies (MINORS criteria) and reported using the synthesis without meta-analysis guideline (SWiM).ResultsOne hundred eighty patients underwent treatment for liver metastases from colorectal cancer. The median transverse diameter of tumours treated by IRE was <3 cm. Ninety-four (52%) tumours were adjacent to major hepatic inflow/outflow structures or the vena cava. IRE was undertaken under general anaesthesia with cardiac cycle synchronisation and with the use of either CT or ultrasound for lesion localisation. Probe spacing was less than 3.2 cm for all ablations. There were two (1.1%) procedure-related deaths in 180 patients. There was one (0.5%) post-operative haemorrhage requiring laparotomy, one (0.5%) bile leak, five (2.8%) post-procedure biliary strictures and a zero incidence of post-IRE liver failure.ConclusionsThis systematic review shows that IRE for colorectal liver metastases can be accomplished with low procedure-related morbidity and mortality. Further prospective study is required to assess the role of IRE in the portfolio of treatments for patients with liver metastases from colorectal cancer.

Dataset Information

Neutrophils are important for the development of pro-reparative macrophages after irreversible electroporation of the liver in mice.

Publications

Neutrophils are important for the development of pro-reparative macrophages after irreversible electroporation of the liver in mice.

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