Activation of Nrf2/HO-1 signaling pathway exacerbates cholestatic liver injury.

Nuclear factor erythroid 2-related factor-2 (Nrf2) antioxidant signaling is involved in liver protection, but this generalization overlooks conflicting studies indicating that Nrf2 effects are not necessarily hepatoprotective. The role of Nrf2/heme oxygenase-1 (HO-1) in cholestatic liver injury (CLI) remains poorly defined. Here, we report that Nrf2/HO-1 activation exacerbates liver injury rather than exerting a protective effect in CLI. Inhibiting HO-1 or ameliorating bilirubin transport alleviates liver injury in CLI models. Nrf2 knockout confers hepatoprotection in CLI mice, whereas in non-CLI mice, Nrf2 knockout aggravates liver damage. In the CLI setting, oxidative stress activates Nrf2/HO-1, leads to bilirubin accumulation, and impairs mitochondrial function. High levels of bilirubin reciprocally upregulate the activation of Nrf2 and HO-1, while antioxidant and mitochondrial-targeted SOD2 overexpression attenuate bilirubin toxicity. The expression of Nrf2 and HO-1 is elevated in serum of patients with CLI. These results reveal an unrecognized function of Nrf2 signaling in exacerbating liver injury in cholestatic disease.

[Study on mitigating effect and mechanism of Cichorium glandulosum n-butanol extraction site on CCl_4-induced chronic liver injury in rats].

This study aims to investigate the mitigating effect and mechanism of Cichorium glandulosum n-butanol extraction site(CGE) on the disease in carbon tetrachloride(CCl_4)-induced chronic liver injury model in rats. A chronic liver injury model was constructed by subcutaneous injection of CCl_4 olive oil solution, and after four weeks of CGE treatment, serum levels of aspartate aminotransferase(AST), alanine aminotransferase(ALT), alkaline phosphatase(AKP), hydroxyproline(HYP), interleukin-4(IL-4), interleukin-6(IL-6), malondialdehyde(MDA), superoxide dismutase(SOD), and tumor necrosis factor-α(TNF-α) were detected. Liver tissue was processed by hematoxylin-eosin(HE) staining and Masson staining to observe the structure of the rat liver. qPCR and Western blot were used to examine the expression of transforming growth factor-ß1(TGF-ß1)/small mothers against decapentaplegic(Smad), Toll-like receptor 4(TLR4), α-smooth muscle actin(α-SMA), and fibronectin(Fn) in rat liver tissue and hepatic stellate-T6(HSC-T6) and evaluate the inhibitory effect of CGE on HSC activation. The results showed that CGE could significantly reduce the serum levels of AST, ALT, AKP, HYP, and affect the levels of related inflammatory indexes including IL-4, IL-6, and TNF-α, and MDA in CCl_4-induced chronic liver injury in rats and had no effect on SOD activity, which could delay the process of liver injury, alleviate the hepatic collagen deposition and inflammatory infiltration, and had significant efficacy in mitigating chronic liver injury in rats. CGE could inhibit α-SMA and TLR4 protein expression in the liver tissue and reverse the increased TGF-ß1/Smad, Fn, and TLR4-related expression in HSC-T6 in vitro. The above results indicated that CGE exerted hepatoprotective effects in rats by inhibiting HSC activation and alleviated CCl_4-induced chronic liver injury in rats and could ameliorate inflammatory response and slight liver fibrosis in rat liver tissue. Its pharmacodynamic mechanism might be related to TGF-ß1/Smad and TLR4-related expression.

A macroporous composite sponge with high water absorbency and active coagulation mechanism for traumatic hemostasis and anti-infection.

The development of a composite sponge with high water absorbency and active coagulation mechanism for traumatic hemostasis and anti-infection remains a challenge. Herein, we developed a composite sponge using gelation, swelling, and freeze-drying methods based on quaternized chitosan, succinimidyl-modified F127, and bioactive glass. The sponge exhibited macroporous structure, high porosity, and water absorbency. When exposed to blood, it strongly interacted with blood cells, promoting their adhesion, aggregation, and activation. Moreover, it activated the intrinsic coagulation pathway. The sponge/powder demonstrated superior hemostatic capacity to commercial gauze, gelatin sponge, Yunnan Baiyao, and chitosan hemostatic powder in rat tail amputation, liver superficial injury, liver resection, and liver semi-perforation wound models. The sponge also presented robust anti-infection activity against methicillin-resistantStaphylococcus aureusandEscherichia coli. Additionally, the sponge showed low cytotoxicity, hemolysis activity, inflammation response, and systemic toxicity, demonstrating its favorable biocompatibility.

The Effect of Pringle Maneuver Applied during Living Donor Hepatectomy on the Ischemia-Reperfusion Injury Observed in the Donors and Recipients.

Background and Objectives: The aim of this study is to evaluate the clinical and laboratory changes of ischemia and reperfusion injury in the remnant livers of donors with and without Pringle maneuver. Furthermore, we evaluated the recipients who have been transplanted with liver grafts from these donors. Methods and Materials: A total of 108 patients (54 living liver donors and 54 liver recipients) who underwent donor hepatectomy and recipients who living donor liver transplantation, were included in this randomized double-blind study between February 2021 and June 2021. The donors were divided into two groups: Pringle maneuver applied (n = 27) and Pringle maneuver not applied (n = 27). Similarly, recipients with implanted liver obtained from these donors were divided into two groups as the Pringle maneuver was performed (n = 27) and not performed (n = 27). Blood samples from donors and recipients were obtained on pre-operative, post-operative 0 h day (day of surgery), post-operative 1st day, post-operative 2nd day, post-operative 3rd day, post-operative 4th day, post-operative 5th day, and liver tissue was taken from the graft during the back table procedures. Liver function tests and complete blood count, coagulation tests, IL-1, IL-2, IL-6, TNF-α, and ß-galactosidase measurements, and histopathological findings were examined. Results: There was no statistically significant difference in the parameters of biochemical analyses for ischemia-reperfusion injury at all periods in the donors with and without the Pringle maneuver. Similarly, there was no statistically significant difference between in the recipients in who received liver grafts harvested with and without the Pringle maneuver. There was no statistically significant difference between the two recipient groups in terms of perioperative bleeding and early bile duct complications (p = 0.685). In the histopathological examinations, hepatocyte damage was significantly higher in the Pringle maneuver group (p = 0.001). Conclusions: Although the histological scoring of hepatocyte damage was found to be higher in the Pringle maneuver group, the Pringle maneuver did not augment ischemia-reperfusion injury in donors and recipients that was evaluated by clinical and laboratory analyses.

A spatiotemporal atlas of cholestatic injury and repair in mice.

Cholestatic liver injuries, characterized by regional damage around the bile ductular region, lack curative therapies and cause considerable mortality. Here we generated a high-definition spatiotemporal atlas of gene expression during cholestatic injury and repair in mice by integrating spatial enhanced resolution omics sequencing and single-cell transcriptomics. Spatiotemporal analyses revealed a key role of cholangiocyte-driven signaling correlating with the periportal damage-repair response. Cholangiocytes express genes related to recruitment and differentiation of lipid-associated macrophages, which generate feedback signals enhancing ductular reaction. Moreover, cholangiocytes express high TGFß in association with the conversion of liver progenitor-like cells into cholangiocytes during injury and the dampened proliferation of periportal hepatocytes during recovery. Notably, Atoh8 restricts hepatocyte proliferation during 3,5-diethoxycarbonyl-1,4-dihydro-collidin damage and is quickly downregulated after injury withdrawal, allowing hepatocytes to respond to growth signals. Our findings lay a keystone for in-depth studies of cellular dynamics and molecular mechanisms of cholestatic injuries, which may further develop into therapies for cholangiopathies.

Cirrhosis Increases the Rate of Failure of Nonoperative Management in Blunt Liver Injuries.

Pre-existing cirrhosis is associated with increased mortality in blunt liver injury. Despite widespread use of nonoperative management (NOM) for blunt liver injury, there is a relative paucity of data regarding how pre-existing cirrhosis impacts the success of NOM. Herein, we perform a retrospective cohort study using ACS TQIP 2017-2020 data to assess the relationship between cirrhosis and failure of NOM for adult patients with blunt liver injury. 37,176 patients were included (342 cirrhosis and 36,834 without cirrhosis). After propensity-score matching, patients with pre-existing cirrhosis had higher rates of failure of NOM (32.2 vs 14.1%, p < 0.01) and in-hospital mortality (36.3 vs 10.8%, p < 0.01) than patients without cirrhosis. Hesitancy to operate on patients with pre-existing cirrhosis and trauma, as well as significant underlying coagulopathy, may explain these findings.

Self-Healing Hydrogel Containing Decellularized Liver Matrix and Endothelial Cell-Covered Hepatocyte Spheroids for Rescue of Injured Hepatocytes.

Liver fibrosis occurs in many chronic liver diseases, while severe fibrosis can lead to liver failure. A chitosan-phenol based self-healing hydrogel (CP) integrated with decellularized liver matrix (DLM) is proposed in this study as a 3D gel matrix to carry hepatocytes for possible therapy of liver fibrosis. To mimic the physiological liver microenvironment, DLM is extracted from pigs and mixed with CP hydrogel to generate DLM-CP self-healing hydrogel. Hepatocyte spheroids coated with endothelial cells (ECs) are fabricated using a customized method and embedded in the hydrogel. Hepatocytes injured by exposure to CCl4-containing medium are used as the in vitro toxin-mediated liver fibrosis model, where the EC-covered hepatocyte spheroids embedded in the hydrogel are co-cultured with the injured hepatocytes. The urea synthesis of the injured hepatocytes reaches 91% of the normal level after 7 days of co-culture, indicating that the hepatic function of injured hepatocytes is rescued by the hybrid spheroid-laden DLM-CP hydrogel. Moreover, the relative lactate dehydrogenase activity of the injured hepatocytes is decreased 49% by the hybrid spheroid-laden DLM-CP hydrogel after 7 days of co-culture, suggesting reduced damage in the injured hepatocytes. The combination of hepatocyte/EC hybrid spheroids and DLM-CP hydrogel presents a promising therapeutic strategy for hepatic fibrosis.

Effectiveness of a thrombin-gelatin flowable for treating severe liver bleeding: an experimental study.

BACKGROUND: Current scientific evidence has pointed out the relevance of hemostatic products for improving clinical outcomes in liver trauma, including increased survival rates and reductions in bleeding-related complications. The purpose of this study was to compare the use of the gelatin-thrombin flowable (Flowable) versus the standard technique of Packing in a new experimental liver injury model. METHODS: Twenty-four swine were prospectively randomized to receive either Flowable or standard packing technique. We used a novel severe liver injury model, in which the middle and left suprahepatic veins were selectively injured, causing an exsanguinating hemorrhage. The main outcome measure was the percentage of lost blood volume. RESULTS: The median total percentage of total blood volume per animal lost, from injury to minute 120, was significantly lower in the Flowable group (15.2%; interquartile range: 10.7-46.7%) than in the Packing group (64.9%; Interquartile range: 53.4-73.0%) (Hodges-Lehmann median difference: 41.1%; 95% CI: 18.9-58.0%, p = 0.0034). The 24-hour survival rate was significantly higher in the Flowable group (87.0%) than in the Packing group (0.0%) (Hazard ratio (HR) 0.08; 95% confidence interval 0.102 to 0.27; p < 0.0001). Mean-arterial pressure was significantly lower at minute 60 and 120 in the Flowable group than in the packing group (p = 0.0258 and p = 0.0272, respectively). At minute 120, hematocrit was higher in the Flowable than in the packing group (Hodges-Lehmann median difference: 5.5%; 95%CI: 1.0 to11.0, p = 0.0267). Finally, the overall-surgical-procedure was significantly shorter with Flowable than with Packing (Hodges-Lehmann median difference: 39.5 s, 95% CI: 25.0 to 54.0 s, p = 0.0004). CONCLUSIONS: The use of the Flowable was more effective in achieving hemostasis, reducing blood loss, and improving survival rates than standard packing in a severe porcine-liver bleeding model.

Role of Macrophages in Liver Fibrosis.

Liver fibrosis, which ultimately leads to liver cirrhosis and hepatocellular carcinoma, is a major health burden worldwide. The progression of liver fibrosis is the result of the wound-healing response of liver to repeated injury. Hepatic macrophages are cells with high heterogeneity and plasticity and include tissue-resident macrophages termed Kupffer cells, and recruited macrophages derived from circulating monocytes, spleen and peritoneal cavity. Studies have shown that hepatic macrophages play roles in the initiation and progression of liver fibrosis by releasing inflammatory cytokines/chemokines and pro-fibrogenic factors. Furthermore, the development of liver fibrosis has been shown to be reversible. Hepatic macrophages have been shown to alternately regulate both the regression and turnover of liver fibrosis by changing their phenotypes during the dynamic progression of liver fibrosis. In this review, we summarize the role of hepatic macrophages in the progression and regression of liver fibrosis.

Multienzyme Active Manganese Oxide Alleviates Acute Liver Injury by Mimicking Redox Regulatory System and Inhibiting Ferroptosis.

Drug-induced liver injury (DILI) is a severe condition characterized by impaired liver function and the excessive activation of ferroptosis. Unfortunately, there are limited options currently available for preventing or treating DILI. In this study, MnO2 nanoflowers (MnO2Nfs) with remarkable capabilities of mimicking essential antioxidant enzymes, including catalase, superoxide dismutase (SOD), and glutathione peroxidase are successfully synthesized, and SOD is the dominant enzyme among them by density functional theory. Notably, MnO2Nfs demonstrate high efficiency in effectively eliminating diverse reactive oxygen species (ROS) such as hydrogen peroxide (H2O2), superoxide anion (O2 •-), and hydroxyl radical (•OH). Through in vitro experiments, it is demonstrated that MnO2Nfs significantly enhance the recovery of intracellular glutathione content, acting as a potent inhibitor of ferroptosis even in the presence of ferroptosis activators. Moreover, MnO2Nfs exhibit excellent liver accumulation properties, providing robust protection against oxidative damage. Specifically, they attenuate acetaminophen-induced ferroptosis by inhibiting ferritinophagy and activating the P62-NRF2-GPX4 antioxidation signaling pathways. These findings highlight the remarkable ROS scavenging ability of MnO2Nfs and hold great promise as an innovative and potential clinical therapy for DILI and other ROS-related liver diseases.

Diagnóstico y tratamiento de los quistes hepáticos. Utilidad de los marcadores tumorales intraquísticos (CEA y CA 19.9.) / Diagnosis and treatment of hepatic cysts: Usefulness of intracystic tumor markers (CEA and CA 19.9)

Introducción: El tratamiento de los quistes hepáticos requiere del diagnóstico diferencial de quiste simple hepático (QSH) de la neoplasia mucinosa quística (NMQ) hepática. Las características radiológicas no son patognomónicas. Algunos estudios han sugerido la utilidad de los marcadores tumorales (MKT) intraquísticos. Métodos: Análisis retrospectivo de base de datos prospectiva incluyendo pacientes diagnosticados de QSH sintomático desde el 2003 hasta el 2021. El objetivo del estudio es evaluar los resultados del tratamiento de los QSH sintomáticos y analizar la utilidad de la determinación de «carcinoembryonic antigen» (CEA) y «carbohydrate antigen» CA 19.9 intraquísticos. Resultados: Se incluyeron 50 pacientes tratados por quiste sintomático. En 15 pacientes el primer tratamiento fue el drenaje percutáneo. En 35 pacientes se realizó fenestración laparoscópica. Cuatro pacientes se diagnosticaron de lesiones premalignas/malignas (NMQ, NPIB, linfoma B); tres de ellos requirieron una segunda cirugía tras la fenestración y el diagnóstico anatomopatológico. La mediana de los valores de CEA y CA- 19.9 fue de 196μg/L y 227.321U/mL respectivamente. Los pacientes con lesiones premalignas no tuvieron valores elevados de MKT. El valor predictivo positivo fue del 0% en ambos MKT, y el valor predictivo negativo fue de 89% y 91% respectivamente. Conclusiones: Los valores de CEA y CA 19.9 intraquísticos no permiten distinguir los QSH de las NMH. El tratamiento más resolutivo de los QSH sintomáticos es la fenestración quirúrgica. El análisis anatomopatológico de la pared del quiste posibilita su correcto diagnóstico, permitiendo indicar una reintervención quirúrgica en los casos de NMQ.(AU)

Introduction: To decide treatment of hepatic cysts diagnosis between simple hepatic cyst (SHC) and cystic mucinous neoplasm (CMN). Radiological features are not pathognomonic. Some studies have suggested the utility of intracystic tumor markers. Methods: Retrospective analysis of our prospective database including patients treated due to symptomatic SHC from 2003 to 2021. The aim of the study was to evaluate the results of treatment of symptomatic SHC and the usefulness of the determination of intracystic “carcinoembryonic antigen” (CEA) and “carbohydrate antigen” CA 19.9. Results: Fifty patients diagnosed and treated for symptomatic SHC were included. In 15 patients the first treatment was percutaneous drainage. In 35 patients the first treatment was laparoscopic fenestration. Four patients were diagnosed of premalignant or malignant liver cystic lesions (MCN, IPMN, and lymphoma B); three of them required surgery after initial fenestration and pathological diagnosis. Median CEA and CA 19.9 were 196μg/L and 227.321U/mL, respectively. Patients with malignant or premalignant pathology did not have higher levels of intracystic tumor markers. Positive predictive value was 0% for both markers, and negative predictive value was 89% and 91%, respectively. Conclusion: Values of intracystic tumor markers CEA and CA 19.9 do not allow distinguishing simple cysts from cystic liver neoplasms. The most effective treatment for symptomatic simple liver cysts is surgical fenestration. The pathological analysis of the wall of the cysts enables the correct diagnosis, allowing to indicate a surgical reintervention in cases of hepatic cyst neoplasia.(AU)

Partial Resuscitative Endovascular Balloon Occlusion of the Aorta Aids in the Successful Non-Operative Management of a Life-Threatening Penetrating Liver Injury.

In recent years, isolated non-operative management of penetrating liver injuries has become the standard of care for the hemodynamically stable patient. However, when the patient becomes hemodynamically unstable, adjuncts such as resuscitative endovascular balloon occlusion of the aorta (REBOA) deployed in Zone 1 can be used to achieve complete aortic occlusion from the celiac axis down. Unfortunately, hemorrhage control through REBOA comes at the risk of deadly intra-abdominal ischemia. Partial REBOA (pREBOA) introduces the opportunity to make targeted changes in volume and thus titrate the amount of aortic occlusion in real-time to adequately manage hemorrhage while allowing some distal blood flow. This is a novel approach and one which may give providers more time to gain definitive hemorrhage control while minimizing the morbidity of ischemia. Here, we present a case of life-threatening penetrating liver injury that was successfully managed non-operatively with the assistance of p-REBOA.

The use and timing of angioembolization in pediatric blunt liver and spleen injury.

BACKGROUND: Nonoperative management (NOM) is the standard of care for the management of blunt liver and spleen injuries (BLSI) in the stable pediatric patient. Angiography with embolization (AE) is used as an adjunctive therapy in the management of adult BLSI patients, but it is rarely used in the pediatric population. In this planned secondary analysis, we describe the current utilization patterns of AE in the management of pediatric BLSI. METHODS: After obtaining IRB approval at each center, cohort data was collected prospectively for children admitted with BLSI confirmed on CT at 10 Level I pediatric trauma centers (PTCs) throughout the United States from April 2013 to January 2016. All patients who underwent angiography with or without embolization for a BLSI were included in this analysis. Data collected included patient demographics, injury details, organ injured and grade of injury, CT finding specifics such as contrast blush, complications, failure of NOM, time to angiography and techniques for embolization. RESULTS: Data were collected for 1004 pediatric patients treated for BLSI over the study period, 30 (3.0%) of which underwent angiography with or without embolization for BLSI. Ten of the patients who underwent angiography for BLSI failed NOM. For patients with embolized splenic injuries, splenic salvage was 100%. Four of the nine patients undergoing embolization of the liver ultimately required an operative intervention, but only one patient required hepatorrhaphy and no patient required hepatectomy after AE. Few angiography studies were obtained early during hospitalization for BLSI, with only one patient undergoing angiography within 1 hour of arrival at the PTC, and 7 within 3 hours. CONCLUSION: Angioembolization is rarely used in the management of BLSI in pediatric trauma patients with blunt abdominal trauma and is generally used in a delayed fashion. However, when implemented, angioembolization is associated with 100% splenic salvage for splenic injuries. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Isolated injury of the caudate lobe of the liver due to cardiopulmonary resuscitation.

Chest compressions are the mainstay of cardiopulmonary resuscitation. Secondary injuries are frequently reported, most frequently to the thorax and less frequently to the abdomen. Review of existing literature highlights liver lacerations as the most common abdominal injury following cardiopulmonary resuscitation; however, an isolated hepatic caudate lobe injury due to CPR has not yet been reported. We discuss existing literature regarding resuscitation-related injuries, report a case of an isolated hepatic caudate lobe injury due to cardiopulmonary resuscitation, and discuss possible mechanisms of injury.

Association of Contrast Extravasation Grade With Massive Transfusion in Pediatric Blunt Liver and Spleen Injuries: A Multicenter Retrospective Cohort Study.

BACKGROUND: This study aimed to assess whether the grade of contrast extravasation (CE) on CT scans was associated with massive transfusion (MT) requirements in pediatric blunt liver and/or spleen injuries (BLSI). METHODS: This multicenter retrospective cohort study included pediatric patients (≤16 years old) who sustained BLSI between 2008 and 2019. MT was defined as transfusion of all blood products ≥40 mL/kg within the first 24 h of admission. Associations between CE and MT requirements were assessed using multivariate logistic regression analysis with cluster-adjusted robust standard errors to calculate the adjusted odds ratio (AOR). RESULTS: A total of 1407 children (median age: 9 years) from 83 institutions were included in the analysis. Overall, 199 patients (14 %) received MT. CT on admission revealed that 54 patients (3.8 %) had CE within the subcapsular hematoma, 100 patients (7.1 %) had intraparenchymal CE, and 86 patients (6.1 %) had CE into the peritoneal cavity among the overall cohort. Multivariate analysis, adjusted for age, sex, age-adjusted shock index, injury severity, and laboratory and imaging factors, showed that intraparenchymal CE and CE into the peritoneal cavity were significantly associated with the need for MT (AOR: 2.50; 95 % CI, 1.50-4.16 and AOR: 4.98; 95 % CI, 2.75-9.02, respectively both p < 0.001). The latter significant association persisted in the subgroup of patients with spleen and liver injuries. CONCLUSION: Active CE into the free peritoneal cavity on admission CT was independently associated with a greater probability of receiving MT in pediatric BLSI. The CE grade may help clinicians plan blood transfusion strategies. LEVEL OF EVIDENCE: Level 4; Therapeutic/Care management.

MultiCenter Study of Intra-Abdominal Abscess Formation After Major Operative Hepatic Trauma.

INTRODUCTION: One of the significant complications of operative liver trauma is intra-abdominal abscesses (IAA). The objective of this study was to determine risk factors associated with postoperative IAA in surgical patients with major operative liver trauma. METHODS: A retrospective multi-institutional study was performed at 13 Level 1 and Level 2 trauma centers from 2012 to 2021. Adult patients with major liver trauma (grade 3 and higher) requiring operative management were enrolled. Univariate and multivariate analyses were performed. RESULTS: Three hundred seventy-two patients were included with 21.2% (n = 79/372) developing an IAA. No difference was found for age, gender, injury severity score, liver injury grade, and liver resections in patients between the groups (P > 0.05). Penetrating mechanism of injury (odds ratio (OR) 3.42, 95% confidence interval (CI) 1.54-7.57, P = 0.02), intraoperative massive transfusion protocol (OR 2.43, 95% CI 1.23-4.79, P = 0.01), biloma/bile leak (OR 2.14, 95% CI 1.01-4.53, P = 0.04), hospital length of stay (OR 1.04, 95% CI 1.02-1.06, P < 0.001), and additional intra-abdominal injuries (OR 2.27, 95% CI 1.09-4.72, P = 0.03) were independent risk factors for IAA. Intra-abdominal drains, damage control laparotomy, total units of packed red blood cells, number of days with an open abdomen, total abdominal surgeries, and blood loss during surgery were not found to be associated with a higher risk of IAA. CONCLUSIONS: Patients with penetrating trauma, massive transfusion protocol activation, longer hospital length of stay, and injuries to other intra-abdominal organs were at higher risk for the development of an IAA following operative liver trauma. Results from this study could help to refine existing guidelines for managing complex operative traumatic liver injuries.