Hepatic Wound Research Articles

Extracellular Matrix and Hepatic Wound Healing before Fibrosis.

The hepatic extracellular matrix (ECM) is most accurately depicted as a dynamic compartment that comprises a diverse range of players that work bidirectionally with hepatic cells to regulate overall homeostasis. Although the classic meaning of the ECM referred to only proteins directly involved in generating the ECM structure, such as collagens, proteoglycans, and glycoproteins, the definition of the ECM is now broader and includes all components associated with this compartment. The ECM is critical in mediating phenotype at the cellular, organ, and even organismal levels. The purpose of this review is to summarize the prevailing mechanisms by which ECM mediates hepatic phenotype and discuss the potential or established role of this compartment in the response to hepatic injury in the context of steatotic liver disease.

A Comprehensive Review of The Therapeutic Potential of Elaeocarpus Ganitrus

Elaeocarpus ganitrus, also known as Rudraksha, is a member of the Elaeocarpaceae family and has a long history of antidepressant and antibacterial benefits against various illnesses. Elaeocarpus ganitrus has been used in Unani and Ayurveda medicine as an antidepressant, an antibiotic, and as an external treatment for mental disease, epilepsy, liver discomfort, and stomach pain. In addition, it is used to treat a variety of other conditions, including hepatic diseases, dyspepsia, skin infections, blood purification, asthma, tumors, and wounds. Their biological effects include their antioxidant, anti-inflammatory, neuroprotective, anticancer, hepatoprotective, immunomodulatory, antifertility, antibacterial, and antidepressant properties. To further explore the trends and perspectives for future research, a thorough discussion of Elaeocarpus ganitrus' taxonomic classification, traditional uses, botanical description, phytochemical components, pharmacology, and safety aspects is required.

Unaltered hepatic wound healing response in male rats with ancestral liver injury

The possibility that ancestral environmental exposure could result in adaptive inherited effects in mammals has been long debated. Numerous rodent models of transgenerational responses to various environmental factors have been published but due to technical, operational and resource burden, most still await independent confirmation. A previous study reported multigenerational epigenetic adaptation of the hepatic wound healing response upon exposure to the hepatotoxicant carbon tetrachloride (CCl4) in male rats. Here, we comprehensively investigate the transgenerational effects by repeating the original CCl4 multigenerational study with increased power, pedigree tracing, F2 dose-response and suitable randomization schemes. Detailed pathology evaluations do not support adaptive phenotypic suppression of the hepatic wound healing response or a greater fitness of F2 animals with ancestral liver injury exposure. However, transcriptomic analyses identified genes whose expression correlates with ancestral liver injury, although the biological relevance of this apparent transgenerational transmission at the molecular level remains to be determined. This work overall highlights the need for independent evaluation of transgenerational epigenetic inheritance paradigms in mammals.

Comparing High- and Low-Model for End-Stage Liver Disease Living-Donor Liver Transplantation to Determine Clinical Efficacy: A Systematic Review and Meta-Analysis (CHALICE Study).

Various studies have demonstrated that low-Model for End-Stage Liver Disease (MELD) living-donor liver transplant (LDLT) recipients have better outcomes with improved patient survival than deceased-donor liver transplantation (DDLT) recipients. LDLT recipients gain the most from being transplanted at MELD <25-30; however, some existing data have outlined that LDLT may provide equivalent outcomes in high-MELD and low-MELD patients, although the term "high" MELD is arbitrarily defined in the literature and various cut-off scores are outlined between 20 and 30, although most commonly, the dividing threshold is 25. The aim of this meta-analysis was to compare LDLT in high-MELD with that in low-MELD recipients to determine patient survival and graft survival, as well as perioperative and postoperative complications. Following PROSPERO registration CRD-42021261501, a systematic database search was conducted for the published literature between 1990 and 2021 and yielded a total of 10 studies with 2183 LT recipients; 490 were HM-LDLT recipients and 1693 were LM-LDLT recipients. Both groups had comparable mortality at 1, 3 and 5 years post-transplant (5-year HR 1.19; 95% CI 0.79-1.79; p-value 0.40) and graft survival (HR 1.08; 95% CI 0.72, 1.63; p-value 0.71). No differences were observed in the rates of major morbidity, hepatic artery thrombosis, biliary complications, intra-abdominal bleeding, wound infection and rejection; however, the HM-LDLT group had higher risk for pulmonary infection, abdominal fluid collection and prolonged ICU stay. The high-MELD LDLT group had similar patient and graft survival and morbidities to the low-MELD LDLT group, despite being at higher risk for pulmonary infection, abdominal fluid collection and prolonged ICU stay. The data, primarily sourced from high-volume Asian centers, underscore the feasibility of living donations for liver allografts in high-MELD patients. Given the rising demand for liver allografts, it is sensible to incorporate these insights into U.S. transplant practices.

Construction and validation of a novel and severe hepatic injury model in swine focuses on research and training. Observational study

Some hepatic wound models have been developed in pigs with the aim of reproducing liver injury; however, the wound shape, severity, and outcome differ among them. The novel injury profile employed in this study differed from that used elsewhere for standardized, repeatable, reproducible, incising-penetrating, vascular, and severe injury in swine. It is made with a cutting object that penetrates deep into the hepatic parenchyma, always affecting the two suprahepatic veins at the point where they merge into the common trunk.The primary outcome was reproducibility and replicability of the surgical method.The secondary outcome was the analysis of some variables (blood loss, survival, and flow) to validate the model.•This novel method of liver injury provides a liver injury with the following characteristics: standardized, incise-penetrated, deep, bloody, and severe.•This model can be used for research (trauma, hepato-bilio-pancreatic, pharmaceutical) and training (damage control surgery).•Method name: Incising-Penetrating, Vascular and Severe Liver Injury Model in Swine.

Yunnan Baiyao-loaded multifunctional microneedle patches for rapid hemostasis and cutaneous wound healing

Microneedle patches have been extensively employed for wound healing, while the lack of rapid hemostasis efficiency and multiple tissue-repair properties restrict their values in hemorrhagic wound applications. Herein, we propose a Yunnan Baiyao-loaded multifunctional microneedle patch, namely (BY + EGF)@MN, with deep tissue penetration, hemostasis efficiency and regenerative properties for hemorrhagic wound healing. The (BY + EGF)@MNs are designed with a BY-loaded Bletilla striata polysaccharide (BSP) base for rapid hemostasis and epidermal growth factor (EGF)-loaded GelMA tips for subsequent wound healing. As the BSP base can be fastly dissolved and completely release BY in 6 min to promote platelet adhesion and activate coagulation system, while the EGF can achieve a controlled and sustained release behavior in 7 days with the gradual degradation of the GelMA tips, the (BY + EGF)@MNs exhibit strong pro-coagulability and satisfactory hemostatic effect in a rat hepatic hemorrhage wound model. Based on the multifunctional characteristics, we have verified that when applied in rat cutaneous wounds, the proposed MNs can accelerate the wound healing process by enhancing neovascularization, fibroblast density, and collagen deposition. Thus, we believe that such (BY + EGF)@MNs are promising candidates for rapid hemostasis and diverse wound healing applications.Graphical

A Super Tough, Rapidly Biodegradable, Ultrafast Hemostatic Bioglue.

Death happening due to massive hemorrhage has been involved in military conflicts, traffic accidents, and surgical injuries of various human disasters. Achieving rapid and effective hemostasis to save lives is crucial in urgent massive bleeding situations. Herein, a covalent cross-linked AG-PEG glue based on extracellular matrix-like amino-gelatin (AG) and PEG derivatives is developed. The AG-PEG glue gelatinizes fast and exhibits firm and indiscriminate close adhesion with various moist tissues upon being dosed. The formed glue establishes an adhesive and robust barrier to seal the arterial, hepatic, and cardiac hemorrhagic wounds, enabling it to withstand up to 380mmHg blood pressure in comparison with normal systolic blood pressure of 60-180mmHg. Remarkably, massive bleeding from a pig cardiac penetrating hole with 6mm diameter is effectively stopped using the glue within 60s. Postoperative indexes of the treated pig gradually recover and the cardiac wounds regrow significantly at 14days. Possessing on-demand solubility, self-gelling, and rapid degradability, the AG-PEG glue may provide a fascinating stop-bleeding approach for clinical hemostasis and emergency rescue.

Testing Cell Migration, Invasion, Proliferation, and Apoptosis in Hepatic Stellate Cells.

The hepatic wound repair process involves cell types including healthy and injured hepatocytes, Kupffer and inflammatory cells, sinusoidal endothelial cells (SECs), and hepatic stellate cells (HSCs). Normally, in their quiescent state, HSCs are a reservoir for vitamin A, but in response to hepatic injury, they become activated myofibroblasts that play a key role in the hepatic fibrotic response. Activated HSCs express extracellular matrix (ECM) proteins, elicit anti-apoptotic responses, and proliferate, migrate, and invade hepatic tissues to protect hepatic lobules from damage. Extended liver injury can lead to fibrosis and cirrhosis, the deposition of ECM that is driven by HSCs. Here we describe in vitro assays that quantify activated HSC responses in the presence of inhibitors targeting hepatic fibrosis.

Abstract 11717: Expression of Tumor Endothelial Marker 1 in Cardiac Fibroblasts is Associated With Atrial Fibrosis and Regulates Cell Behaviors of Cardiac Fibroblasts

Background: Tumor endothelial marker 1 (TEM1 or CD248) is a transmembrane protein that expresses in mesenchymal lineage-derived cells only during embryogenesis. Re-upregulation of TEM1 in fibroblasts has been found in hepatic fibrosis, renal fibrosis and wound healing. Atrial fibrosis plays an important role in atrial fibrillation (AF) and stroke. We evaluated TEM1 expression in atrial fibrosis and its physiological significance. Methods and Results: All data were presented as mean ± standard error. In 10 patients (pts) with AF undergoing indicated cardiac surgery and Maze procedure, left atrial (LA) appendage was excised. Immunofluorescence staining showed TEM1 expressed in LA cardiac fibroblasts (CFs) in AF pts but not in normal LA tissue purchased from the US Biomax, Inc. Sirius Red staining showed more LA fibrosis in AF than normal LA tissue (7.51±0.40% vs. 3.80±0.51%, p&lt;0.01). In AF pts, higher LA TEM1 expression detected by western blotting was associated with larger LA fibrosis. In 20 AF pts (15 men, mean age 57.5 ± 2.8 yrs) undergoing catheter ablation, LA blood samples were taken and soluble TEM1 (sTEM1) was measured by ELISA. Peak atrial longitudinal strain (PALS) measured by speckle tracking echocardiography before ablation was used as an atrial fibrosis marker. There was a significantly negative correlation of the sTEM1 levels in LA with PALS (ρ=-0.453, p&lt;0.05) indicating increased sTEM1 was associated with atrial fibrosis. In vitro study showed recombinant TEM1 protein (rTEM1) increased proliferation of cultured CFs (saline vs rTEM1 10, 50 and 100 nM, BrdU absorbance: 0.55±0.02 vs. 0.62±0.04 vs. 0.73±0.04 vs. 0.74±0.04, p&lt;0.05) and reduced starvation-induced apoptosis (cell death ELISA absorbance: 1.06±0.09 vs. 0.61±0.05 vs. 0.49±0.11 vs. 0.33±0.02, p&lt;0.05). Transwell assay showed rTEM1 induced increased CFs migration. Conclusions: The study results indicate that TEM1 upregulation in CFs is associated with atrial fibrosis and TEM1 changes the cell behaviors of CFs. Further studies are undergoing to clarify if TEM1 knockdown could alleviate atrial fibrosis.

Clinical Outcomes of Adult Living Donor Liver Transplantation in High MELD Recipients: A Systematic Review and Meta-Analysis

Introduction: There is a clear survival advantage of living donor liver transplantation (LDLT) over waiting for deceased donor liver transplantation (DDLT) for patients with low Model for End-Stage Liver Disease (MELD) score. Results from several centers suggest that the outcomes following LDLT in patients with high-MELD(HM) and low-MELD(LM) are comparable. The aim of study was to verify this observation by performing a meta-analysis of available literature to determine patient survival and graft survival and postoperative outcomes. Methods: Following PROSPERO registration CRD-42021261501, a systematic database search was conducted for literature published between 1990-2021. Ten studies with 2,183 LDLT recipients were identified (N=490 HM group and N=1,693 LM group) and meta-analysis was performed using RevMan 5.3 and STATA/SE-16. Results: Patients in the HM group had comparable mortality at 1, 3 and 5 years post-transplant compared to patients LM group (5-year Hazard Ratio(HR)1.19; 95%CI 0.79-1.79; P-value 0.40). Graft survival was also comparable (5-year HR1.08; 95%CI 0.72-1.63; P-value 0.71.) No statistically significant difference was observed in terms of major morbidity, hepatic artery thrombosis, biliary complications, intraabdominal bleeding, wound infection and rejection. However, HM group had statistically significant higher risk for pulmonary infection, abdominal fluid collection and prolonged ICU stay(Figure 1, Table 1). Conclusions: HM patients submitted to LDLT had overall comparable survival, graft survival and major morbidity rate compared to LM group despite higher risk for pulmonary infection, abdominal fluid collection and prolonged ICU stay.Tabled 1FP13-4Table1 Post transplant outcomesA. OutcomesOdds ratio95%CIP-valueI2 (%)Major morbidity1.530.92-2.540.10$41%Hepatic artery thrombosis1.180.52-2.670.70$0%Biliary complications1.060.72-1.570.75$14%Wound infections1.460.51-4.240.48$0%Intraabdominal bleeding1.870.98-3.540.06$0%Pulmonary infections2.071.05-4.080.04**40%Abdominal fluid collections2.261.21-4.240.01**0%B. OutcomesMean difference95%CIP-valueI2 (%)Length of ICU stay1.140.43-1.840.00∗∗29%Strength: I2 --Mild to moderate heterogeneity, $: non-significant difference or comparable outcomes, *: significant difference Open table in a new tab Strength: I2 --Mild to moderate heterogeneity, $: non-significant difference or comparable outcomes, *: significant difference

Previous liver regeneration induces fibro-protective mechanisms during thioacetamide-induced chronic liver injury.

Chronic liver injury is characterised by continuous or repeated epithelial cell loss and inflammation. Hepatic wound healing involves matrix deposition through activated hepatic stellate cells (HSCs) and the expansion of closely associated Ductular Reactions and liver progenitor cells (LPCs), which are thought to give rise to new epithelial cells. In this study, we used the murine thioacetamide (TAA) model to reliably mimic these injury and regeneration dynamics and assess the impact of a recovery phase on subsequent liver injury and fibrosis. Age-matched naïve or 6-week TAA-treated/4-week recovered mice (C57BL/6 J, n = 5-9) were administered TAA for six weeks (C57BL/6 J, n = 5-9). Sera and liver tissues were harvested at key time points to assess liver injury biochemically, by real-time PCR for fibrotic mediators, Sirius Red staining and hydroxyproline assessment for collagen deposition as well as immunofluorescence for inflammatory, HSC and LPC markers. In addition, primary HSCs and the HSC cell line LX-2 were co-cultured with the well-characterised LPC line BMOL and analysed for potential changes in expression of fibrogenic mediators. Our data demonstrate that recovery from a previous TAA insult, with LPCs still present on day 0 of the second treatment, led to a reduced TAA-induced disease progression with less severe fibrosis than in naïve TAA-treated animals. Importantly, primary activated HSCs significantly reduced pro-fibrogenic gene expression when co-cultured with LPCs. Taken together, previous TAA injury established a fibro-protective molecular and cellular microenvironment. Our proof-of principle HSC/LPC co-culture data demonstrate that LPCs communicate with HSCs to regulate fibrogenesis, highlighting a key role for LPCs as regulatory cells during chronic liver disease.

Pedicled Tubular Omental Patch for Tamponade of Transfixing Gunshot Bilobar Liver Injury: A Case Report

Introduction: Liver injuries are frequent in abdominal trauma and may be managed using a variety of methods. The operative management of deep, penetrating wounds generally involves balloon tamponade of the wound tract using a Sengstaken-Blakemore catheter. Case Presentation: A haemodynamically unstable 34-year-old male with multiple thoracoabdominal gunshot wounds was transferred to the operating theatre. At laparotomy, a grade 3 transfixing (through and through) bilobar hepatic wound was discovered with active hemorrhage. Unfortunately, no suitable balloon catheters were available, so, as an alternative, tamponade of the wound tract was successfully achieved using a tubular omental patch. Discussion: Omental patches are commonly used in the management of perforated duodenal ulcers and have been used to prevent recurrence following hepatic cyst de-roofing. To the authors’ knowledge, this is the first description of this technique for the management of penetrating bilobar transfixing hepatic injury. Conclusion: A tubular omental patch may be used to achieve tamponade of deep wounds in penetrating hepatic trauma. This could be a particularly useful technique in resource-poor environments, or where a suitable balloon catheter is otherwise unavailable.

Phytochemistry and pharmacological potential of Cassia absus - a review.

Cassia absus is a plant of the family fabaceae with Ayurvedic ethnomedical records. It is used in traditional medicine for the treatment of bronchitis, asthma, cough, conjunctivitis, leucoderma, renal and hepatic diseases, constipation, tumors, venereal ulcer, headache, hemorrhoids and wound healing. Preliminary invitro and invivo studies have provided valuable scientific evidence for its use. This review aims to summarize reported pharmacognosy, traditional uses, phytochemistry and pharmacological potential of C.absus while identifying potential areas of further research of plant. The review comprises literature pertaining to the evidence base therapeutic potential, pharmacognosy and phytochemistry of C.absus spanning from 1935 to 2016 using published articles in peer-reviewed journals, ethno botanical text books, and worldwide accepted scientific databases via electronic search (Elsevier, Google Scholar, PubMed, Scopus, Springer, Web of Science, Wiley online library). Kew Botanical Garden databases and the Plant List were used to authenticate the scientific names. Different pharmacological experiments in many in-vitro and in-vivo models have proved the potential of C.absus with antihypertensive, antifertility, antifungal, anti-inflammatory, anti-hyperglycemic, anti-glycation, antibacterial activity, α- amylase inhibitory activity, antioxidant and reducing activitity etc. chaksine, iso-chaksine, saturated and unsaturated fatty acids, chrysophanol, aloe-emodin and a wide range of chemical compounds have also been reported. Toxicity studies reveal the nontoxic nature of C.absus at a dose of 2000mg/kg, however, plant possess reproductive toxicity and can be used as birth control or abortifacient. Reported activities suggest that there is sufficient pharmacological potential for developing C.absus as a drug for hypertension, infections, diabetes and its complications. However, heterogeneity in study protocol and conflicting results mask the ability to replicate these studies. So, future studies should be replicated in line with best practices. More toxicological studies would aid the progress to clinical trial studies. Various ethno medical uses of C.absus have not been evaluated yet.

Clinical effect of precise liver resection for large hepatocellular carcinoma

Objective To evaluate the clinical effect of precise liver resection for large hepatocellular carcinoma (HCC) under the guidance of precision surgery theory. Methods The retrospective and descriptive study was conducted. The clinical data of 49 patients with HCC who were admitted to the First Affiliated Hospital of Sun Yat-Sen University between June 2014 and June 2015 were collected. The preoperative assessments of general condition and liver function were conducted, and the ratio of future liver volume/standard liver volume (FLV/SLV) was calculated. Patients underwent right hemihepatectomy, extended right hemihepatectomy or associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) based on preoperative comprehensive assessment. Observation indicators: (1) results of preoperative assessment; (2) operation situations: surgical procedures, time of hepatectomy, volumes of intraoperative blood loss and perioperative blood transfusion; time and volume of intraoperative blood loss in the first surgery, interval time between the first and second surgery, growth rate of liver volume up to the second surgery, time and volume of intraoperative blood loss in the second surgery; (3) postoperative situations: duration of postoperative hospital stay, postoperative complications (hepatic dysfunction, bile leakage, intra-abdominal infection, wound infection, pleural effusion, peritoneal effusion and subphrenic effusion); (4) follow-up situation. Follow-up using outpatient examination was performed to detect 1-year recurrence rate of patients up to June 2016. Measurement data with normal distribution were represented as ±s and measurement data with skewed distribution were represented as M (range). Results (1) Results of preoperative assessment: of 49 patients, grade A of Child-pugh classification was found in 46 patients and grade B in 3 patients. ICG R15 35% was detected in 46 patients, and ICG R15>15% or FLV/SLV<35% in 3 patients. (2) Operation situations: of 49 patients, 44, 2 and 3 patients underwent right hemihepatectomy, extended right hemihepatectomy and ALPPS, respectively. Operation time, volume of intraoperative blood loss, number of patients with perioperative blood transfusion and volume of perioperative blood transfusion were 230 minutes (range, 170-405 minutes), 400 mL (range, 100-5 000 mL), 19, 550 mL (range, 200-2 750 mL) in 44 patients undergoing right hemihepatectomy and 2 undergoing extended right hemihepatectomy, respectively. Three patients with ALPPS underwent successfully the first and second surgeries. Operation time, volume of intraoperative blood loss and interval time between the first and second surgeries were 80 minutes, 190 minutes, 180 minutes, 100 mL, 300 mL, 150 mL, 9 days, 11 days and 13 days in 3 patients with ALPPS, respectively. Growth rate of liver volume up to the second surgery, operation time and volume of intraoperative blood loss in the second surgery were 88.4%, 78.0%, 94.6%, 180 minutes, 215 minutes, 150 minutes, 100 mL, 100 mL, 400 mL in 3 patients with ALPPS, respectively. (3) Postoperative situations: duration of postoperative hospital stay of 44 patients with right hemihepatectomy and 2 with extended right hemihepatectomy was 17 days (range, 9-45 days). Eleven patients had postoperative complications. One patient with hepatic dysfunction was cured by liver protection therapy. One patient with bile leakage and abdominal infection was cured by symptomatic and antibiotic treatments. Two patients with wound infection received wound dressing and then wound was healed. Seven patients with pleural effusion, peritoneal effusion and subphrenic effusion received percutaneous catheter drainage, and no residual effusion was detected. Three patients with ALPPS didn't have postoperative complications. (4) Follow-up situation: all the 49 patients were followed up. The postoperative recurrence was detected in 12 patients within 1 year, with a recurrence rate of 24.5% (12/49). Conclusion Precise liver resection for large HCC under the guidance of precision surgery theory can effectively evaluate surgery risks and reduce the incidence of postoperative hepatic dysfunction. Key words: Carcinoma, hepatocellular; Precision hepatic surgery; Hepatectomy; Liver failure

Child Abdominal Trauma Due to Attack of Cattles While Working on Farms in Burkina Faso

Introduction: Cattle are strong animals very often used in agriculture in rural Africa. Unpredictable in their behavior, they regularly inflict injuries to farmers, some of whom are children in rural Africa. Objective: The purpose of this study was to describe the clinical, therapeutic and evolutionary aspects of abdominal trauma caused by bovidae to children on farms in Burkina Faso. Patients and Method: This is a descriptive study covering the period from January 2014 through December 2016 and was conducted in the General Surgery Unit of the Tenkodogo Regional Hospital in Burkina Faso. It included all patients under the age of 17, victims of abdominal trauma by cattle on farms. Result: A total of 68 patients were identified, which is 3% of all patients under 17 admitted to the service during the same period. The average age of patients was 10.5 years, with a standard variation of 3.6 years. The majority (73.5%) of the patients were boys. The main lesional mechanisms found were horn strokes (88.2%). We noted 35 eviscerations without visceral perforation, 15 intestinal perforations, 6 hepatic wounds and 5 splenic wounds. In 7 cases, there were non-penetrating wounds. All patients underwent surgical intervention under anesthesia. The average length of hospital was 6 days. Two deaths were recorded, making a mortality rate of 3%. Conclusion: Abdominal traumas of the child by attack of cattle are frequent during farm works in rural Burkina Faso. The injuries are sometimes serious. Wearing protective equipment for children should be considered during farm work.

Embrionary way to create a fatty liver in portal hypertension.

Portal hypertension in the rat by triple partial portal vein ligation produces an array of splanchnic and systemic disorders, including hepatic steatosis. In the current review these alterations are considered components of a systemic inflammatory response that would develop through three overlapping phenotypes: The neurogenic, the immune and the endocrine. These three inflammatory phenotypes could resemble the functions expressed during embryonic development of mammals. In turn, the inflammatory phenotypes would be represented in the embryo by two functional axes, that is, a coelomic-amniotic axis and a trophoblastic yolk-sac or vitelline axis. In this sense, the inflammatory response developed after triple partial portal vein ligation in the rat would integrate both functional embryonic axes on the liver interstitial space of Disse. If so, this fact would favor the successive development of steatosis, steatohepatitis and fibrosis. Firstly, these recapitulated embryonic functions would produce the evolution of liver steatosis. In this way, this fat liver could represent a yolk-sac-like in portal hypertensive rats. After that, the systemic recapitulation of these embryonic functions in experimental prehepatic portal hypertension would consequently induce a gastrulation-like response in which a hepatic wound healing reaction or fibrosis occur. In conclusion, studying the mechanisms involved in embryonic development could provide key results for a better understanding of the nonalcoholic fatty liver disease etiopathogeny.

The orphan nuclear receptor COUP-TFII coordinates hypoxia-independent proangiogenic responses in hepatic stellate cells

Hepatic stellate cell (HSC) transdifferentiation into collagen-producing myofibroblasts is a key event in hepatic fibrogenesis, but the transcriptional network that controls the acquisition of the activated phenotype is still poorly understood. In this study, we explored whether the nuclear receptor chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) is involved in HSC activation and in the multifunctional role of these cells during the response to liver injury. COUP-TFII expression was evaluated in normal and cirrhotic livers by immunohistochemistry and Western blot. The role of COUP-TFII in HSC was assessed by gain and loss of function transfection experiments and by generation of mice with COUP-TFII deletion in HSC. Molecular changes were determined by gene expression microarray and RT-qPCR. We showed that COUP-TFII is highly expressed in human fibrotic liver and in mouse models of hepatic injury. COUP-TFII expression rapidly increased upon HSC activation and it was associated with the regulation of genes involved in cell motility, proliferation and angiogenesis. Inactivation of COUP-TFII impairs proliferation and invasiveness in activated HSC and COUP-TFII deletion in mice abrogate HSC activation and angiogenesis. Finally, co-culture experiments with HSC and liver sinusoidal endothelial cells (SEC) showed that COUP-TFII expression in HSC influenced SEC migration and tubulogenesis via a hypoxia-independent and nuclear factor kappaB-dependent mechanism. This study elucidates a novel transcriptional pathway in HSC that is involved in the acquisition of the proangiogenic phenotype and regulates the paracrine signals between HSC and SEC during hepatic wound healing. In this study, we identified an important regulator of HSC pathobiology. We showed that the orphan receptor COUP-TFII is an important player in hepatic neoangiogenesis. COUP-TFII expression in HSC controls the crosstalk between HSC and endothelial cells coordinating vascular remodelling during liver injury. ArrayExpress accession E-MTAB-1795.

Omentum “Sausage” patch tamponade for bilobar transfixing hepatic gunshot wound

Omentum “Sausage” patch tamponade for bilobar transfixing hepatic gunshot wound

Moderate (2%, v/v) Ethanol Feeding Alters Hepatic Wound Healing after Acute Carbon Tetrachloride Exposure in Mice.

Wound healing consists of three overlapping phases: inflammation, proliferation, and matrix synthesis and remodeling. Prolonged alcohol abuse can cause liver fibrosis due to deregulated matrix remodeling. Previous studies demonstrated that moderate ethanol feeding enhances liver fibrogenic markers and frank fibrosis independent of differences in CCl4-induced liver injury. Our objective was to determine whether or not other phases of the hepatic wound healing response were affected by moderate ethanol after CCl4 exposure. Mice were fed moderate ethanol (2% v/v) for two days and then were exposed to CCl4 and euthanized 24–96 h later. Liver injury was not different between pair- and ethanol-fed mice; however, removal of necrotic tissue was delayed after CCl4-induced liver injury in ethanol-fed mice. Inflammation, measured by TNFα mRNA and protein and hepatic Ly6c transcript accumulation, was reduced and associated with enhanced hepatocyte apoptosis after ethanol feeding. Hepatocytes entered the cell cycle equivalently in pair- and ethanol-fed mice after CCl4 exposure, but hepatocyte proliferation was prolonged in livers from ethanol-fed mice. CCl4-induced hepatic stellate cell activation was increased and matrix remodeling was prolonged in ethanol-fed mice compared to controls. Taken together, moderate ethanol affected each phase of the wound healing response to CCl4. These data highlight previously unknown effects of moderate ethanol exposure on hepatic wound healing after acute hepatotoxicant exposure.

Hepatic matrix metalloproteinase-10 exerts a hepatoprotective role after acute liver injury

After injuries that lead to a loss of liver tissue a regenerative and reparative response is performed in order to restore an adequate hepatic mass. The remodeling of the extracellular matrix, accompanies the liver regeneration and when the reparative reaction goes awry in the setting of chronic liver injury, could be involved in the carcinogenic process (1,2). Following the damage, a provisional matrix is deposed, intended to be successively replaced, which has the function of stabilizing the lesional area and constitutes a support for guiding regenerating cells. Matrix metalloproteinases are increasingly recognized as important modulators of the matrix remodeling process. Matrix metalloproteinase-10 (MMP-10) has been implicated in the reparative process in other organs and has effects on the plasminogen system, which plays a fundamental role in liver repair (3). The hepatic expression of MMP10 in animal models of acute liver injury was tested in order to investigate the role of MMP-10 in liver repair and regeneration. The liver regeneration after two thirds partial hepatectomy (PH) and bile duct ligation (BDL) models were examined. Hepatic MMP-10 expression, analyzed by immunohistochemistry, western blot and qPCR showed a rise early after injury. In the MMP10-deficient mice a diminished and delayed resolution of necrotic lesions, enhanced fibrogenesis and a fibrinogen/fibrin and fibronectin compromised turnover were observed. These findings showed that the MMP10 expression plays a role in the hepatic wound healing response probably through its profibrinolytic activity.