Beyond the classical description of eosinophil functions in parasite infections and allergic diseases, emerging evidence supports a critical role of eosinophils in resolving inflammation and ...promoting tissue remodeling. However, the role of eosinophils in liver injury and the underlying mechanism of their recruitment into the liver remain unclear.
Hepatic eosinophils were detected and quantified using flow cytometry and immunohistochemical staining. Eosinophil-deficient (ΔdblGata1) mice were used to investigate the role of eosinophils in 3 models of acute liver injury. In vivo experiments using Il33-/- mice and macrophage-depleted mice, as well as in vitro cultures of eosinophils and macrophages, were performed to interrogate the mechanism of eotaxin-2 (CCL24) production.
Hepatic accumulation of eosinophils was observed in patients with acetaminophen (APAP)-induced liver failure, whereas few eosinophils were detectable in healthy liver tissues. In mice treated with APAP, carbon tetrachloride or concanavalin A, eosinophils were recruited into the liver and played a profound protective role. Mice deficient of macrophages or IL-33 exhibited impaired hepatic eosinophil recruitment during acute liver injury. CCL24, but not CCL11, was increased after treatment of each hepatotoxin in an IL-33 and macrophage-dependent manner. In vitro experiments demonstrated that IL-33, by stimulating IL-4 release from eosinophils, promoted the production of CCL24 by macrophages.
This is the first study to demonstrate that hepatic recruitment of and protection by eosinophils occur commonly in various models of acute liver injury. Our findings support further exploration of eosinophils as a therapeutic target to treat APAP-induced acute liver injury.
The current study unveils that eosinophils are recruited into the liver and play a protective function during acute liver injury caused by acetaminophen overdose. The data demonstrate that IL-33-activated eosinophils trigger macrophages to release high amounts of CCL24, which promotes hepatic eosinophil recruitment. Our findings suggest that eosinophils could be an effective cell-based therapy for the treatment of acetaminophen-induced acute liver injury.
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•Eosinophils are recruited to the liver in multiple models of acute injury and play a protective role.•Crosstalk between eosinophils and macrophages plays an important role in eosinophil recruitment to the injured liver.•IL-33 is selectively released from liver sinusoidal endothelial cells during APAP-induced liver injury.•IL-33, by stimulating IL-4 release from eosinophils, promotes the production of CCL24 by macrophages.
Hepatic ischemia and reperfusion (IR) injury contributes to the morbidity and mortality associated with liver transplantation. microRNAs (miRNAs) constitute a family of noncoding RNAs that regulate ...gene expression at the posttranslational level through the repression of specific target genes. Here, we hypothesized that miRNAs could be targeted to enhance hepatic ischemia tolerance. A miRNA screen in a murine model of hepatic IR injury pointed us toward the liver-specific miRNA miR122. Subsequent studies in mice with hepatocyte-specific deletion of miR122 (miR122loxP/loxP Alb-Cre+ mice) during hepatic ischemia and reperfusion revealed exacerbated liver injury. Transcriptional studies implicated hypoxia-inducible factor-1α (HIF1α) in the induction of miR122 and identified the oxygen-sensing prolyl hydroxylase domain 1 (PHD1) as a miR122 target. Further studies indicated that HIF1α-dependent induction of miR122 participated in a feed-forward pathway for liver protection via the enhancement of hepatic HIF responses through PHD1 repression. Moreover, pharmacologic studies utilizing nanoparticle-mediated miR122 overexpression demonstrated attenuated liver injury. Finally, proof-of-principle studies in patients undergoing orthotopic liver transplantation showed elevated miR122 levels in conjunction with the repression of PHD1 in post-ischemic liver biopsies. Taken together, the present findings provide molecular insight into the functional role of miR122 in enhancing hepatic ischemia tolerance and suggest the potential utility of pharmacologic interventions targeting miR122 to dampen hepatic injury during liver transplantation.
We describe the investigation of Cryptococcus neoformans infection in three recipients of cadaveric organ transplants from one donor with unrecognized cryptococcal meningoencephalitis. This report ...emphasizes the importance and difficulty of recognizing fungal infection pre-transplant in the donor with an undifferentiated neurologic condition. Evaluation for cryptococcosis in donors with unexplained neurologic symptoms should be considered.
Background
. This article describes transmission of Cryptococcus neoformans by solid organ transplantation.
Methods.
We reviewed medical records and performed molecular genotyping of isolates to determine potential for donor transmission of Cryptococcus.
Results
. Cryptococcosis was diagnosed in 3 recipients of organs from a common donor with an undifferentiated neurologic condition at the time of death. Cryptococcal meningoencephalitis was later diagnosed in the donor at autopsy. The liver and 1 kidney recipient developed cryptococcemia and pneumonia and the other kidney recipient developed cryptococcemia and meningitis; 2 patients recovered with prolonged antifungal therapy. We tested 4 recipient isolates with multilocus sequence typing and found they had identical alleles.
Conclusions.
Our investigation documents the transmission of Cryptococcus neoformans by organ transplantation. Evaluation for cryptococcosis in donors with unexplained neurologic symptoms should be strongly considered.
Eosinophils are a myeloid cell subpopulation that mediates type 2 T helper cell immune responses. Unexpectedly, we identified a rapid accumulation of eosinophils in 22 human liver grafts after ...hepatic transplantation. In contrast, no eosinophils were detectable in healthy liver tissues before transplantation. Studies with two genetic mouse models of eosinophil deficiency and a mouse model of antibody-mediated eosinophil depletion revealed exacerbated liver injury after hepatic ischemia and reperfusion. Adoptive transfer of bone marrow-derived eosinophils normalized liver injury of eosinophil-deficient mice and reduced hepatic ischemia and reperfusion injury in wild-type mice. Mechanistic studies combining genetic and adoptive transfer approaches identified a critical role of suppression of tumorigenicity (ST2)-dependent production of interleukin-13 by eosinophils in the hepatoprotection against ischemia-reperfusion-induced injury. Together, these data provide insight into a mechanism of eosinophil-mediated liver protection that could serve as a therapeutic target to improve outcomes of patients undergoing liver transplantation.
Coronavirus disease 2019 (COVID-19) poses a serious risk to patients with chronic kidney disease (CKD) and renal transplant. While COVID-19 vaccination is recommended before transplant, there are ...limited data comparing vaccine timing. Our aim is to evaluate serological responses to COVID-19 vaccines pre- and post-renal transplant and the durability of antibody levels.
We retrospectively evaluated the antibody response of adult renal transplant recipients who had received at least a primary series of the COVID-19 vaccine. The patients were divided into two groups based on the timing; pre- or post-transplant. Antibody titer levels were evaluated at least 4 weeks after vaccination for each group. Titer durability was assessed by calculating the median titer level of individuals.
A total of 139 patients were identified between January 2019 and April 2022. Twenty-nine patients were excluded because of previous COVID-19 infection, and 15 patients were excluded each for insufficient vaccine doses and lack of titer data. Forty patients were included for the pre-transplant group and 40 for post-transplant. The number of pre-transplant patients who developed antibodies (39 patients, 97.5%) was significantly greater than the number of post-transplant patients (21 patients, 52.5%) with p < .01. The median post-vaccination titer levels were significantly greater in the pre-transplant group up to 5 months after vaccination (p < .05). The pre-transplant group's titers seemed sustained even after renal transplantation.
Vaccinating renal transplant patients before transplant results in increased achievement of seroresponse, higher levels of antibody titers, and sustained titers following transplant. Larger and prospective studies are warranted to confirm the findings.
Complex portal vein thrombosis (PVT) is a challenge in liver transplantation (LT). Extra-anatomical approaches to portal revascularization, including renoportal (RPA), left gastric vein (LGA), ...pericholedochal vein (PCA), and cavoportal (CPA) anastomoses, have been described in case reports and series. The RP4LT Collaborative was created to record cases of alternative portal revascularization performed for complex PVT.
An international, observational web registry was launched in 2020. Cases of complex PVT undergoing first LT performed with RPA, LGA, PCA, or CPA were recorded and updated through 12/2021.
A total of 140 cases were available for analysis: 74 RPA, 18 LGA, 20 PCA, and 28 CPA. Transplants were primarily performed with whole livers (98%) in recipients with median (IQR) age 58 (49-63) years, model for end-stage liver disease score 17 (14–24), and cold ischemia 431 (360-505) minutes. Post-operatively, 49% of recipients developed acute kidney injury, 16% diuretic-responsive ascites, 9% refractory ascites (29% with CPA, p <0.001), and 10% variceal hemorrhage (25% with CPA, p = 0.002). After a median follow-up of 22 (4-67) months, patient and graft 1-/3-/5-year survival rates were 71/67/61% and 69/63/57%, respectively. On multivariate Cox proportional hazards analysis, the only factor significantly and independently associated with all-cause graft loss was non-physiological portal vein reconstruction in which all graft portal inflow arose from recipient systemic circulation (hazard ratio 6.639, 95% CI 2.159-20.422, p = 0.001).
Alternative forms of portal vein anastomosis achieving physiological portal inflow (i.e., at least some recipient splanchnic blood flow reaching transplant graft) offer acceptable post-transplant results in LT candidates with complex PVT. On the contrary, non-physiological portal vein anastomoses fail to resolve portal hypertension and should not be performed.
Complex portal vein thrombosis (PVT) is a challenge in liver transplantation. Results of this international, multicenter analysis may be used to guide clinical decisions in transplant candidates with complex PVT. Extra-anatomical portal vein anastomoses that allow for at least some recipient splanchnic blood flow to the transplant allograft offer acceptable results. On the other hand, anastomoses that deliver only systemic blood flow to the allograft fail to resolve portal hypertension and should not be performed.
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•Cases of complex portal vein thrombosis undergoing first LT with extra-anatomical portal vein reconstruction were recorded.•Reconstructions delivering splanchnic blood to transplant graft offer acceptable post-transplant results.•Reconstructions delivering only systemic blood to graft result in dismal post-transplant survival.
Patients infected with hepatitis C virus (HCV) frequently develop renal failure after liver transplantation.
To describe renal histologic characteristics and concomitant clinical features in ...HCV-infected patients with end-stage cirrhosis.
Case series.
Single-center liver transplant program in the United States.
30 patients who received liver transplants for HCV-induced cirrhosis.
Kidney biopsy during liver engraftment.
Clinical data and laboratory tests of renal function within 6 months before liver transplantation.
Twenty-five patients had immune-complex glomerulonephritis: membranoproliferative glomerulonephritis type 1 (n = 12), IgA nephropathy (n = 7), and mesangial glomerulonephritis (n = 6). Of these patients, 10 had normal serum creatinine levels, normal urinalysis results, and normal quantitative proteinuria. For 5 others, the only renal abnormality was an increased serum creatinine level. No patient had cryoglobulins in the blood or kidney.
This small observational study did not include patients with nonviral cirrhosis and did not document post-transplantation outcomes.
Immune-complex glomerulonephritis was common in patients with end-stage HCV-induced cirrhosis and was often clinically silent. Its potential to cause renal failure after liver transplantation may be underappreciated.
Surgical resection of primary or metastatic tumors of the liver offers patients the best long-term survival. Liver resections may not be appropriate in patients with bilobar metastases, liver ...dysfunction, or severe comorbidities. Radiofrequency ablation (RFA) is a technique used to destroy unresectable hepatic tumors through thermocoagulation. We retrospectively reviewed a consecutive series of patients undergoing RFA with unresectable hepatic tumors for local recurrence and overall survival. Under an Institutional Review Board-approved protocol, all patients treated with RFA at the University of Alabama at Birmingham from September 1, 1998, to June 15, 2005, were identified. During this time period, 189 lesions in 107 patients were treated with RFA. Patients' charts were retrospectively reviewed. Data is presented as mean +/- SEM. Significance is defined as P < 0.05. Patient demographics revealed 62 per cent males and 38 per cent females with a mean age of 59 (+/- 1) years. Hepatocellular carcinoma (HCC) represented 54 per cent of the tumors treated. Metastatic colorectal cancer represented 22 per cent and the remaining 24 per cent were other metastatic tumors. Overall recurrence rates for all tumors after RFA was 53 per cent. Local recurrence rates for HCC, colorectal cancer, and other metastatic lesions were 27.6 per cent, 29.1 per cent, and 52 per cent, respectively. The morbidity rate for the procedure was 11 per cent. There was one mortality (0.9%) related to RFA. Laparoscopic RFA for HCC in Childs-Pugh Class C cirrhotics (n = 6) resulted in 50 per cent of patients being transplanted with no evidence of disease at a mean follow-up period of 14 months. RFA is a safe and effective way for treating HCC and other unresectable tumors in the liver that are not eligible for hepatic resection. More effective control of systemic recurrence will dictate survival in the majority of patients with metastatic cancers. Local ablation for HCC in cirrhotic patients may be an effective bridge to transplantation. Liver transplantation may still be the most effective long-term treatment for localized HCC.
Hepatic ischemia and reperfusion (IR) injury contributes to the morbidity and mortality associated with liver transplantation. microRNAs (miRNAs) constitute a family of noncoding RNAs that regulate ...gene expression at the posttranslational level through the repression of specific target genes. Here, we hypothesized that miRNAs could be targeted to enhance hepatic ischemia tolerance. A miRNA screen in a murine model of hepatic IR injury pointed us toward the liver-specific miRNA miR122. Subsequent studies in mice with hepatocyte-specific deletion of miR122 (miR122.sup.IoxP/IoxPAlb-Cre.sup.+ mice) during hepatic ischemia and reperfusion revealed exacerbated liver injury. Transcriptional studies implicated hypoxia-inducible factor-1alpha (HIF1alpha) in the induction of miR122 and identified the oxygen-sensing prolyl hydroxylase domain 1 (PHD1) as a miR122 target. Further studies indicated that HIF1alpha-dependent induction of miR122 participated in a feed-forward pathway for liver protection via the enhancement of hepatic HIF responses through PHD1 repression. Moreover, pharmacologic studies utilizing nanoparticle-mediated miR122 overexpression demonstrated attenuated liver injury. Finally, proof-of-principle studies in patients undergoing orthotopic liver transplantation showed elevated miR122 levels in conjunction with the repression of PHD1 in post-ischemic liver biopsies. Taken together, the present findings provide molecular insight into the functional role of miR122 in enhancing hepatic ischemia tolerance and suggest the potential utility of pharmacologic interventions targeting miR122 to dampen hepatic injury during liver transplantation.
Hepatic ischemia and reperfusion (IR) injury contributes to the morbidity and mortality associated with liver transplantation. microRNAs (miRNAs) constitute a family of noncoding RNAs that regulate ...gene expression at the posttranslational level through the repression of specific target genes. Here, we hypothesized that miRNAs could be targeted to enhance hepatic ischemia tolerance. A miRNA screen in a murine model of hepatic IR injury pointed us toward the liver-specific miRNA miR122. Subsequent studies in mice with hepatocyte-specific deletion of miR122 during hepatic ischemia and reperfusion revealed exacerbated liver injury. Transcriptional studies implicated hypoxia-inducible factor–1α (HIF1α) in the induction of miR122 and identified the oxygen-sensing prolyl hydroxylase domain 1 (PHD1) as a miR122 target. Further studies indicated that HIF1α-dependent induction of miR122 participated in a feed-forward pathway for liver protection via the enhancement of hepatic HIF responses through PHD1 repression. Moreover, pharmacologic studies utilizing nanoparticle-mediated miR122 overexpression demonstrated attenuated liver injury. Finally, proof-of-principle studies in patients undergoing orthotopic liver transplantation showed elevated miR122 levels in conjunction with the repression of PHD1 in post-ischemic liver biopsies. Taken together, the present findings provide molecular insight into the functional role of miR122 in enhancing hepatic ischemia tolerance and suggest the potential utility of pharmacologic interventions targeting miR122 to dampen hepatic injury during liver transplantation.
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