Ischemia and reperfusion injury (IRI) is a dynamic process that involves two distinctive yet interrelated phases of ischemic organ damage and inflammation‐mediated reperfusion injury. Although ...multiple cellular and molecular pathways contribute and regulate tissue/organ damage, integration of different players into a unified mechanism is warranted. The crosstalk between innate and adaptive immune systems plays a significant role in the pathogenesis of liver IRI. In this review, we focus on recent progress in the mechanism of liver innate immune activation by IR. Kupffer cells (KC), DCs, NK, as well as T cells initiate local inflammation response, the hallmark of IRI, by utilizing distinctive immune receptors to recognize and/or trigger various molecules, both endogenous and exogenous. The interlocked molecular signaling pathways in the context of multiple liver cell types, the IRI kinetics and positive versus negative regulatory loops in the innate immune activation process are discussed. Better appreciation of molecular interactions that mediate these intricate cascades, should allow for the development of novel therapeutic approached against IRI in liver transplant recipients.
Liver inflammation triggered by the insults of peri‐transplant ischemia and reperfusion is an innate immune‐dominated local response regulated by CD4+ T cells.
Although the roles of the metabolic stress in organ ischemia‐reperfusion injury (IRI) have been well recognized, the question of whether and how these stress responses regulate innate immune ...activation against IR remains unclear. In a murine liver partial warm ischemia mode, we showed that prolonged ischemia triggered endoplasmic reticulum (ER) stress response, particularly, the activating transcription factor 6 (ATF6) branch, in liver Kupffer cells (KCs) and altered their responsiveness against Toll‐like receptor (TLR) stimulation. Ischemia‐primed cells increased pro‐, but decreased anti‐, inflammatory cytokine productions. Alleviation of ER stress in vivo by small chemical chaperon 4‐phenylbutyrate or ATF6 small interfering RNA (siRNA) diminished the pro‐inflammatory priming effect of ischemia in KCs, leading to the inhibition of liver immune response against IR and protection of livers from IRI. In vitro, ATF6 siRNA abrogated the ER stress‐mediated pro‐inflammatory enhancement of macrophage TLR4 response, by restricting NF‐κB and restoring Akt activations. Thus, ischemia primes liver innate immune cells by ATF6‐mediated ER stress response. The IR‐induced metabolic stress and TLR activation function in synergy to activate tissue inflammatory immune response.
This study demonstrates that ischemia promotes pro‐inflammatory innate immune activation by activating ATF6 signaling pathways in murine liver ischemia and reperfusion injury.
The shortage of organs has led centers to expand their criteria for the acceptance of marginal donors. The combination of multiple marginal factors seems to be additive on graft injury. In this ...review, the utility of various marginal donors in patients requiring liver transplantation will be described, including older donors, steatotic livers, non-heart-beating donors, donors with viral hepatitis, and donors with malignancies. The pathophysiology of the marginal donor will be discussed, along with strategies for minimizing the ischemia reperfusion injury experienced by these organs. Finally, new strategies for improving the function of the marginal/expanded donor liver will be reviewed. (
Liver Transpl 2003;9:651-663.)
Invasive fungal infections (IFIs) are a common complication in liver transplant recipients. There are no previous randomized trials of an echinocandin for the prevention of IFIs in solid organ ...transplant recipients. In a randomized, double‐blind trial conducted at University‐affiliated transplant centers, 200 high‐risk liver transplant recipients (100 patients per group) received either anidulafungin or fluconazole for antifungal prophylaxis. Randomization was stratified by Model for End‐Stage Liver Disease score ≥30 and receipt of a pretransplant antifungal agent. The primary end point was IFI in a modified intent‐to‐treat analysis. The overall incidence of IFI was similar for the anidulafungin (5.1%) and the fluconazole groups (8.0%) (OR 0.61, 95% CI 0.19–1.94, p = 0.40). However, anidulafungin prophylaxis was associated with less Aspergillus colonization or infection (3% vs. 9%, p = 0.08), lower breakthrough IFIs among patients who had received pretransplant fluconazole (0% vs. 27%, p = 0.07), and fewer cases of antifungal resistance (no cases vs. 5 cases). Both drugs were well‐tolerated. Graft rejection, fungal‐free survival, and mortality were similar for both groups. Thus, anidulafungin and fluconazole have similar efficacy for antifungal prophylaxis in most liver transplant recipients. Anidulafungin may be beneficial if the patient has an increased risk for Aspergillus infection or received fluconazole before transplantation.
This randomized, double‐blind trial shows that anidulafungin and fluconazole have similar efficacy for antifungal prophylaxis in most liver transplant recipients at high risk for invasive fungal infections, although anidulafungin may be beneficial for patients who have an increased risk for Aspergillus infection or received fluconazole before transplantation. See editorial by Huprikar on page 2683.
Liver transplantation is the gold standard of care in patients with end‐stage liver disease and those with tumors of hepatic origin in the setting of liver dysfunction. From 1988 to 2009, liver ...transplantation in the United States grew 3.7‐fold from 1713 to 6320 transplants annually. The expansion of liver transplantation is chiefly driven by scientific breakthroughs that have extended patient and graft survival well beyond those expected 50 years ago. The success of liver transplantation is now its primary obstacle, as the pool of donor livers fails to keep pace with the growing number of patients added to the national liver transplant waiting list. This review focuses on three major challenges facing liver transplantation in the United States and discusses new areas of investigation that address each issue: (1) the need for an expanded number of useable donor organs, (2) the need for improved therapies to treat recurrent hepatitis C after transplantation and (3) the need for improved detection, risk stratification based upon tumor biology and molecular inhibitors to combat hepatocellular carcinoma.
The authors discuss three critical obstacles that confront the field of liver transplantation today and identify solutions that can expand organ transplantation and improve care for a population in need.
The presence of an intrahepatic cholangiocarcinoma (iCCA) in a cirrhotic liver is a contraindication for liver transplantation in most centers worldwide. Recent investigations have shown that “very ...early” iCCA (single tumors ≤2 cm) may have acceptable results after liver transplantation. This study further evaluates this finding in a larger international multicenter cohort. The study group was composed of those patients who were transplanted for hepatocellular carcinoma or decompensated cirrhosis and found to have an iCCA at explant pathology. Patients were divided into those with “very early” iCCA and those with “advanced” disease (single tumor >2 cm or multifocal disease). Between January 2000 and December 2013, 81 patients were found to have an iCCA at explant; 33 had separate nodules of iCCA and hepatocellular carcinoma, and 48 had only iCCA (study group). Within the study group, 15/48 (31%) constituted the “very early” iCCA group and 33/48 (69%) the “advanced” group. There were no significant differences between groups in preoperative characteristics. At explant, the median size of the largest tumor was larger in the “advanced” group (3.1 2.5‐4.4 versus 1.6 1.5‐1.8). After a median follow‐up of 35 (13.5‐76.4) months, the 1‐year, 3‐year, and 5‐year cumulative risks of recurrence were, respectively, 7%, 18%, and 18% in the very early iCCA group versus 30%, 47%, and 61% in the advanced iCCA group, P = 0.01. The 1‐year, 3‐year, and 5‐year actuarial survival rates were, respectively, 93%, 84%, and 65% in the very early iCCA group versus 79%, 50%, and 45% in the advanced iCCA group, P = 0.02. Conclusion: Patients with cirrhosis and very early iCCA may become candidates for liver transplantation; a prospective multicenter clinical trial is needed to further confirm these results. (Hepatology 2016;64:1178‐1188)
Extended gas clouds have been previously detected surrounding the brightest known close-in transiting hot Jupiter exoplanets, HD 209458 b and HD 189733 b; we observed the distant but more extreme ...close-in hot Jupiter system, WASP-12, with Hubble Space Telescope (HST). Near-UV (NUV) transits up to three times deeper than the optical transit of WASP-12 b reveal extensive diffuse gas, extending well beyond the Roche lobe. Our spectra reveal significantly enhanced absorption (greater than 3sigma below the median) at ~200 individual wavelengths on each of two HST visits; 65 of these wavelengths are consistent between the two visits, using a strict criterion for velocity matching that excludes matches with velocity shifts exceeding ~20 km s super(-1). Our Visit 2 NUV light curves show evidence for a stellar flare. We show that some of the possible transit detections in resonance lines of rare elements may be due instead to non-resonant transitions in common species. We present optical observations and update the transit ephemeris.
Ischemia/reperfusion (I/R) injury is a multifactorial process detrimental to liver graft function. An understanding of the mechanisms involved in I/R injury is essential for the design of therapeutic ...strategies to improve the outcome of liver transplantation. The generation of reactive oxygen species subsequent to reoxygenation inflicts tissue damage and initiates a cellular cascade leading to inflammation, cell death, and ultimate organ failure. The accruing evidence suggests that Kupffer cells and T cells mediate the activation of neutrophil inflammatory responses. Activated neutrophils infiltrate the injured liver in parallel with increased expression of adhesion molecules on endothelial cells. The heme oxygenase (HO) system is among the most critical of the cytoprotective mechanisms activated during the cellular stress, exerting anti-oxidant and anti-inflammatory functions, modulating the cell cycle, and maintaining the microcirculation. The activation of toll-like receptors (TLR) on Kupffer cells may provide the triggering signal for pro-inflammatory responses in the I/R injury sequence. Indeed, dissecting TLR downstream signaling pathways plays a fundamental role in exploring novel therapeutic strategies based on the concept that hepatic I/R injury represents a case for host “innate” immunity.
The Model for End‐Stage Liver Disease (MELD) system has dramatically increased the number of recipients requiring pretransplant renal replacement therapy (RRT) prior to liver transplantation (LT). ...Factors affecting post‐LT outcomes and the need for intraoperative RRT (IORRT) were analyzed in 500 consecutive recipients receiving pretransplant RRT, including comparisons among recipients not receiving IORRT (No‐IORRT, n = 401), receiving planned IORRT (Pl‐IORRT, n = 70), and receiving emergent, unplanned RRT after LT initiation (Em‐IORRT, n = 29). Despite a median MELD of 39, overall 30‐day, 1‐, 3‐ and 5‐year survivals were 93%, 75%, 68% and 65%, respectively. Em‐IORRT recipients had significantly more intraoperative complications (arrhythmias, postreperfusion syndrome, coagulopathy) compared with both No‐IORRT and Pl‐IORRT and greater 30‐day graft loss (28% vs. 10%, p = 0.004) and need for retransplantation (24% vs. 10%, p = 0.099) compared with No‐IORRT. A risk score based on multivariate predictors of IORRT accurately identified recipients with chronic (sensitivity 84%, specificity 72%, concordance‐statistic c‐statistic 0.829) and acute (sensitivity 93%, specificity 61%, c‐statistic 0.776) liver failure requiring IORRT. In this largest experience of LT in recipients receiving RRT, we report excellent survival and propose a practical model that accurately identifies recipients who may benefit from IORRT. For this select group, timely initiation of IORRT reduces intraoperative complications and improves posttransplant outcomes.
This analysis of liver transplantation in high‐acuity recipients receiving pretransplant renal replacement therapy reports excellent long‐term survival and describes a novel predictive model to identify the subset of recipients who may benefit from intraoperative renal replacement therapy.
Abstract
We measured the chromospheric activity of the four hot Jupiter hosts WASP-43, WASP-51/HAT-P-30, WASP-72 and WASP-103 to search for anomalous values caused by the close-in companions. The ...Mount Wilson Ca ii H & K S-index was calculated for each star using observations taken with the Robert Stobie Spectrograph at the Southern African Large Telescope. The activity level of WASP-43 is anomalously high relative to its age and falls among the highest values of all known main-sequence stars. We found marginal evidence that the activity of WASP-103 is also higher than expected from the system age. We suggest that for WASP-43 and WASP-103 star–planet interactions (SPI) may enhance the Ca ii H & K core emission. The activity levels of WASP-51/HAT-P-30 and WASP-72 are anomalously low, with the latter falling below the basal envelope for both main-sequence and evolved stars. This can be attributed to circumstellar absorption due to planetary mass-loss, though absorption in the interstellar medium may contribute. A quarter of known short-period planet hosts exhibit anomalously low activity levels, including systems with hot Jupiters and low-mass companions. Since SPI can elevate and absorption can suppress the observed chromospheric activity of stars with close-in planets, their Ca ii H & K activity levels are an unreliable age indicator. Systems where the activity is depressed by absorption from planetary mass-loss are key targets for examining planet compositions through transmission spectroscopy.
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