CD4+ T cells, upon activation and expansion, develop into different T helper cell subsets with different cytokine profiles and distinct effector functions. Until recently, T cells were divided into Th1 or Th2 cells, depending on the cytokines they produce. A third subset of IL-17-producing effector T helper cells, called Th17 cells, has now been discovered and characterized. Here, we summarize the current information on the differentiation and effector functions of the Th17 lineage. Th17 cells produce IL-17, IL-17F, and IL-22, thereby inducing a massive tissue reaction owing to the broad distribution of the IL-17 and IL-22 receptors. Th17 cells also secrete IL-21 to communicate with the cells of the immune system. The differentiation factors (TGF-β plus IL-6 or IL-21), the growth and stabilization factor (IL-23), and the transcription factors (STAT3, RORγt, and RORα) involved in the development of Th17 cells have just been identified. The participation of TGF-β in the differentiation of Th17 cells places ...

IL-17 and Th17 Cells.

The hepatic stellate cell has surprised and engaged physiologists, pathologists, and hepatologists for over 130 years, yet clear evidence of its role in hepatic injury and fibrosis only emerged following the refinement of methods for its isolation and characterization. The paradigm in liver injury of activation of quiescent vitamin A-rich stellate cells into proliferative, contractile, and fibrogenic myofibroblasts has launched an era of astonishing progress in understanding the mechanistic basis of hepatic fibrosis progression and regression. But this simple paradigm has now yielded to a remarkably broad appreciation of the cell's functions not only in liver injury, but also in hepatic development, regeneration, xenobiotic responses, intermediary metabolism, and immunoregulation. Among the most exciting prospects is that stellate cells are essential for hepatic progenitor cell amplification and differentiation. Equally intriguing is the remarkable plasticity of stellate cells, not only in their variable intermediate filament phenotype, but also in their functions. Stellate cells can be viewed as the nexus in a complex sinusoidal milieu that requires tightly regulated autocrine and paracrine cross-talk, rapid responses to evolving extracellular matrix content, and exquisite responsiveness to the metabolic needs imposed by liver growth and repair. Moreover, roles vital to systemic homeostasis include their storage and mobilization of retinoids, their emerging capacity for antigen presentation and induction of tolerance, as well as their emerging relationship to bone marrow-derived cells. As interest in this cell type intensifies, more surprises and mysteries are sure to unfold that will ultimately benefit our understanding of liver physiology and the diagnosis and treatment of liver disease.

/pdf/hepatic-stellate-cells-protean-multifunctional-and-enigmatic-1ctrvjmfhn.pdf

Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver

Meta-analyses of studies yielding sex-specific risk of potentially traumatic events (PTEs) and posttraumatic stress disorder (PTSD) indicated that female participants were more likely than male participants to meet criteria for PTSD, although they were less likely to experience PTEs. Female participants were more likely than male participants to experience sexual assault and child sexual abuse, but less likely to experience accidents, nonsexual assaults, witnessing death or injury, disaster or fire, and combat or war. Among victims of specific PTEs (excluding sexual assault or abuse), female participants exhibited greater PTSD. Thus, sex differences in risk of exposure to particular types of PTE can only partially account for the differential PTSD risk in male and female participants.

/pdf/sex-differences-in-trauma-and-posttraumatic-stress-disorder-2z87gssboo.pdf

Sex differences in trauma and posttraumatic stress disorder: a quantitative review of 25 years of research.

EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis

EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis.

Kupffer cells (KC) constitute 80-90% of the tissue macrophages present in the body. They reside within the lumen of the liver sinusoids, and are therefore constantly exposed to gut-derived bacteria, microbial debris and bacterial endotoxins, known to activate macrophages. Upon activation KC release various products, including cytokines, prostanoides, nitric oxide and reactive oxygen species. These factors regulate the phenotype of KC themselves, and the phenotypes of neighboring cells, such as hepatocytes, stellate cells, endothelial cells and other immune cells that traffic through the liver. Therefore, KC are intimately involved in the liver's response to infection, toxins, ischemia, resection and other stresses. This review summarizes established basic concepts of KC function as well as their role in the pathogenesis of various liver diseases.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1478-3231.2006.01342.x

Role of Kupffer cells in host defense and liver disease.

Tauroursodeoxycholic acid inserts the apical conjugate export pump, Mrp2, into canalicular membranes and stimulates organic anion secretion by protein kinase C-dependent mechanisms in cholestatic rat liver.

Preservation injury of the liver: mechanisms and novel therapeutic strategies.

Long-term therapy and retreatment of hepatorenal syndrome type 1 with ornipressin and dopamine.

Temporary clamping of the portal triad, ie, inflow occlusion by the Pringle maneuver,1 is a common strategy to minimize bleeding during hepatic resection. However, portal triad clamping can induce relevant ischemia reperfusion injury (IRI) and failure of the remnant liver.2–7 Because prolonged ischemia is frequently unavoidable to achieve radical tumor resection,2 therapeutic strategies to minimize IRI are needed.

The precise sequence of events leading to IRI following warm liver ischemia has not been completely elucidated. However, there is substantial evidence that activation of Kupffer cells (KC), the generation of reactive oxygen species, (ROS) and disturbances of the hepatic microcirculation contribute to reperfusion injury.6,8–12 During reperfusion activated KC produce mediators of inflammation and release ROS into the sinusoidal space.6,12 The resulting vascular oxidant stress has been discovered as potential mechanism of hepatic perfusion failure.13–16 ROS can activate redox-sensitive transcription factors, thereby activating proinflammatory genes and adding to the hepatic damage.17,18 Furthermore, ROS may contribute to the activation of calcium–dependent proteases (calpains)19 which mediate several intracellular processes resulting in necrotic or apoptotic cell death.20,21

Thus, ROS can be considered as signal molecules, which trigger several pivotal mechanisms of reperfusion injury. Consequently, antioxidant strategies appear a promising approach to prevent hepatic reperfusion injury.10 Recent studies investigated the therapeutic potential of the endogenous antioxidant glutathione (GSH), in particular since it has a low toxicity in humans22 and is cost-effective. Earlier studies indicated that GSH is able to react spontaneously with nearly all oxidants formed during inflammation.23–25 Subsequent studies demonstrated that GSH released through the GSH transporter of hepatocytes may act as an endogenous defense system against KC–derived ROS, thereby protecting the hepatic vasculature from damage by KC.8 The hepatic GSH content which can decrease rapidly during preoperative starvation is pivotal for this defense system.26 Thus, any intervention increasing hepatic or plasma GSH levels should convey protection against reperfusion injury. Compounds with potential therapeutic value include N–acetylcysteine,27 methionine,28 glutathione esters29 but also GSH itself. As shown recently in vitro, treatment of cold preserved livers with 2 or 4 mM GSH upon reperfusion prevented cell damage to hepatocytes in the model of cell-free rat liver perfusion.30

Therefore, the purpose of this study was to test the hypothesis that intravenous administration of GSH protects the rat liver against reperfusion injury after prolonged warm ischemia in vivo. In particular, the aims of the current study were: to investigate a potential influence of intravenously applied GSH on necrotic and apoptotic cell death, disturbances of the hepatic microcirculation and animal survival and to determine the functional significance of changes of the extra- and intracellular antioxidant capacity.

Manfred Bilzer

Papers

Role of Kupffer cells in host defense and liver disease.

Tauroursodeoxycholic acid inserts the apical conjugate export pump, Mrp2, into canalicular membranes and stimulates organic anion secretion by protein kinase C-dependent mechanisms in cholestatic rat liver.

Preservation injury of the liver: mechanisms and novel therapeutic strategies.

Long-term therapy and retreatment of hepatorenal syndrome type 1 with ornipressin and dopamine.

Glutathione protects the rat liver against reperfusion injury after prolonged warm ischemia.