Neutralization of CXCL10 accelerates liver regeneration in carbon tetrachloride-induced acute liver injury

Remodeling of hepatic tissue structure following injury requires the coordinated action of hepatocytes, hepatic stellate cells (HSCs), and endothelial cells. However, their in vivo properties are not fully understood. We report here that the chemokine CXCL10 regulates hepatic tissue remodeling in a carbon tetrachloride (CCl(4))-induced acute liver injury in mice. The production of CXCL10 was enhanced by hepatocytes after CCl(4) exposure. Neutralization of CXCL10 protected mice from acute liver dysfunction and diminished hepatocellular loss. The hepatoprotective effect was associated with increased numbers of 5'-bromo-2' deoxyuridine (BrdU)+ hepatocytes from day 1 and with accumulation of HSCs and endothelial cells within the injured zones from day 3. In vitro, recombinant CXCL10 directly inhibited the proliferation of hepatocytic cells, establishing a novel role of CXCL10 in modulating hepatocyte proliferation, in addition to a previously reported angiostatic role. In summary, neutralization of CXCL10 initially stimulates hepatocyte proliferation and, subsequently, HSC migration and angiogenesis to facilitate remodeling of hepatic cords. Thus, CXCL10 can be a novel therapeutic target for acute hepatocellular damage by regulating liver tissue remodeling.     

Role of neutrophils in the pathogenesis of acute inflammatory liver injury

Polymorphonuclear leukocytes (neutrophils) are essential in the defense against invading microorganisms, tissue trauma or any inciting inflammatory signals. Hepatic infiltration of neutrophils is an acute response to recent or ongoing liver injury, hepatic stress or unknown systemic inflammatory signals. Once neutrophils reach the liver, they can cause mild-to-severe tissue damage and consequent liver failure. For neutrophils to appear in the liver, neutrophils have to undergo systemic activation (priming) by inflammatory mediators such as cytokines, chemokines, complement factors, immune complexes, opsonized particles and other biologically active molecules, e.g., platelet activating factor. Neutrophils accumulated in the hepatic microvasculature (sinusoids and postsinusoidal venules) can extravasate (transmigrate) into the hepatic parenchyma if they receive a signal from distressed cells. Transmigration can be mediated by a chemokine gradient established towards the hepatic parenchyma and generally involves orchestration by adhesion molecules on neutrophils (beta(2) integrins) and on endothelial cells (intracellular adhesion molecules, ICAM-1). After transmigration, neutrophils adhere to distressed hepatocytes through their beta(2) integrins and ICAM-1 expressed on hepatocytes. Neutrophil contact with hepatocytes mediate oxidative killing of hepatocytes by initiation of respiratory burst and neutrophil degranulation leading to hepatocellular oncotic necrosis. Neutrophil-mediated liver injury has been demonstrated in a variety of diseases and chemical/drug toxicities. Relevant examples are discussed in this review.     

GRPR antagonist protects from drug‐induced liver injury by impairing neutrophil chemotaxis and motility

Drug‐induced liver injury (DILI) is a major cause of acute liver failure (ALF), where hepatocyte necrotic products trigger liver inflammation, release of CXC chemokine receptor 2 (CXCR2) ligands (IL‐8) and other neutrophil chemotactic molecules. Liver infiltration by neutrophils is a major cause of the life‐threatening tissue damage that ensues. A GRPR (gastrin‐releasing peptide receptor) antagonist impairs IL‐8‐induced neutrophil chemotaxis in vitro. We investigated its potential to reduce acetaminophen‐induced ALF, neutrophil migration, and mechanisms underlying this phenomenon. We found that acetaminophen‐overdosed mice treated with GRPR antagonist had reduced DILI and neutrophil infiltration in the liver. Intravital imaging and cell tracking analysis revealed reduced neutrophil mobility within the liver. Surprisingly, GRPR antagonist inhibited CXCL2‐induced migration in vivo, decreasing neutrophil activation through CD11b and CD62L modulation. Additionally, this compound decreased CXCL8‐driven neutrophil chemotaxis in vitro independently of CXCR2 internalization, induced activation of MAPKs (p38 and ERK1/2) and downregulation of neutrophil adhesion molecules CD11b and CD66b. In silico analysis revealed direct binding of GRPR antagonist and CXCL8 to the same binding spot in CXCR2. These findings indicate a new potential use for GRPR antagonist for treatment of DILI through a mechanism involving adhesion molecule modulation and possible direct binding to CXCR2.     

Human Thy-1 induces secretion of matrix metalloproteinase-9 and CXCL8 from human neutrophils

Neutrophils are the first cells arriving at sites of acute inflammation. On their way from blood to the site of inflammation, neutrophils have to adhere to endothelial cells (EC), to transverse the basement membrane and subsequently to travel through the interstitial matrix. Recently, we have shown that human Thy-1 is an alternate EC receptor for the leukocyte integrin Mac-1 that contributes to leukocyte recruitment to sites of inflammation, providing a new pathway for adhesion and transmigration of neutrophils. Here, we studied the effect of Thy-1-mediated adhesion on neutrophil functions. Binding of neutrophils to recombinant human Thy-1 stimulated the release of MMP-9 from neutrophils, resulting in their enhanced migration through collagen-IV and matrigel. Further, we showed that neutrophil interaction with Thy-1 stimulated secretion of CXCL8 and thus could support the attraction of additional neutrophils to inflammatory sites. Blocking experiments confirmed the pivotal roles of Thy-1 on activated dermal EC or fibroblasts and its counter receptor CD18 on neutrophils for the regulation of MMP-9 and CXCL8 release from neutrophils. Our results support the general concept that the function of 'adhesion molecules' in particular of human Thy-1, may not only be to provide mechanical support but also regulate neutrophil functions.     

Neutrophil infiltration to the brain is platelet‐dependent,and is reversed by blockade of platelet GPIbα

Neutrophils are key components of the innate immune response, providing host defence against infection and being recruited to non‐microbial injury sites. Platelets act as a trigger for neutrophil extravasation to inflammatory sites but mechanisms and tissue‐specific aspects of these interactions are currently unclear. Here, we use bacterial endotoxin in mice to trigger an innate inflammatory response in different tissues and measure neutrophil invasion with or without platelet reduction. We show that platelets are essential for neutrophil infiltration to the brain, peritoneum and skin. Neutrophil numbers do not rise above basal levels in the peritoneum and skin and are decreased (~60%) in the brain when platelet numbers are reduced. In contrast neutrophil infiltration in the lung is unaffected by platelet reduction, up‐regulation of CXCL‐1 (2·4‐fold) and CCL5 (1·4‐fold) acting as a compensatory mechanism in platelet‐reduced mice during lung inflammation. In brain inflammation targeting platelet receptor GPIbα results in a significant decrease (44%) in platelet‐mediated neutrophil invasion, while maintaining platelet numbers in the circulation. These results suggest that therapeutic blockade of platelet GPIbα could limit the harmful effects of excessive inflammation while minimizing haemorrhagic complications of platelet reduction in the brain. The data also demonstrate the ability to target damaging brain inflammation in stroke and related disorders without compromising lung immunity and hence risk of pneumonia, a major complication post stroke. In summary, our data reveal an important role for platelets in neutrophil infiltration to various tissues, including the brain, and so implicate platelets as a key, targetable component of cerebrovascular inflammatory disease or injury.     

Liver sinusoidal endothelial cells induce immunosuppressive IL‐10‐producing Th1 cells via the Notch pathway

Under homeostasis, liver sinusoidal endothelial cells (LSECs) shift intrahepatic T‐cell responses towards tolerance. However, the role of LSECs in the regulation of T‐cell‐induced liver inflammation is less clear. Here, we studied the capacity of LSECs to modulate pro‐inflammatory Th1‐cell differentiation in mice. Using in vitro co‐culture systems and subsequent cytokine analysis, we showed that LSECs induced high amounts of the anti‐inflammatory cytokine IL‐10 in developing Th1 cells. These LSEC‐stimulated Th1 cells had no pro‐inflammatory capacity in vivo but instead actively suppressed an inflammatory Th1‐cell‐induced delayed‐type hypersensitivity reaction. Blockage of IL‐10 signaling in vivo inhibited immunosuppressive activity of LSEC‐stimulated Th1 cells. We identified the Notch pathway as a mechanism how LSECs trigger IL‐10 expression in Th1 cells. LSECs expressed high levels of the Delta‐like and Jagged family of Notch ligands and induced expression of the Notch target genes hes‐1 and deltex‐1 in Th1 cells. Blockade of Notch signaling selectively inhibited IL‐10 induction in Th1 cells by LSECs. Our findings suggest that LSEC‐induced IL‐10 expression in Th1 cells via the Notch pathway may contribute to the control of hepatic inflammatory immune responses by induction of a self‐regulatory mechanism in pro‐inflammatory Th1 cells.     

Tissue-specific ICAM-1 expression and neutrophil transmigration in the copper-deficient rat

Dietary copper deficiency promotes neutrophil accumulation in rat lungs. We have now investigated the potential mechanisms of this effect. Male weanling rats were fed a Cu-adequate (6.0 mg diet) or Cu-deficient diet (0.30 mg) for 4 wks. Endothelial intercellular adhesion molecule-1 (ICAM-1) expression was measured in vivo and in vitro using a radiolabeled monoclonal antibody to rat ICAM-1. Tissue neutrophil accumulation was measured by myeloperoxidase (MPO) content and neutrophil transendothelial migration was assessed in vitro. Dietary copper deficiency had no effects on the expression of ICAM-1 in lung, liver, heart, kidney, or cremaster. However, MPO content was significantly greater in the lungs of copper-deficient rats. Endotoxin-induced ICAM-1 expression was greater in the lungs and hearts of copper-deficient rats. Similarly, cultured rat endothelial cells that were Cu-chelated expressed more ICAM-1 after endotoxin. This correlated with the significant increase in MPO in lungs of copper-deficient rats treated with endotoxin. The results suggest a tissue-specific difference in ICAM-1 expression and neutrophil accumulation during inflammation in copper-deficient rats. The findings suggest that lung inflammatory mechanisms are particularly sensitive to copper deficiency.     

Hepatic ischemia/reperfusion injury--a fresh look

Ischemia/reperfusion (I/R) injury is a multifactorial process that affects graft function after liver transplantation. 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 cascade of deleterious cellular responses leading to inflammation, cell death, and ultimate organ failure. Increased experimental evidence has suggested 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 system is among the most critical of the cytoprotective mechanisms activated during cellular stress, exerting antioxidant and anti-inflammatory functions, modulating the cell cycle, and maintaining the microcirculation. Finally, the activation of toll-like receptors on Kupffer cells may play a fundamental role in exploring new therapeutic strategies based on the concept that hepatic I/R injury represents a case for a host "innate" immunity.     

Involvement of up-regulated CXC chemokine ligand 16/scavenger receptor that binds phosphatidylserine and oxidized lipoprotein in endotoxin-induced lethal liver injury via regulation of T-cell recruitment and adhesion

A murine model of endotoxin-induced lethal liver injury induced by Mycobacterium bovis BCG plus lipopolysaccharide (LPS) has been widely accepted and used. It has been reported that T cells play an important role in the pathogenesis of liver damage in this model. However, the precise mechanisms involved in regulation of the trafficking of effector T cells need to be elucidated. In the present study, we first reported that CXCL16/SR-PSOX (CXC chemokine ligand 16/scavenger receptor that binds phosphatidylserine and oxidized lipoprotein), a chemokine containing both membrane-anchored and soluble forms, was strongly up-regulated and predominantly distributed in the vascular endothelium in the injured liver tissue in the model. The secretory and membrane-anchored CXCL16/SR-PSOX functioned as a chemokine and an adhesive molecule, respectively, to attract T cells to a tumor necrosis factor alpha-activated endothelial cell line (SVEC) in vitro. To further identify the pathophysiological roles of CXCL16/SR-PSOX in the liver injury, the anti-CXCL16 antibody was administered to the BCG-primed mice before LPS challenge in vivo. Significant protection effects were observed with 70% of mice regarding lethality, the massive necrosis in the liver was reduced, and the intrahepatic infiltrating T cells were significantly inhibited. Taken together, these findings strongly suggest that functional CXCL16/SR-PSOX, as both a chemokine and an adhesion molecule, may be involved in the pathogenesis of the endotoxin-induced lethal liver injury via recruitment and adhesion of activated T cells to the vascular endothelium.     

Involvement of the CXCL12/CXCR4 pathway in the advanced liver disease that is associated with hepatitis C virus or hepatitis B virus

Chronic hepatitis C virus (HCV) and hepatitis B virus (HBV) infection is accompanied by inflammation and fibrosis eventually leading to cirrhosis. The chemokine CXCL12 is involved in chronic inflammatory conditions. The role of the CXCL12/CXCR4 pathway in HCV- and HBV-associated liver inflammation and fibrosis was therefore studied. The levels and tissue localization of CXCL12 in liver and plasma of HCV and HBV patients were tested using immunohistochemistry and ELISA. The expression and function of CXCR4 on liver-infiltrating lymphocytes (LIL) were tested by FACS and transwell migration assays. We found that CXCL12 is expressed by bile duct epithelial cells in normal liver tissue. Bile duct proliferation and liver fibrosis in chronic HCV and HBV infection result in the anatomical re-distribution of CXCL12 in the liver. Moreover, CXCL12 is up-regulated in the endothelium of neo-blood-vessels formed in active inflammatory foci and is significantly elevated, compared with controls, in the plasma of patients with advanced liver fibrosis. Complementing these observations were others indicating that over 50% of LIL express CXCR4 and, in response to CXCL12, migrated and adhered to fibronectin. These observations suggest an important role for the CXCL12/CXCR4 pathway in recruitment and retention of immune cells in the liver during chronic HCV and HBV infection.     

The role of endothelial cells in the resolution of acute inflammation

Endothelial cells are key regulators of the inflammatory response. Lining blood vessels, they provide in the steady state an antiinflammatory, anticoagulatory surface. However, in the case of injury or infection, endothelial cells control the adhesion and migration of inflammatory cells, as well as the exchange of fluid from the bloodstream into the damaged tissue. Thus, expression of endothelial adhesion molecules, cytokines, and changes in permeability need to be tightly regulated to allow for a controlled inflammatory response. Acute inflammation is characterized by tissue infiltration of neutrophils, followed by monocytes/macrophages. For successful tissue regeneration and healing, the acute inflammatory response needs to be actively shut down, a process called resolution of inflammation. Unsuccessful resolution may lead to excessive tissue damage and ultimately results in chronic, self-promoting inflammation. This review will summarize recent advances in the field of endothelial biology, which point to an active participation of the endothelial barrier in the resolving process.     

肝脏靶向表达趋化因子CXCL10 抑制ConA 诱导的肝脏损伤

目的:本研究探索趋化因子CXCL10 在免疫介导的肝脏损伤方面的作用及其作用机制。方法:尾静脉高压注 射CXCL10 表达载体72 h 后检测肝脏中CXCL10 的表达水平;再尾静脉注射刀豆蛋白(Concanavalin A,ConA)诱导免疫介导的 肝脏损伤;检测并比较CXCL10 表达组和对照组的谷丙转氨酶(Alanine aminotransferase,ALT)水平、组织损伤水平、,IFN-γ水 平、TNF-α水平及调节性T 细胞比例和数量的差异。结果:CXCL10 表达载体注射72 h 后,肝脏中CXCL10 的表达水平显著升 高;CXCL10 表达质粒预处理可以有效减轻ConA 诱导的肝脏损伤,CXCL10 表达组小鼠血清中的ALT 水平显著低于对照组, CXCL10 表达组小鼠血清中,IFN-γ和TNF-α的水平明显低于对照组,CXCL10 表达组小鼠肝脏中调节性T 细胞比例和数量高 于对照组。结论:趋化因子CXCL10 表达载体预处理可减少炎性细胞因子并减轻ConA 诱导的肝脏损伤,对治疗免疫介导的肝 炎具有重要意义。     

A C-terminal CXCL8 peptide based on chemokine–glycosaminoglycan interactions reduces neutrophil adhesion and migration during inflammation

Leucocyte recruitment is critical during many acute and chronic inflammatory diseases. Chemokines are key mediators of leucocyte recruitment during the inflammatory response, by signalling through specific chemokine G-protein-coupled receptors (GPCRs). In addition, chemokines interact with cell-surface glycosaminoglycans (GAGs) to generate a chemotactic gradient. The chemokine interleukin-8/CXCL8, a prototypical neutrophil chemoattractant, is characterized by a long, highly positively charged GAG-binding C-terminal region, absent in most other chemokines. To examine whether the CXCL8 C-terminal peptide has a modulatory role in GAG binding during neutrophil recruitment, we synthesized the wild-type CXCL8 C-terminal [CXCL8 (54–72)] (Peptide 1), a peptide with a substitution of glutamic acid (E) 70 with lysine (K) (Peptide 2) to increase positive charge; and also, a scrambled sequence peptide (Peptide 3). Surface plasmon resonance showed that Peptide 1, corresponding to the core CXCL8 GAG-binding region, binds to GAG but Peptide 2 binding was detected at lower concentrations. In the absence of cellular GAG, the peptides did not affect CXCL8-induced calcium signalling or neutrophil chemotaxis along a diffusion gradient, suggesting no effect on GPCR binding. All peptides equally inhibited neutrophil adhesion to endothelial cells under physiological flow conditions. Peptide 2, with its greater positive charge and binding to polyanionic GAG, inhibited CXCL8-induced neutrophil transendothelial migration. Our studies suggest that the E70K CXCL8 peptide, may serve as a lead molecule for further development of therapeutic inhibitors of neutrophil-mediated inflammation based on modulation of chemokine–GAG binding.     

Critical role of CXC chemokines in endotoxemic liver injury in mice

Tissue accumulation of leukocytes constitutes a rate-limiting step in endotoxin-induced tissue injury. Chemokines have the capacity to regulate leukocyte trafficking. However, the role of CXC chemokines, i.e., macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (KC), in leukocyte recruitment, microvascular perfusion failure, cellular injury, and apoptosis in the liver remains elusive. Herein, mice were challenged with lipopolysaccharide (LPS) in combination with D-galactosamine, and intravital microscopy of the liver microcirculation was conducted 6 h later. It was found that immunoneutralization of MIP-2 and KC did not reduce LPS-induced leukocyte rolling and adhesion in postsinusoidal venules. In contrast, pretreatment with monoclonal antibodies against MIP-2 and KC abolished (83% reduction) extravascular recruitment of leukocytes in the livers of endotoxemic mice. Notably, endotoxin challenge increased the expression of CXC chemokines, which was mainly confined to hepatocytes. Moreover, endotoxin-induced increases of liver enzymes and hepatocellular apoptosis were decreased by more than 82% and 68%, respectively, and sinusoidal perfusion was restored in mice passively immunized against MIP-2 and KC. In conclusion, this study indicates that intravascular accumulation of leukocytes in the liver is independent of CXC chemokines in endotoxemic mice. Instead, our novel data suggest that CXC chemokines are instrumental in regulating endotoxin-induced transmigration and extravascular tissue accumulation of leukocytes. Indeed, these findings demonstrate that interference with MIP-2 and KC functions protects against septic liver damage and may constitute a potential therapeutic strategy to control pathological inflammation in endotoxemia.     

Endothelial paxillin and focal adhesion kinase (FAK) play a critical role in neutrophil transmigration

During an inflammatory response, endothelial cells undergo morphological changes to allow for the passage of neutrophils from the blood vessel to the site of injury or infection. Although endothelial cell junctions and the cytoskeleton undergo reorganization during inflammation, little is known about another class of cellular structures, the focal adhesions. In this study, we examined several focal adhesion proteins during an inflammatory response. We found that there was selective loss of paxillin and focal adhesion kinase (FAK) from focal adhesions in proximity to transmigrating neutrophils; in contrast the levels of the focal adhesion proteins β1-integrin and vinculin were unaffected. Paxillin was lost from focal adhesions during neutrophil transmigration both under static and flow conditions. Down-regulating endothelial paxillin with siRNA blocked neutrophil transmigration while having no effect on rolling or adhesion. As paxillin dynamics are regulated partly by FAK, the role of FAK in neutrophil transmigration was examined using two complementary methods. siRNA was used to down-regulate total FAK protein while dominant-negative, kinase-deficient FAK was expressed to block FAK signaling. Disruption of the FAK protein or FAK signaling decreased neutrophil transmigration. Collectively, these findings reveal a novel role for endothelial focal adhesion proteins paxillin and FAK in regulating neutrophil transmigration.     

裸鼠肝窦内皮细胞的分离、培养及鉴定

背景：建立裸鼠肝窦内皮细胞的原代分离培养方法,进一步研究其生长特点及生物学特性。 目的：建立裸鼠肝窦内皮细胞的原代分离、培养方法,并鉴定其纯度及观察其生物学特性。   方法：无菌下摘除裸鼠肝脏,剪成 1 mm3大小,Ⅳ型胶原酶在 37 ℃恒温下消化,应用CD146免疫磁珠分选肝窦内皮细胞,在倒置显微镜观察内皮细胞形态及生长特性,用von-Willebrand因子免疫细胞化学验证分选细胞的表面蛋白表达,鉴定肝窦内皮细胞的纯度,Hochest 33342 测定凋亡。 结果与结论：分离的肝窦内皮细胞纯度达95%以上,活力好,光镜下可以看到典型的铺路石样形态,von-Willebrand因子免疫细胞化学染色阳性。肝窦内皮细胞在体外培养3周后凋亡。提示Ⅳ型胶原酶消化加CD146免疫磁珠分选肝窦内皮细胞纯度高,方法可靠。        

Diminished adhesion of Anaplasma phagocytophilum-infected neutrophils to endothelial cells is associated with reduced expression of leukocyte surface selectin

Anaplasma phagocytophilum propagates within neutrophils and causes a disease marked by inflammatory tissue injury or complicated by opportunistic infections. We hypothesized that infection with A. phagocytophilum modifies the binding of neutrophils to endothelial cells and the expression of neutrophil adhesion molecules and studied these changes in vitro. Infected dimethyl sulfoxide-differentiated HL-60 cells and neutrophils showed reduced binding to cultured brain and systemic endothelial cells and lost expression of P-selectin glycoprotein ligand 1 (PSGL-1, CD162) and L-selectin (CD62L) (to 33 and 5% of control values, respectively), at a time when the levels of beta(2) integrin and immunoglobulin superfamily adhesion molecules and activation markers Mac-1 and intercellular adhesion molecule 1 increased (5 to 10 times that of the control). The loss of CD162 and CD62L expression was inhibited by EDTA, which suggests that neutrophil activation and sheddase cleavage occurred. The loss of selectin expression and the retained viability of the neutrophils persisted for at least 18 h with A. phagocytophilum infection, whereas Escherichia coli and Staphylococcus aureus rapidly killed neutrophils. The adhesion defect might increase the numbers of infected cells and their persistence in the blood prior to tick bites. However, decreased CD162 expression and poor endothelial cell binding may partly explain impaired host defenses, while simultaneous neutrophil activation may aggravate inflammation. These observations may help us to understand the modified biological responses, host inflammation, and immune response that occur with A. phagocytophilum infections.     

IL-13 Activates STAT6 and Inhibits Liver Injury Induced by Ischemia/Reperfusion

Hepatic ischemia/reperfusion injury is initiated by the activation of Kupffer cells and their subsequent release of proinflammatory mediators, including tumor necrosis factor-alpha (TNFalpha). These mediators stimulate a cascade of events including up-regulation of CXC chemokines and vascular endothelial adhesion molecules, leading to hepatic neutrophil recruitment and tissue injury. Interleukin-13 (IL-13) is a cytokine that has been shown to suppress macrophage production of proinflammatory mediators. The objective of the current study was to determine whether IL-13 could regulate the liver inflammatory injury induced by ischemia and reperfusion. C57BL/6 mice underwent 90 minutes of partial hepatic ischemia followed by reperfusion with or without intravenous administration of recombinant murine IL-13. Hepatic ischemia/reperfusion increased expression of TNFalpha and macrophage inflammatory protein-2 (MIP-2), leading to hepatic neutrophil recruitment, hepatocellular injury, and liver edema. Administration of IL-13 reduced the production of TNFalpha and MIP-2 mRNA and protein. IL-13 suppressed liver neutrophil recruitment by up to 72% and hepatocellular injury and liver edema were each reduced by >60%. Administration of IL-13 had no effect on liver NFkappaB activation, but greatly increased the activation of STAT6. The data suggest that the hepatoprotective effects of IL-13 may be a result of STAT6 activation.     

Helicobacter-induced chronic active lymphoid aggregates have characteristics of tertiary lymphoid tissue

Susceptible strains of mice that are naturally or experimentally infected with murine intestinal helicobacter species develop hepatic inflammatory lesions that have previously been described as chronic active hepatitis. The inflammatory infiltrates in some models of chronic autoimmunity or inflammation resemble tertiary lymphoid organs hypothesized to arise by a process termed lymphoid organ neogenesis. To determine whether hepatic inflammation caused by infection with helicobacter could give rise to tertiary lymphoid organs, we used fluorescence-activated cell sorting, immunohistochemistry, and in situ hybridization techniques to identify specific components characteristic of lymphoid organs in liver tissue sections and liver cell suspensions from helicobacter-infected mice. Small venules (high endothelial venules [HEVs]) in inflammatory lesions in Helicobacter species-infected livers were positive for peripheral node addressin. Mucosal addressin cell adhesion molecule also stained HEVs and cells with a staining pattern consistent with scattered stromal cells. The chemokines SLC (CCL 21) and BLC (CXCL13) were present, as were B220-positive B cells and T cells. The latter included a na?ve (CD45lo-CD62Lhi) population. These findings suggest that helicobacter-induced chronic active hepatitis arises through the process of lymphoid organ neogenesis.     

Expression of cell adhesion molecules and their beta1 and beta2 integrin ligands in human liver peliosis

The expression of the following cell adhesion molecules and their beta1 and beta2 integrin ligands was investigated in the liver tissue from 3 patients with non-bacillar peliosis using light and electron microscope immunohistochemistry: intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, platelet endothelial cell adhesion molecule-1 (PECAM-1), leukocyte function-associated antigen-1 (LFA-1), macrophage antigen-1 (Mac-1), and very late antigen-4 (VLA-4). We found a parallel enhancement of the adhesion molecules expression in the dilated sinusoids and cavities in all 3 cases with peliosis. Mononuclear blood cells were detected in the sinusoids and sometimes perisinusoidally. These cells were mainly ICAM-1-, LFA-1-, and VLA-4-positive. At the ultrastructural level, ICAM-1-positive immune deposits were observed on the membrane of sinusoidal endothelial cells, Kupffer cells, and hepatocytes. The expression of cell adhesion molecules on liver sinusoids in peliosis is probably triggered by factors released from damaged endothelial cells and hepatocytes. The prevalence of the ICAM-1/LFA-1 and VCAM-1/VLA-4 patterns of mononuclear blood cell/sinusoidal cell interactions could support the macrophage-induced or lymphocyte-induced type of liver injury. PECAM-1 was also included in the non-specific immune response in peliosis. The presence of erythrostasis or thrombosis in liver sinusoids could participate in the induction of adhesion molecule expression in peliosis.