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Following liver injury, hepatic stellate cells (HSC) undergo proliferation and migrate into damaged areas in response to chemotactic factors. HSC have been shown to regulate leukocyte trafficking by secreting monocyte chemotactic protein-1 (MCP-1), a chemokine that recruits monocytes and lymphocytes. In this study, we explored whether MCP-1 exerts biological actions on HSC. HSC were isolated from normal human livers, cultured on plastic, and studied in their myofibroblast-like phenotype, and three different cells lines were used. Chemotaxis was measured in modified Boyden chambers. The tissue response to injury involves the coordinated recruitment and activation of a number of cells in the attempt to repair the damage provoked by toxic, infectious, or immunological mechanisms. Inflammatory cells recruited at sites of damage are responsible for the scavenging of the necrotic cells, whereas myofibroblasts secrete extracellular matrix components and restore the integrity of the tissue. Within the liver, hepatic stellate cells (HSC) are responsible for this second part of the wound-healing response. 1,2 In normal liver, HSC fulfill the role of retinoid storage and metabolism, and their phenotype is referred to as quiescent. However, following injury, HSC undergo differentiation toward an activated phenotype characterized by proliferation and increased secretion of extracellular matrix components. This process is associated with enhanced or de novo expression of receptors for several soluble mediators, such as platelet-derived growth factor (PDGF), transforming growth factor-␤, or thrombin, which mediate the increase in cell proliferation and extracellular matrix production. [3][4][5] Therefore, HSC are the main cell type involved in the deposition of matrix that leads to fibrosis and cirrhosis. Another feature of cells involved in tissue repair is their ability to migrate into the damaged areas according to concentration gradients of chemotactic factors. 6 We have recently shown that HSC share this ability to respond to chemotactic factors such as PDGF. 7 Recent investigation has pointed out additional characteristics of the HSC that are relevant for the hepatic wound healing response. 2 HSC have been shown to express several molecules that are capable of regulating leukocyte trafficking, including chemokines. [8][9][10][11][12] These latter are a group of cytokines that exhibit chemoattractant properties for relatively specific groups of leukocytes. Four classes of chemokines have been recognized according to the position of conserved cysteine residues and differences in the spectrum of target cells. 13 The group of CXC chemokines includes a variety of factors, such as interleukin-8, which are mainly, but not exclusively, chemotactic for neutrophils. 13 Lymphotactin, a cytokine that specifically attracts lymphocytes, is the only known member of the C class of chemokines. 13 A novel cell-associated chemokine characterized by a CX3C motif and higher molecular weight has been recently identified. 14 Chemokines of the ...

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Late hepatic artery thrombosis (HAT) is a rare complication after orthotopic liver transplantation (OLT), conventionally described as occurring more than 30 days after surgery. Only a few reports document its course. In a consecutive series of 634 OLTs (704 grafts), 11 patients (1.7%) had late HAT, diagnosed a median of 6 months (range, 1.8 to 79 months) after OLT. Clinical variables were compared with those of 415 patients without HAT who had a complete database and follow-up, including cytomegalovirus (CMV) surveillance. At presentation, 11 patients had fever, 4 patients had jaundice. Hepatic abscesses were present in 6 patients (3 patients with biliary leak), 4 patients had biliary tree necrosis (2 patients with biliary leak), and 1 patient had no biliary complications. Five patients (45%) underwent accessory hepatic artery anastomosis versus 73 patients (17%) without HAT (P < .05). Five patients (45%) with late HAT had CMV infection versus 14% without HAT (P < .05). Two episodes of late HAT (11 and 79 months) occurred in patients who underwent re-OLT for early HAT (3.9%). Re-OLT was performed in 8 patients a median of 11 days (range, 3 to 37 days) after diagnosis (preceded by intravenous antibiotics and percutaneous drainage). The other 3 patients underwent partial hepatectomy (1 patient), external percutaneous drainage as unfit for surgery (1 patient), and antibiotic therapy only (1 patient). Death occurred in 4 patients who underwent re-OLT (50%) because of septicemia at 11, 23, and 60 days after re-OLT and 17 days after a third OLT. There was one late death (30 months) after partial hepatectomy (hepatitis C recurrence) and one death 6 months after long-term biliary drainage because of sepsis. The 5 survivors have good health with normal liver function test results at a median 52 months (range, 6 to 57 months). In conclusion, late HAT presents with fever caused by hepatic abscesses or biliary leak associated with biliary ischemia and necrosis. CMV infection and accessory hepatic artery anastomosis are risk factors for late HAT in our cohort. Early intervention followed by re-OLT can salvage patients. (Liver Transpl 2003;9: 605-611.) H epatic artery thrombosis (HAT) after orthotopic liver transplantation (OLT) is a potentially lifethreatening complication that occurs in 1.6% to 10.5% of adult liver transplant recipients and 10% to 25% of pediatric cadaver recipients. 1-3 HAT carries a mortality rate of 27% to 58%. 1,4,5 When re-OLT is not performed, the mortality rate increases to 73%. 5 HAT occurring early after OLT is associated with acute fulminant hepatic failure, biliary tract necrosis and leaks, or relapsing bacteremia and results in a high rate of graft loss and patient mortality. Late HAT generally is associated with a milder clinical course than acute HAT. [6][7][8] The time that divides early and late HAT has not been agreed on. Because technical aspects and surgical complications are associated with HAT development in the first 30 days after OLT, it is common practice to use 1 month from OLT to d...

. Differential requirement of members of the MAPK family for CCL2 expression by hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol 287: G18 -G26, 2004. First published March 11, 2004 10.1152/ajpgi.00336. 2003.-Hepatic stellate cells (HSC) coordinate the liver wound-healing response through secretion of several cytokines and chemokines, including CCL2 (formerly known as monocyte chemoattractant protein-1). In this study, we evaluated the role of different proteins of the MAPK family (ERK, p38 MAPK , and JNK) in the regulation of CCL2 expression by HSC, as an index of their proinflammatory activity. Several mediators activated all three MAPK, including TNF, IL-1, and PDGF. To assess the relative role of the different MAPKs, specific pharmacological inhibitors were used; namely, SB203580 (p38 MAPK ), SP600125 (JNK), and PD98059 (MEK/ERK). The efficacy and specificity of the different inhibitors in our cellular system were verified analyzing the enzymatic activity of the different MAPKs using in vitro kinase assays and/or testing the inhibition of phosphorylation of downstream substrates. SB203580 and SP600125 dose-dependently inhibited CCL2 secretion and gene expression induced by IL-1 or TNF. In contrast, inhibition of ERK did not affect the upregulation of CCL2 induced by the two cytokines. Finally, activin A was also found to stimulate CCL2 expression and to activate ERK, JNK, p38, and their downstream targets. Unlike in cells exposed to proinflammatory cytokines, all three MAPKs were required to induce CCL2 secretion in response to activin. We conclude that members of the MAPK family differentially regulate cytokine-induced chemokine expression in human HSC. activin; chemokines; fibrosis; platelet-derived growth factor STUDIES CONDUCTED IN DIFFERENT laboratories have highlighted the importance of hepatic stellate cells (HSC) in the pathophysiology of the liver response to injury (30). HSC are not only the major matrix-producing cells during chronic liver injury, but they contribute to the modulation of the liver "wound-healing" response through several biological actions. A critical aspect of acute and chronic tissue damage is represented by the recruitment of inflammatory cells, and HSC have been shown to modulate the inflammatory response via secretion of several soluble mediators that regulate the recruitment and activation of leukocytes (reviewed in Ref. 20). In general, low expression of these mediators in quiescent HSC becomes dramatically upregulated on activation, suggesting that the modulation of inflammation occurs in conditions associated with tissue injury and the transition of HSC to a myofibroblastlike phenotype.The chemokine family of cytokines is a large group of proteins capable of regulating migration of target cells via activation of specific membrane receptors (1). Chemokine receptors were initially identified on leukocytes, and several studies (25) have investigated the role of chemokines in the regulation of inflammatory cell recruitment in conditions of liver injury. However...

CMV viremia as detected by PCR does not affect the progression of HCV recurrence in liver grafts.

Cirrhosis due to hepatitis C is now the commonest indication for liver transplantation in Western Europe and in the United States. Graft reinfection is almost universal. The natural history of recurrent hepatitis C ranges from minimal damage to cirrhosis in a few months or years. Different virus and host immune factors are involved in the pathogenesis of hepatitis and are determinants of the outcome. The association between immunosuppression and severity of HCV recurrence is conflicting and remains to be evaluated fully. The treatment of recurrent HCV disease with IFN or ribavirin, as monotherapy, is ineffective. Preliminary results from combination therapy, however, are encouraging. Currently, a reasonable approach would be to treat patients with histological and clinical disease progression. New approaches for the prophylaxis of recurrent hepatitis C are under evaluation but whether this treatment will influence the severity of liver disease or the outcome of recurrence is still unknown.