88 In a series of experiments that tested the role of acute phase

88 In a series of experiments that tested the role of acute phase proteins in our model of partial (30% graft) OLT in mice, we found that pentoxifylline (PTX) rescued the failure of regeneration and restored animal survival.89 PTX was found to confer its protective effects through enhanced production of IL-6, while down-regulating TNFα production, because the protective effects of PTX was lost in IL-6 knockout mice. This data also indicated that 3-deazaneplanocin A molecular weight IL-6 acts downstream to TNFα and that inhibition of TNFα, possibly resulting from the ischemic injury, might also be beneficial in this model. Similar data are available following

extensive hepatectomy, i.e., in the absence of the associated insults inherent to OLT such as ischemia/reperfusion injury. For example, IL-6 or the endogenous receptor

agonist cardiotrophin-1 rescued hepatocyte proliferation and animal survival in rodent models of 90% hepatectomy82 or ischemia/reperfusion injury.90 www.selleckchem.com/products/apo866-fk866.html However, chronic exposure to the cytokine IL-6 may cause deleterious effects by increasing proapoptotic proteins (Bax).91 Similar effects were documented for complement, which was permissive and protective only in a balanced low dose, but induced damage at higher doses.92 We conclude from these observations that there seems to be a labile equilibrium for acute phase cytokines during the initial phase of liver regeneration. Although regeneration cannot be triggered in the absence of these molecules, their excess may contribute to organ failure in the situation of extensive tissue loss or the presence of underlying

pathological conditions such as steatosis. Platelet-derived serotonin has recently been identified as a major contributing factor to liver regeneration.93 In a first set of experiments, antibody-mediated thrombocytopenia or various pharmacological inhibitions of platelet actions impaired 上海皓元 liver regeneration. To identify the critical component in platelets, mice lacking a rate-limiting enzyme (tryptophan hydroxylase-1) involved in the early step of peripheral serotonin biosynthesis, displayed blunted liver regeneration after hepatectomy. This defect was corrected with the use of 5-hydroxy tryptophan, a precursor of serotonin which does not require the action of tryptophan hydroxylase-1. In addition to the use of 5-hydroxy tryptophan receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) restored regeneration in mice deficient in tryptophan hydroxylase-1.93 Similar results were observed in our model of partial (30%) OLT. The use of DOI reversed the failure of hepatocyte proliferation and rescued animal survival.94 These effects appeared independent from the IL-6 pathway, i.e., from the protective effects of PTX. Others found that thrombocytosis enhances hepatocyte proliferation in mice subjected to extended hepatectomy, a mechanisms possibly related to signaling pathway involving signal transducer and activator of transcription 3 (Stat3) and Akt.

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