Expression of insulin-like growth factor I by activated hepatic stellate cells reduces fibrogenesis and enhances regeneration after liver injury

BACKGROUND/AIM: Hepatic stellate cells (HSCs) express alpha-smooth muscle actin (alphaSMA) and acquire a profibrogenic phenotype upon activation by noxious stimuli. Insulin-like growth I (IGF-I) has been shown to stimulate HSCs proliferation in vitro, but it has been reported to reduce liver damage and fibrogenesis when given to cirrhotic rats. METHODS: The authors used transgenic mice (SMP8-IGF-I) expressing IGF-I under control of alphaSMA promoter to study the influence of IGF-I synthesised by activated HSCs on the recovery from liver injury. RESULTS: The transgene was expressed by HSCs from SMP8-IGF-I mice upon activation in culture and in the livers of these animals after CCl4 challenge. Twenty four hours after administration of CCl4 both transgenic and wild type mice showed similar extensive necrosis and increased levels of serum transaminases. However at 72 hours SMP8-IGF-I mice exhibited lower serum transaminases, reduced hepatic expression of alphaSMA, and improved liver morphology compared with wild type littermates. Remarkably, at this time all eight CCl4 treated wild type mice manifested histological signs of liver necrosis that was severe in six of them, while six out of eight transgenic animals had virtually no necrosis. In SMP8-IGF-I mice robust DNA synthesis occurred earlier than in wild type animals and this was associated with enhanced production of HGF and lower TGFbeta1 mRNA expression in the SMP8-IGF-I group. Moreover, Colalpha1(I) mRNA abundance at 72 hours was reduced in SMP8-IGF-I mice compared with wild type controls. CONCLUSIONS: Targeted overexpression of IGF-I by activated HSCs restricts their activation, attenuates fibrogenesis, and accelerates liver regeneration. These effects appear to be mediated in part by upregulation of HGF and downregulation of TGFbeta1. The data indicate that IGF-I can modulate the cytokine response to liver injury facilitating regeneration and reducing fibrosis

Leukotriene C4 detection as an early graft function marker in liver transplantation

Leukotrienes are a group of compounds belonging to the eicosanoid family that are formed from the metabolism of arachidonic acid by means of 5-lipoxigenase. Leukotriene C4 (LTC4) has a pronounced proinflammatory character and is formed by combining leukotriene A4 with glutation. This step is catalyzed mainly by the isoenzyme 4-4 of the hepatic glutation transferases, although other enzymes may participate in its formation. The liver plays a decisive part in the formation of this compound despite the fact that it can be synthesized along other cellular lines. In orthotopic liver transplant (OLT), the evaluation of the early functioning of the graft is, in many cases, complex. The difficulty of evaluation lies in the absence of specific markers to indicate when the transplanted organ will prove viable notwithstanding the damage resulting from preservation, and when these lesions are irreversible. The aim of this study is to determine whether there is a relationship between the ability to synthesize LTC4 immediately after OLT and the early functioning of the graft

Plasma levels of leukotriene B4 during hepatic allograft rejection

At the present time, rejection is the most frequent cause of graft dysfunction in liver transplantation. Differential diagnosis between this and other possible causes of dysfunction—preservation injury, vascular, biliary, viral—may well be difficult, as the clinical and analytical findings are often similar; moreover, no markers specific to rejection are available, and histological studies are necessary for a definitive diagnosis. For this reason, markers indicating activity within the immune system need to be established so as to provide a more specific means of distinguishing rejection from other causes of graft dysfunction. The immune response to an allograft is complex, and the intricate mechanisms regulating it are still not entirely understood. Nevertheless, several specialists have drawn connections among changes in the lymphocyte subpopulations, rises in the interleukin-2 levels, expression of the interleukin-2 receptor, and alteration in the expression of antigens belonging to class II in the greater complex of histocompatibility, with rejection of the allograft. Leukotriene B4 (LTB4) is a derivative of the metabolism of arachidonic acid via 5- lipoxygenase, whose in vitro behaviour is to encourage rejection by favoring leukocyte aggregation, proliferation of T lymphocytes, interleukin-1 and -2 secretion, and the development of "natural killer" cell subpopulations. This study examines the role of LTB4 in mediating the immune response to the hepatic allograft in order to assess its usefulness in early diagnosis of rejection

Leukotriene C4 detection as an early graft function marker in liver transplantation

Leukotrienes are a group of compounds belonging to the eicosanoid family that are formed from the metabolism of arachidonic acid by means of 5-lipoxigenase. Leukotriene C4 (LTC4) has a pronounced proinflammatory character and is formed by combining leukotriene A4 with glutation. This step is catalyzed mainly by the isoenzyme 4-4 of the hepatic glutation transferases, although other enzymes may participate in its formation. The liver plays a decisive part in the formation of this compound despite the fact that it can be synthesized along other cellular lines. In orthotopic liver transplant (OLT), the evaluation of the early functioning of the graft is, in many cases, complex. The difficulty of evaluation lies in the absence of specific markers to indicate when the transplanted organ will prove viable notwithstanding the damage resulting from preservation, and when these lesions are irreversible. The aim of this study is to determine whether there is a relationship between the ability to synthesize LTC4 immediately after OLT and the early functioning of the graft