THE INVOLVEMENT OF APOPTOSIS IN INFLAMMATORY LIVER FAILURE

Abstract

Apoptosis was initially described in the early 1970’s; however, an understanding of its full signi~cance did not begin to emerge until the late 1980’s. This recent interest has been due, in part, to its increasing association with the development of multiple organ failure. Several investigators have shown that hepatic failure precedes death from multiple organ failure due to sepsis. Recent progress in the cytokinetic signaling pathways of in_ammation has pointed towards apoptosis as a key intermediary in the onset of liver failure. Innovative research has also provided new tools to study the roles and mechanisms of apoptosis in the liver. This review summarizes these advances and speci~cally addresses a unique role for nitric oxide (NO) in limiting hepatic apoptosis. Multiple organ failure (MOF) emerged as a syndrome during the 1980’s as a result of better regionalized trauma systems and improved intensive care. Patients that would have succumbed to their illnesses and injuries were now surviving longer. MOF has since become the leading cause of late post-injury deaths and the leading cause of morbidity and mortality among patients admitted to the ICU [1]. Systemic infection or sepsis is thought to be the most common cause for the development of MOF [2]. Several studies have reviewed the onset of multiple organ failure as a result of trauma, and found it to be a bimodal phenomenon in which the late onset of MOF is predominated by liver failure with antecedent or coincident infection [3,4]. In the United States, non-traumatic fulminant hepatic failure accounts for roughly 2,000 deaths each year, which is 0.1% of all deaths, and 6% of liver-related deaths. Over 60% of these patients have an infectious etiology for their hepatic failure [5]. In this context it is clear that liver failure following infection or in_ammation contributes signi~cantly to patient morbidity, mortality and the expenditure of precious resources. Epidemiological data, such as these, have prompted numerous investigators to develop models for the study of the relationship between hepatic in_ammation and liver failure. Transcriptional inhibitors have proved very useful towards this end. In 1968, Keppler et al. [6] ~rst noted that the hepatitis induced by the administration of D-galactosamine (GalN) shared similar pathological characteristics with viral hepatitis. GalN is metabolized primarily along the galactose pathway in the liver to produce intermediates, which bind and deplete the available hepatic uridine pool. In this way transcription of new mRNA is inhibited, but can be overcome by the addition of exogenous uridine. Several other transcriptional inhibitors have also been instrumental for the study of hepatic in_ammation, such as Actinomycin D (ActD), which intercalates guanine residues in double-stranded DNA thus preventing it from being an effective template for RNA synthesis [7]. The toxicity of these agents is greatly increased when they are combined with exogenous lipopolysaccharide (LPS) or tumor necrosis factor (TNF), jointly referring to TNFa and TNFb [8]. In the late 80’s and early 1990’s, Marcel Leist and Albrecht Wendel led the group from Konstanz, Germany to fully develop the murine model of endotoxemia in the presence of transcriptional inhibition for the study of hepatic failure [9–16]. They demonstrated that TNF was the terminal mediator of endotoxemia in this model, and that peak serum levels arose 90-120 minutes following intravenous endotoxin administration. These results are consistent with those obtained in humans as well [17]. TNF is a cytokine that is capable of producing a wide variety of physiologic effects, both detrimental and protective [18]. It induces the production of superoxide dismutase, NFjB, as well as the expression of heat shock proteins and the antiprotease plasminogen activator inhibitors, which are protective in many cell lines. However, whether these TNF-induced events are relevant to hepatic apoptosis is unknown. Nonetheless TNF is associated with the development of multi-organ failure and death [19]. The authors demonstrated that transcriptional inhibition sensitized murine hepatocytes to doses of TNF that would otherwise be well tolerated. First they noted that cultured hepatocytes were relatively resistant to the toxic effects of TNF alone. However when incubated in the presence of ActD, even low doses of TNF had cytotoxic effects. Galactosamine and other