Endotoxin and interleukin-1 related hepatic inflammatory response promotes liver failure after partial hepatectomy

Abstract

Impairment of various functions of the liver and concomitantly increased levels of parameters of liver damage, a clinical entity termed liver failure, is commonly seen after partial hepatectomy. We investigated in a rat model whether damage of the remnant liver was due to local inflammatory responses, and related to endotoxin or interleukin-1 (IL-1). To address this question, the effects of partial hepatectomy on infiltration of immunocompetent cells and expression of major histocompatibility complex (MHC) class II antigen of macrophages in the remnant liver was studied using immunohistochemical techniques. Specific intervention with recombinant N-terminal bactericidal/permeability-increasing protein (rBPI23) to neutralize endotoxin and with IL-1 receptor antagonist (IL-1ra) to block IL-1 activity was used to examine the respective roles of endotoxin and IL-1. After partial hepatectomy, we found an influx of neutrophils, an increased expression of MHC class II antigens, and morphologic changes of Kupffer cells consistent with activation. These inflammatory events coincided with increased serum levels of markers of liver damage (aspartate aminotransferase, alanine aminotransferase, ammonia). Both neutralization of endotoxin and blocking of IL-1 activity reduced hepatic inflammation and reduced serum levels of aminotransferases and ammonia. In addition, liver cell proliferation as assessed by staining for proliferating cell nuclear antigen (PCNA) expression was significantly enhanced when either endotoxin or IL-1 effects were blocked. Thus, our results suggest that local hepatic inflammatory responses inhibit liver cell proliferation and promote liver failure, presumably by affecting the functional capacity of the remnant liver.

Expression of Presumed Specific Early and Late Factors Associated with Liver Regeneration in Different Rat Surgical Models

“…It was, however, increased after PCS, as it was in the ligated lobes after PBL in our study (Stärkel et al, 2001) and in other studies (Uemura et al, 2000). It has been demonstrated that administration of exogenous recombinant IL-1␤ in vivo diminishes the replicating surge of hepatocyte DNA synthesis after PH (Boulton et al, 1997), whereas blocking its effect by administration of IL-1␤ receptor antagonists during the first 24 hours after PH enhances hepatocyte proliferation in rats (Boermeester et al, 1995). This cytokine might exert a negative growth modulator effect preventing uncontrolled hepatocyte proliferation (Higashitsuji et al, 1995).…”

Nonparenchymal cells from regenerating rat liver generate interleukin-1? and -1?: A mechanism of negative regulation of hepatocyte proliferation

“…41 cytokine. While this study was in progress, Boermeester et al showed that hepatocyte proliferation was enhanced in rats As discussed below, this is a potential mechanism by which nonparenchymal cell generation of IL-1 might be initiated given IL-1ra during the first 24 hours after partial hepatectomy, 45 an observation that would be predicted from the after hepatectomy in vivo, but these observations also raise the possibility that the in vitro findings we described were inhibitory role that we postulate for IL-1 in the events following partial hepatectomy. an artifact caused by cell manipulation.…”

Bactericidal/Permeability-Increasing Protein Preserves Leukocyte Functions After Major Liver Resection

“…After major liver resection, the hepatic mononuclear phagocytic system, the body's main clearing mechanism for endotoxin, is reduced, [13][14][15][16] allowing spillover of gut-derived bacteria and endotoxin into the systemic circulation. 17,18 Indeed, endotoxin was demonstrated in plasma from patients undergoing a hemihepatectomy, whereas in plasma from patients undergoing other major abdominal surgery, endotoxin was not detectable. 19 Endotoxin can induce an enhanced expression of leukocyte and endothelial adhesion molecules and is a potent stimulator of the PMN oxidative burst in vitro and in vivo.…”