Role of Neutrophils in the Synergistic Liver Injury from Monocrotaline and Bacterial Lipopolysaccharide Exposure

Abstract

Synergistic liver injury develops in Sprague-Dawley rats from administration of a small, noninjurious dose (7.4 x 10(6) EU/kg) of bacterial lipopolysaccharide (LPS) given 4 h after a nontoxic dose (100 mg/kg) of the pyrrolizidine alkaloid, monocrotaline (MCT). Previous studies demonstrated that liver injury is mediated through inflammatory factors, such as Kupffer cells and tumor necrosis factor alpha (TNF-alpha), rather than through simple interaction between MCT and LPS. In the present study, the hypothesis that neutrophils (polymorphonuclear leukocytes or PMNs) are causally involved in this injury model is tested, and the interdependence between PMNs and other inflammatory components is explored. Hepatic PMN accumulation and the appearance of cytokine-induced neutrophil chemoattractant-1 in plasma preceded the onset of liver injury, suggesting that PMNs contribute to toxicity. Hepatic PMN accumulation was partially dependent on TNF-alpha. Prior depletion of PMNs in MCT/LPS-cotreated animals resulted in attenuation of both hepatic parenchymal cell (HPC) and sinusoidal endothelial cell (SEC) injury at 18 h. PMN depletion did not, however, protect against early SEC injury that occurred before the onset of HPC injury at 6 h. This observation suggests that SEC injury is not entirely dependent on PMNs in this model. In vitro, MCT caused PMNs to degranulate in a concentration-dependent manner. These results provide evidence that PMNs are critical to the HPC injury caused by MCT/LPS cotreatment and contribute to the progression of SEC injury.

Coagulation-Mediated Hypoxia and Neutrophil-Dependent Hepatic Injury in Rats Given Lipopolysaccharide and Ranitidine

“…PMN immunohistochemistry was performed on formalin-fixed liver sections as described previously (Yee et al, 2003a). Hepatic PMN accumulation was evaluated by identifying the average number of PMNs counted in 10 to 20 randomly selected high-power fields (400ϫ).…”

“…Indeed, RAN is rendered hepatotoxic in rats cotreated with a small, noninjurious dose of the potent inflammagen, bacterial lipopolysaccharide (LPS) (Luyendyk et al, 2003b). Hepatocellular injury in rats given a large, hepatotoxic dose of LPS and in several models of LPS-augmented xenobiotic hepatotoxicity occurs by a neutrophil (PMN)-dependent mechanism (Hewett et al, 1992;Barton et al, 2000;Yee et al, 2003a). Activated PMNs release proteases (i.e., elastase and cathepsin G) that kill hepatocytes (HPCs) in vitro (Ho et al, 1996), and inhibition of PMN elastase reduces LPS-induced liver injury in vivo (Ishii et al, 2002).…”

ANIT toxicity toward mouse hepatocytes in vivo is mediated primarily by neutrophils via CD18

“…It occurs in response to a variety of xenobiotic agents, including carbon tetrachloride (14), acetaminophen (39), galatosamine/endotoxin (29), and monocrotaline/endotoxin (57). Drug-related hepatic inflammation can result from drug-induced oxidant stress or the local upregulation of inflammatory mediators (19); whatever the stimulus, neutrophil invasion often worsens the liver damage caused by the xenobiotic itself (13,29,57).…”

Co-Exposure Effects of LPS with Various Aflatoxin B1 Doses in Isolated Perfused Rat Liver Model

“…Enhancement of AFB1-induced hepatotoxicity by LPS depends on tumor necrosis factor α [3]. In addition, synergistic liver injury from LPS is suggested in rats of exposure with monocrotaline [25]. In all studies cited above examined as in vivo, it likely seems LPS increased hepatotoxicity AFB1 through activation of inflammatory cells and production of soluble inflammatory mediators.…”

“…This cytokine can increase the expression of endothelial cells of adhesion molecules that cause PMNs accumulation. Furthermore, a rat neutrophil chemoattractant (CINC-1) contribute to the recruitment of hepatic PMNs [25,26]. Thus, both LPS-induced TNF-α and CINC-1 that secret from hepatic parenchymal cells and sinusoidal endothelial cells contribute in accumulation of hepatic PMNs.…”