| Sign In to gain access to subscriptions and/or personal tools. |
Role of Neutrophils in the Pathogenesis of Acute Inflammatory Liver Injury
1 Department of Pathobiology, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, TX 77843-4467, USA Correspondence: Address correspondence to: Shashi K. Ramaiah, Department of Pathobiology, College of Veterinary Medicine, Texas A&M University, MS-4467, College Station, TX 77843-4467; e-mail:sramaiah{at}cvm.tamu.edu
Polymorphonuclear leukocytes (neutrophils) are essential in the defense against invading microorganisms, tissue trauma or any inciting inflammatory signals. Hepatic infiltration of neutrophils is an acute response to recent or ongoing liver injury, hepatic stress or unknown systemic inflammatory signals. Once neutrophils reach the liver, they can cause mild-to-severe tissue damage and consequent liver failure. For neutrophils to appear in the liver, neutrophils have to undergo systemic activation (priming) by inflammatory mediators such as cytokines, chemokines, complement factors, immune complexes, opsonized particles and other biologically active molecules, e.g., platelet activating factor. Neutrophils accumulated in the hepatic microvasculature (sinusoids and postsinusoidal venules) can extravasate (transmigrate) into the hepatic parenchyma if they receive a signal from distressed cells. Transmigration can be mediated by a chemokine gradient established towards the hepatic parenchyma and generally involves orchestration by adhesion molecules on neutrophils (β2 integrins) and on endothelial cells (intracellular adhesion molecules, ICAM-1). After transmigration, neutrophils adhere to distressed hepatocytes through their β2 integrins and ICAM-1 expressed on hepatocytes. Neutrophil contact with hepatocytes mediate oxidative killing of hepatocytes by initiation of respiratory burst and neutrophil degranulation leading to hepatocellular oncotic necrosis. Neutrophil-mediated liver injury has been demonstrated in a variety of diseases and chemical/drug toxicities. Relevant examples are discussed in this review.
Key Words: Inflammation • injury • liver • neutrophils • toxicity
The liver plays an important role in the innate immune response, providing the first line of defense against microbes and toxins crossing the intestinal barrier (Janeway, 2002). Kupffer cells, the resident macrophages in the liver, are critical for the rapid clearance of microorganisms from the systemic circulation (Gregory and Wing, 2002; Nagy, 2003). Although Kupffer cells by themselves are highly phagocytic and are able to remove microorganisms, they also facilitate generation of inflammatory response leading to recruitment of inflammatory cells such as neutrophils, monocytes, T and B lymphocytes, as well as natural killer (NK) cells, to the liver. Mediators of neutrophilic inflammation generated by Kupffer cells include tumor necrosis factor  (TNF-), interleukins (IL-1, and IL-6), chemokines and reactive oxygen species (ROS) (Sweet and Hume, 1996). These inflammatory mediators will then activate neutrophils in the hepatic microvasculature (sinusoids and postsinusoidal venules) leading to a variety of events culminating in hepatocellular death (Figure 1). Ischemia-reperfusion injury (IRI), toxicity of ethanol (ETOH), acetaminophen (APAP), and alpha-naphthyl-isothiocyanate (ANIT) are examples, which are discussed in this review, where neutrophils contribute to or even dominate the injury mechanism.
Liver injury mediated by neutrophils has been reported in a number of experimental animal models such as ischemia-reperfusion injury (Jaeschke et al., 1990), endotoxemia (Jaeschke et al., 1991), alcoholic hepatitis (Bautista, 2002; Jaeschke, 2002; Ramaiah et al., 2004), obstructive cholestasis (Gujral et al., 2003), ANIT toxicity (Hill et al., 1999; Xu et al., 2004) and APAP toxicity (Liu et al., 2006). Drug/chemical-related liver inflammation can result from chemical/drug-induced oxidant stress and tissue injury and/or by the local upregulation of inflammatory mediators. Whatever the stimulus, neutrophil invasion often exacerbates the liver damage caused by the drug/chemical. To understand the mechanism of liver injury, it is important to review the pathophysiology of neutrophil recruitment into hepatic vasculature, which includes neutrophil activation within the hepatic vasculature, neutrophil transmigration or extravasation and adherence of neutrophils to hepatocytes causing a respiratory burst and oxidant stress-mediated killing of hepatocytes.
Neutrophil Accumulation in the Liver
Neutrophil Extravasation into Liver Parenchyma It has been reported that increased production of CXC chemokines within hepatocytes can cause neutrophil infiltration, extravasation, and consequent neutrophil-dependent cytotoxicity (Colletti et al., 1996; Maher et al., 1997; Lentsch et al., 1998). However, CXC chemokine formation does not always lead to neutrophil extravasation (Simonet et al., 1994; Dorman et al., 2005). For CXC chemokines to have an effect, the mediators need to be produced in the right location to establish a chemotactic gradient, at the right time and in sufficient quantities relative to other potential chemoattractants. Neutrophils do not attack healthy cells but respond to distressed or dying cells (Jaeschke, 2006). Thus, apoptosis is known to trigger neutrophilic inflammation (Figure 1, Jaeschke et al., 1998; Lawson et al., 1998; Faouzi et al., 2001). Blocking apoptosis by pancaspase inhibitors effectively prevented neutrophil extravasation into the parenchyma, suggesting a role of apoptosis in mediating neutrophil extravasation (Jaeschke et al., 1998). Although it has been shown that apoptotic hepatocytes can generate enough CXC chemokines to trigger neutrophil infiltration into liver (Faouzi et al., 2001), in the presence of other potent proinflammatory mediators, this effect appears to be of limited relevance (Ito et al., 2006). Direct cell contact of the neutrophil with apoptotic hepatocytes through endothelial cell gaps may have induced extravasation (Ito et al., 2006). Necrosis can also incite additional neutrophilic infiltration either by cell content release through complement activation or by reactive oxygen species (ROS) generation. Lipid peroxidation products including lipid aldehydes are potent chemotactic factors for neutrophils (Jaeschke, 2000). In addition to mediators originating from the injured cells, the activated neutrophils can also generate potent chemotactic factors such as leukotriene B4, which can recruit more neutrophils into the inflammatory site as seen during ischemia-reperfusion injury (Jaeschke, 2003).
Adherence of Neutrophils, Respiratory Burst and Cytotoxicity
TNF- In addition to the described mechanisms for the amplification of the inflammatory response, an even more complex picture begins to emerge. Damaged cells release cell contents into the tissue and blood. Among others, liver cells can release calpains, which are calcium-regulated cytosolic cysteine proteases that exists in several isoforms; activation of these enzymes has been implicated in liver damage mainly by progression of liver injury (Limaye et al., 2003, 2006; Mehendale and Limaye, 2005). Experimental intervention with cal-pain inhibitors substantially mitigates progression of liver injury initiated by toxicants (Rose et al., 2006). Similarly, the release of deoxyribonuclease 1 during cell necrosis has been suggested to promote the expansion of the injury (Napirei et al., 2006). On the other hand, it was reported that necrotic cells release of high mobility group box-1 (HMGB-1) protein, which can bind to the toll-like receptor-4 on macrophages and promote cytokine formation, which causes neutrophil recruitment into the liver (Scaffidi et al., 2002). Thus, necrotic cell death resulting from killing by neutrophils or by direct toxicity of drugs/chemicals can directly and indirectly amplify the neutrophilic inflammatory response by a complex network of mediators and mechanisms.
Ischemia-Reperfusion-Mediated Liver Injury During transplantation, liver surgery (Pringle maneuver), and hemorrhagic shock, the liver can be exposed to prolonged periods of ischemia, which results in cellular stress and cell death during ischemia itself and also during reperfusion. In fact, the inflammatory response triggered by the early injury is a critical factor in the organ damage during reperfusion (Jaeschke, 2003). The acute inflammatory response during reperfusion consists of 2 phases: 1. A Kupffer cell-mediated injury phase (0–6 h of reperfusion) where Kupffer cells generate reactive oxygen and aggravate the ischemic damage (Jaeschke and Farhood, 1991; Jaeschke et al., 1991a). In addition, activated Kupffer cells and infiltrating lymphocytes generate a number of cytokines, which further promote the inflammatory response (Colletti et al., 1990; Lentsch et al., 2003). 2. A neutrophil-induced injury phase (6–24 h of reperfusion), where neutrophils are fully activated, generate reactive oxygen and dominate the injury process (Jaeschke et al., 1990, 1992; Hasegawa et al., 2005). Oxidant stress and injury by neutrophils can be strongly attenuated by blocking antibodies directed against CD11b (Jaeschke et al., 1993b) or CD18 (Liu et al., 1995) and by inhibiting NADPH oxidase (Hasegawa et al., 2005). However, blocking ICAM-1 was markedly less effective in this model (Farhood et al., 1995). These findings suggested that the extravasation process was less dependent on integrin/ICAM-1 interactions. The extensive endothelial cell damage during ischemia and reperfusion facilitates the extravasation process without the need for adhesion molecule involvement. On the other hand, the adherence to the target cells and most importantly the adherence-dependent oxidant stress depends strictly on CD11b/CD18. These observations during reperfusion are different compared to other models of neutrophil-induced injury such as obstructive cholestasis. Here, the extravasation process into the parenchyma is dependent on β2 integrin/ICAM-1 interactions and the reduced oxidant stress and injury in animals deficient of these adhesion molecules is mainly caused by the prevention of neutrophil extravasation (Gujral et al., 2003, 2004a).
Neutrophil activation and recruitment during reperfusion is mediated by TNF-
Alcoholic Hepatitis The histomorphological pattern of alcoholic steatohepatitis in human alcoholics consists of the infiltration of polymorphonuclear neutrophils, hepatocyte degeneration, ballooning, and oncotic necrosis (Galambos, 1972; Bautista, 2002; Diehl, 2002). Similar pathologic changes are noted in rodent models (Apte et al., 2005; Ramaiah et al., 2005). There is no direct evidence that ethanol per se causes inflammation. The presence of fat in the liver seems to be a prerequisite to the development of neutrophilic inflammation, possibly because a fatty liver is more vulnerable to various hitherto unidentified factors that trigger inflammation (Day and James, 1998). For instance, there is evidence for an involvement of bacterial endotoxins and viral hepatitis (Thurman et al., 1998). Furthermore, oxidative stress induced either by dietary polyunsaturated fatty acids or by iron supplementation may aggravate the neutrophilic inflammation in experimental models (Nanji et al., 1994; Tsukamoto et al., 1995).
Substantial progress has been made in the general understanding of neutrophil-infiltrative mechanisms in the liver (Figure 2, Pennington et al., 1998; Lieber, 2000; Bautista, 2002; French, 2002; Jaeschke, 2002). However, the precise mechanisms of neutrophil-mediated injury in alcoholic hepatitis remain unclear. The role of inflammatory mediators TNF-
Recent evidence suggests that a novel class of extracellular proteins called matricellular proteins (MCP) play a critical role in the pathogenesis of several inflammatory diseases (Kim et al., 1997; O’Regan and Berman, 2000; Francki et al., 2001; Sodek et al., 2002). Unlike extracellular matrix proteins MCPs are involved in cell-to-cell and cell-to-matrix communication rather than structural support. Osteopontin (OPN), is one of the major MCP involved in cell-to-matrix communication and may play a role in several inflammatory diseases including glomerular nephritis (O’Regan and Berman, 2000; Denhardt et al., 2001), inflammation during CCl4-induced hepatotoxicity (Kawashima et al., 1999), in puromycin-induced nephrotoxicity (Denhardt et al., 2001), and nonalcoholic steatohepatitis (Sahai et al., 2004). OPN is also a known chemoattractant for macrophages and neutrophils (Giachelli et al., 1998; Denhardt et al., 2001). The role of OPN in hepatic neutrophil infiltration during ASH was recently tested in a rat model of ASH.
In this study it was identified that OPN (native and thrombin-cleaved form) was induced within the hepatocytes in the ASH rodent model and there was a strong correlation between cleaved form of OPN and hepatic neutrophil infiltration (Banerjee et al., 2006a). These studies implicate OPN as a new mediator in the pathogenesis of neutrophilic ASH. The mechanisms by which OPN signals to neutrophils remains to be studied but based on previous reports (Giachelli et al., 1998; Denhardt et al., 2001), it can be speculated that OPN directly activates neutrophils via
Alpha Naphthylisothiocyanate (ANIT) Liver Toxicity There are several studies that have investigated the mechanisms behind neutrophil infiltration into the liver during ANIT toxicity (Dahm et al., 1991; Jean and Roth, 1995; Hill et al., 1999; Kodali et al., 2006). Adhesion molecules such as β2(CD18)integrins and chemokines have been the major focus of investigation of ANIT-mediated neutrophil infiltration (Xu et al., 2004). Using CD18-deficient mice, it was shown that ANIT induced neutrophil inflammation in via both CD18-dependent and -independent mechanisms (Kodali et al., 2006). It was suggested that CD18 positive neutrophils augment ANIT toxicity worsening hepatocellular necrosis but with little impact on the ANIT-mediated biliary epithelial cell damage and cholestasis (Kodali et al., 2006). Chemoattractants such as PAF, leukotriene B4 and lipid peroxidation products, e.g., 4-hydroxynonenal, have been investigated as possible candidates in ANIT-mediated neutrophil infiltration (Evans et al., 1991; Henderson, 1994; Nitti et al., 2002). However, since blockade of these mediators by specific inhibitors did not result in abrogation of ANIT-induced neutrophilic inflammation, it appears that PAF and leukotrienes are not likely involved in neutrophil infiltration (Bailie et al., 1995, 1996). CXC chemokines are other potential candidates that were investigated for ANIT-mediated inflammation. CXC chemokines (MIP-2, KC, IL-8) have been implicated as mediators of hepatic inflammation in a model obstructive cholestasis (Saito and Maher, 2000). Similarly, ANIT induced MIP-2 formation in periportal hepatocytes resulted in increased neutrophilic inflammation in the liver. A study in mice with targeted disruption of CXCR2, a receptor for MIP-2 and KC, showed a 50% reduction of hepatic neutrophil infiltration in response to ANIT (Xu et al., 2004). However, blockade of CXC chemokines did not have any effect on ANIT-induced hepatocellular injury, cholestasis, or fibrosis. Based on this it was suggested that ANIT toxicity can occur even in the absence of chemokine-dependent neutrophil inflammation. However, it has to be kept in mind that only a part of the total hepatic neutrophils actually transmigrate and contribute to the injury (Essani et al., 1995). In addition, severe neutropenia as well as deficiency of CD18 has been demonstrated to protect against the liver cell injury but not cholestasis in this model (Kodali et al., 2006). These results are somewhat different from studies of Dahm et al. (1991), who showed that ANIT toxicity (parenchymal cell and cholangiocyte injury) in rats can be completely blocked when neutrophils were depleted. The discrepancy of these studies may be attributed to the amount of neutrophils actually required to produce the full spectrum of ANIT-liver injury and that CXC chemokines may not be completely responsible for neutrophil infiltration in this model. However, both studies clearly highlight the importance of neutrophils in ANIT-mediated hepatocellular injury.
Acetaminophen Liver Toxicity APAP liver damage is known to activate neutrophils leading to accumulation of these cells in the hepatic vasculature (Lawson et al., 2000). Inflammatory cytokines and CXC chemokines, which can systemically activate neutrophils and trigger their recruitment into the liver (Witthaut et al., 1994; Bajt et al., 2001), are also generated during APAP hepatotoxicity (Takada et al., 1995; Horbach et al., 1997; Lawson et al., 2000). However, the role of neutrophils in the pathophysiology of APAP hepatotoxicity still remains controversial (Jaeschke, 2005). Following APAP administration, a significant number of neutrophils are recruited into the liver closely following the development of cell injury 4–24 hours after drug treatment (Lawson et al., 2000). However, several antibodies against neutrophil β2-integrins did not protect against APAP-induced liver injury (Jaeschke et al., 1991; Lawson et al., 2000). In addition, animals deficient in gp91phox, an essential protein of the activated NADPH oxidase complex in phagocytes, APAP caused a similar oxidant stress, peroxynitrite formation and liver injury as in wild-type animals (James et al., 2003). In support of these findings, a chemical inhibitor of NADPH oxidase did not protect against APAP hepatotoxicity (Cover et al., 2006). In a rat model, an inhibitor of hemeoxygenase 1 (HO-1) attenuated the inflammatory response including hepatic neutrophil infiltration, but had no effect on liver injury (Bauer et al., 2000). Similarly, treatment with pentoxifyline, which is known to improve microcirculatory perfusion, did not affect liver injury (Welty et al., 1993). These studies suggest that neutrophil accumulation within sinusoids is not a relevant factor in APAP-induced liver injury. In addition, primary cultured mouse hepatocytes can be destroyed by APAP through the same mechanisms as hepatocytes in vivo in the absence of any inflammatory cells (Shen et al., 1992; Bajt et al., 2004; Kon et al., 2004) Thus, none of these studies support a relevant role of neutrophils in the mechanism of APAP induced liver injury. In contrast, these studies suggest that the major function of recruited neutrophils is to remove damaged cells or cell debris.
On the other hand, there are few studies that suggest that neutrophils may be involved in APAP-induced hepatotoxicity. IFN- However, causing neutropenia by treatment with the same antibody after APAP bioactivation did not protect (Cover et al., 2006). A recent preliminary study investigating the reasons for these opposite results with the same reagent indicated that causing neutropenia 24 hours before APAP treatment results in an acute phase response with upregulation of protective genes such as metallothionein (Jaeschke and Liu, 2007). Since metallothionein induction alone can protect against APAP hepatotoxicity (Liu et al., 1999), it remains unclear if pretreatment with the anti-Gr-1 antibody reduced APAP hepatotoxicity by causing neutropenia, induction of metallothionein, induction of other stress proteins or a combination of these mechanisms (Jaeschke and Liu, 2007). Liu et al. (2006) also showed protection against APAP liver toxicity in ICAM-1-deficient mice. However, in our hands ICAM-1-deficient mice were not protected (Cover et al., 2006), a result that is consistent with the previously reported ineffectiveness of an anti-CD18 antibody (Lawson et al., 2000). Thus, the predominant experimental evidence does not support a hepatocyte damaging effect for neutrophils in the pathogenesis of APAP-mediated hepatotoxicity in the currently used rodent models. However, the presence of activated neutrophils in the liver during APAP-induced liver injury leaves the possibility open that conditions may develop where neutrophils aggravate APAP hepatotoxicity.
Neutrophil-mediated liver damage is mediated by activation/priming and subsequent accumulation within the hepatic vasculature most notably in the sinusoids. Neutrophil activation is mediated by proinflammatory mediators such as cytokines, CXC chemokines, complement factors and a lesser known recently reported protein, osteopontin. Accumulated neutrophils within the sinusoids sense the chemotactic signal from the hepatic parenchyma leading to neutrophil extravasation, which is mostly dependent on neutrophil integrins and endothelial adhesion molecules. Next, the neutrophils undergo adhesion to hepatocytes via hepatocyte ICAM-1 and neutrophil Mac-1 (CD11b/CD18), which triggers formation of reactive oxygen by NADPH oxidase and release of proteases through degranulation. Neutrophil-derived reactive oxygen species diffuse into target cells and induce an intracellular oxidant stress, which eventually leads to the death of hepatocytes by oncotic necrosis. Characteristic for a neutrophilic hepatitis is that once the process is initiated, it can become a self-aggravating mechanism. The mediators responsible for the promotion of the inflammatory response are not always identified. Neutrophilic proteases can play an important role by facilitating production of inflammatory cytokines and chemokines. Products derived from dying cells can either be chemotactic for neutrophils directly (e.g., LPO products), trigger pro-inflammatory cytokine production by macrophages (e.g., HMGB-1) or cause direct cell damage (e.g., calpain release). In summary, there is extensive experimental evidence to indicate that neutrophils are important determinants of liver damage. Understanding the precise signals that regulate neutrophil infiltration into liver parenchyma and the mechanisms of neutrophil-induced cell damage can reveal therapeutic intervention strategies, which may significantly reduce acute liver failure during neutrophilic hepatitis and facilitate patient recovery when exposed to liver toxic stresses and chemicals.
SKR research is supported by NIH Grant (AA016316) and HJ is supported by NIH grants R01 NIAAA 12916 and R01 NIDDK 070195.
Apte, UM, Banerjee, A, McRee, R, Wellberg, E, & Ramaiah, SK. (2005). Role of osteopontin in hepatic neutrophil infiltration during alcoholic steatohepatitis. Toxicol Appl Pharmacol, 207, 25-38[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Bailie, MB, Dahm, LJ, Peters-Golden, M, Harris, RR, Carter, GW, & Roth, RA. (1995). Leukotrienes and Bailie, MB, Pearson, JM, Fink, GD, & Roth, RA. (1996). Platelet activating factor receptor blockade aloneor in combination with leukotrine synthesis, inhibition does not ameiorate Bajt, ML, Farhood, A, & Jaeschke, H. (2001). Effects of CXC chemokines on neutrophil activation and sequestration in hepatic vasculature. Am J Physiol Gastrointest Liver Physiol, 281, G1188-95 Bajt, ML, Knight, TR, Lemasters, JJ, & Jaeschke, H. (2004). Acetaminophen-induced oxidant stress and cell injury in cultured mouse hepatocytes: protection by N-acetyl cysteine. Toxicol Sci, 80, 343-9 Banerjee, A, Apte, U, Smith, R, & Ramaiah, S. (2006a). Higher neutrophil infiltration mediated by osteopontin is the likely factor for increased susceptibility of females to alcoholic liver disease. J Pathol, 208, 473-85[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Banerjee, A, Burghardt, RC, Johnson, GA, White, FJ, & Ramaiah, SK. (2006b). The temporal expression of osteopontin (SPP-1) in the rodent model of alcoholic steatohepatitis: a potential biomarker. Toxicol Pathol, 34, 373-84 Bauer, I, Vollmar, B, Jaeschke, H, Rensing, H, Kraemer, T, Larsen, R, & Bauer, M. (2000). Transcriptional activation of heme oxygenase-1 and its functional significance in acetaminophen-induced hepatitis and hepatocellular injury in the rat. J Hepatol, 33, 395-406[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Bautista, AP, & Spitzer, JJ. (1992). Platelet activating factor stimulates and primes the liver, Kupffer cells and neutrophils to release superoxide anion. Free Radic Res Commun, 17, 195-209[Web of Science][Medline] [Order article via Infotrieve] Bautista, AP. (1997). Chronic alcohol intoxication induces hepatic injury through enhanced macrophage inflammatory protein-2 production and intercellular adhesion molecule-1 expression in the liver. Hepatology, 25, 335-42[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Bautista, A. (2002). Neutrophilic infiltration in alcoholic hepatitis. Alcohol, 27, 17-21[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Bilzer, M, & Lauterburg, BH. (1991). Effects of hypochlorous acid and chloramines on vascular resistance, cell integrity, and biliary glutathione disulfide in the perfused rat liver: modulation by glutathione. J Hepatol, 13, 84-9[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Casey, CA, Nanji, A, Cederbaum, AI, Adachi, M, & Takahashi, T. (2001). Alcoholic liver disease and apoptosis. Alcohol Clin Exp Res, 25, 49S-53S[Web of Science][Medline] [Order article via Infotrieve] Chosay, JG, Essani, NA, Dunn, CJ, & Jaeschke, H. (1997). Neutrophil margination and extravasation in sinusoids and venules of the liver during endotoxin-induced injury. Am J Physiol, 272, G1195-200[Web of Science][Medline] [Order article via Infotrieve] Colletti, LM, Remick, DG, Burtch, GD, Kunkel, SL, Strieter, RM, & Campbell, DA., Jr. (1990). Role of tumor necrosis factor-alpha in the pathophysiologic alterations after hepatic ischemia/reperfusion injury in the rat. J Clin Invest, 85, 1936-43[Web of Science][Medline] [Order article via Infotrieve] Colletti, LM, Kunkel, SL, Walz, A, Burdick, MD, Kunkel, RG, Wilke, CA, & Strieter, RM. (1996). The role of cytokine networks in the local liver injury following hepatic ischemia/reperfusion in the rat. Hepatology, 23, 506-14[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Colletti, LM, Cortis, A, Lukacs, N, Kunkel, SL, Green, M, & Strieter, RM. (1998). Tumor necrosis factor up-regulates intercellular adhesion molecule 1, which is important in the neutrophil-dependent lung and liver injury associated with hepatic ischemia and reperfusion in the rat. Shock, 10, 182-91[Web of Science][Medline] [Order article via Infotrieve] Cover, C, Liu, J, Farhood, A, Malle, E, Waalkes, MP, Bajt, ML, & Jaeschke, H. (2006). Pathophysiological role of the acute inflammatory response during acetaminophen hepatotoxicity. Toxicol Appl Pharmacol, 216, 98-107[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Dahm, LJ, Schultze, AE, & Roth, RA. (1991). An antibody to neutrophils attenuates alpha-naphthylisothiocyanate-induced liver injury. J Pharmacol Exp Ther, 256, 412-20 Day, CP, & James, OF. (1998). Hepatic steatosis: innocent bystander or guilty party? Hepatology, 27, 1463-6[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Denhardt, D, Giachelli, CM, & Rittling, SR. (2001). Role of Osteopontin in cellular signaling and toxicant injury. Ann Rev Pharmacol Toxicol, 41, 723-49[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Diehl, AM. (2002). Liver disease in alcohol abusers: clinical perspective. Alcohol, 27, 7-11[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Dietrich, CG, Ottenhoff, R, de Waart, DR, & Oude Elferink, RP. (2001). Role of MRP2 and GSH in intrahepatic cycling of toxins. Toxicology, 167, 73-81[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Dorman, RB, Gujral, JS, Bajt, ML, Farhood, A, & Jaeschke, H. (2005). Generation and functional significance of CXC chemokines for neutrophil-induced liver injury during endotoxemia. Am J Physiol Gastrointest Liver Physiol, 288, G880-6 Enomoto, N, Yamashita, S, Kono, H, Schemmer, P, Rivera, CA, Enomoto, A, Nishiura, T, Nishimura, T, Brenner, DA, & Thurman, RG. (1999). Development of a new, simple rat model of early alcohol-induced liver injury based on sensitization of Kupffer cells. Hepatology, 29, 1680-9[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Essani, NA, Fisher, MA, Farhood, A, Manning, AM, Smith, CW, & Jaeschke, H. (1995). Cytokine-induced upregulation of hepatic intercellular adhesion molecule-1 messenger RNA expression and its role on the pathophysiology of murine endotoxin shock and acute liver failure. Hepatology, 21, 1632-9[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Evans, RD, Lund, P, & Williamson, DH. (1991). Platelet-activating factor and its metabolic effects. Prostaglandins Leukot Essent Fatty Acids, 44, 1-10[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Faouzi, S, Burckhardt, BE, Hanson, JC, Campe, CB, Schrum, LW, Rippe, RA, & Maher, JJ. (2001). Anti-Fas induces hepatic chemokines and promotes inflammation by an NF-kappa B-independent, caspase-3-dependent pathway. J Biol Chem, 276, 49077-82 Farhood, A, McGuire, GM, Manning, AM, Miyasaka, M, Smith, CW, & Jaeschke, H. (1995). Intercellular adhesion molecule 1 (ICAM-1) expression and its role in neutrophil-induced ischemia-reperfusion injury in rat liver. J Leukoc Biol, 57, 368-74[Abstract] Francki, A, & Sage, EH. (2001). SPARC and the kidney glomerulus: matri-cellular proteins exhibit diverse functions under normal and pathological conditions. Trends Cardiovasc Med, 11, 32[CrossRef][Web of Science][Medline] [Order article via Infotrieve] French, SW. (2002). Alcoholic hepatitis: Inflammatory cell-mediated hepato-cellular injury. Alcohol, 27, 43-6[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Galambos, JT. (1972). Natural history of alcoholic hepatitis. Histological changes. Gastroenterology, 63, 1026-35[Web of Science][Medline] [Order article via Infotrieve] Giachelli, CM, Lombardi, D, Johnson, RJ, Murry, CE, & Almeida, M. (1998). Evidence for a role of osteopontin in macrophage infiltration in response to pathological stimuli in vivo. Am J Pathol, 152, 353-8[Abstract] Gregory, SH, & Wing, EJ. (1998). Neutrophil-Kupffer cell interaction in host defenses to systemic infections. Immunol Today, 19, 507-10[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Gujral, JS, Bucci, TJ, Farhood, A, & Jaeschke, H. (2001). Mechanism of cell death during hepatic ischemia-reperfusion in rats: Apoptosis or necrosis? Hepatology, 33, 397-405[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Gujral, JS, Farhood, A, Bajt, ML, & Jaeschke, H. (2003). Neutrophils aggravate acute liver injury during obstructive choleostasis in bile-duct ligated mice. Hepatology, 38, 355-63[Web of Science][Medline] [Order article via Infotrieve] Gujral, JS, Liu, J, Farhood, A, Hinson, JA, & Jaeschke, H. (2004). Functional importance of ICAM-1 in the mechanism of neutrophil-induced liver injury in bile duct-ligated mice. Am J Physiol Gastrointest Liver Physiol, 286, G499-507 Gujral, JS, Hinson, JA, Farhood, A, & Jaeschke, H. (2004b). NADPH oxidase-derived oxidant stress is critical for neutrophil cytotoxicity during endotoxemia. Am J Physiol Gastrointest Liver Physiol, 287, G234-52 Hasegawa, T, Malle, E, Farhood, A, & Jaeschke, H. (2005). Generation of hypochlorite-modified proteins by neutrophils during ischemia-reperfusion injury in rat liver: attenuation by ischemic preconditioning. Am J Physiol Gastrointest Liver Physiol, 289, G760-7 Henderson, WR., Jr. (1994). The role of leukotrines in inflammation. Ann Intern Med, 121, 684-97 Hill, DA, Jean, PA, & Roth, RA. (1999). Bile duct epithelial cells exposed to Ho, JS, Buchweitz, JP, Roth, RA, & Ganey, PE. (1996). Identification of factors from rat neutrophils responsible for cytotoxicity to isolated hepatocytes. J Leukoc Biol, 59, 716-24[Abstract] Horbach, M, Gerber, E, & Kahl, R. (1997). Influence of acetaminophen treatment and hydrogen peroxide treatment on the release of CINC-related protein and TNF-alpha from a rat hepatocyte cultures. Toxicology, 121, 117-26[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Ishida, Y, Kondo, T, Ohshima, T, Fujiwara, H, Iwakura, Y, & Mukaida, N. (2002). A pivotal involvement of IFN-gamma in the pathogenesis of acetaminophen-induced acute liver injury. FASEB J, 16, 1227-36 Ito, Y, Abril, ER, Bethea, NW, McCuskey, MK, Cover, C, Jaeschke, H, & McCuskey, RS. (2006). Mechanisms and pathophysiological implications of sinusoidal endothelial cell gap formation following treatment with galactosamine/endotoxin in mice. Am J Physiol Gastrointest Liver Physiol, 291, G211-8 Jaeschke, H. (2000). Reactive oxygen and mechanisms of inflammatory liver injury. J Gastroenterol Hepatol, 15, 718-24[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Jaeschke, H. (2002). Neutrophil-mediated tissue injury in alcoholic hepatitis. Alcohol, 27, 23-7[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Jaeschke, H. (2003). Molecular mechanisms of hepatic ischemia-repurfusion injury and preconditioning. Am J Physiol Gastrointest Liver Physiol, 284, G15-26 Jaeschke, H. (2005). Role of inflammation in the mechanism of acetaminophen-induced hepatotoxicity. Expert Opin Drug Metab Toxicol, 1, 389-97 Jaeschke, H. (2006). Mechanisms of neutrophil-mediated liver cell injury during ischemia-reperfusion and other acute inflammatory conditions. (2006). Am J Physiol Gastrointest Liver Physiol, 290, G1083-8 Jaeschke, H, & Bajt, ML. (2006). Intracellular signaling mechanisms of acetaminophen-induced liver cell death. Toxicol Sci, 89, 31-41 Jaeschke, H, Bautista, AP, Spolarics, Z, & Spitzer, JJ. (1991a). Superoxide generation by Kupffer cells and priming of neutrophils during reperfusion after hepatic ischemia. Free Radic Res Commun, 15, 277-84[Web of Science][Medline] [Order article via Infotrieve] Jaeschke, H, Bautista, AP, Spolarics, Z, & Spitzer, JJ. (1992). Superoxide generation by neutrophils and Kupffer cells during in vivo reperfusion after hepatic ischemia in rats. J Leukoc Biol, 52, 377-82[Abstract] Jaeschke, H, & Farhood, A. (1991). Neutrophil and Kupffer cell-induced oxidant stress and ischemia-reperfusion injury in rat liver in vivo. Am J Physiol, 260, G355-62[Web of Science][Medline] [Order article via Infotrieve] Jaeschke, H, Farhood, A, Bautista, AP, Spolarics, Z, & Spitzer, JJ. (1993a). Complement activates Kupffer cells and neutrophils during reperfusion after hepatic ischemia. Am J Physiol, 264, G801-9[Web of Science][Medline] [Order article via Infotrieve] Jaeschke, H, Farhood, A, Bautista, AP, Spolarics, Z, Spitzer, JJ, & Smith, CW. (1993b). Functional inactivation of neutrophils with a Mac-1 (CD11b/CD18) monoclonal antibody protects against ischemia-reperfusion injury in rat liver. Hepatology, 17, 915-23[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Jaeschke, H, Farhood, A, & Smith, CW. (1990). Neutrophils contribute to ischemis-reperfusion injury in rat liver in vivo. FASEB J, 4, 3355-9[Abstract] Jaeschke, H, Farhood, A, & Smith, CW. (1991). Neutrophil-induced liver cell injury in endotoxin shock is a CD11b/CD18-dependent mechanism. Am J Physiol, 261, G1051-6[Web of Science][Medline] [Order article via Infotrieve] Jaeschke, H, Fisher, MA, Lawson, JA, Simmons, CA, Farhood, A, & Jones, DA. (1998). Activation of caspase 3 (CPP32)-like proteases is essential for TNF-alpha-induced hepatic parenchymal cell apoptosis and neutrophil mediated necrosis in a murine endotoxin shock model. J Immunol, 160, 3480-6 Jaeschke, H, & Hasegawa, T. (2006). Role of neutrophils in acute inflammatory liver injury. Liver Inter, 26, 912-9[CrossRef] Jaeschke, H, Ho, YS, Fisher, MA, Lawson, JA, & Farhood, A. (1999). Glutathione peroxidase deficient mice are more susceptible to neutrophil-mediated hepatic parenchymal cell injury during endotoxemia: importance of an intracellular oxidant stress. Hepatology, 29, 443-5[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Jaeschke, H, & Liu, J. (2007). Neutrophil depletion protects against murine acetaminophen hepatotoxicity: another perspective. (Letter). Hepatology, 45, 1588-9[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Jaeschke, H, & Smith, CW. (1997a). Mechanisms of neutrophil-mediated parenchymal cell injury. J Leukocyte Biol, 61, 647-53[Abstract] Jaeschke, H, & Smith, CW. (1997b). Cell adhesion and migration. III. Leukocyte adhesion and transmigration in the liver vasculature. Am J Physiol, 273, G1169-73[Web of Science][Medline] [Order article via Infotrieve] James, LP, McCullough, SS, Knight, TR, Jaeschke, H, & Hinson, JA. (2003). Acetaminophen toxicity in mice lacking NADPH oxidase activity: role of peroxynitrite formation and mitochondrial oxidant stress. Free Radic Res, 37, 1289-97[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Janeway, CA, & Medhitov, R. (2002). Innate immune recognition. Annu Rev Immunol, 20, 197-216[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Jean, PA, & Roth, RA. (1995). Naphthylisothiocyanate disposition in bile and its relationship to liver glutathione and toxicity. Biochem Pharmacol, 50, 1469-74[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Jolow, DJ, Mitchell, JR, Potter, WZ, Davis, DC, Gillette, JR, & Brodie, BB. (1973). Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo. J Pharmacol Exp Ther, 187, 195-202 Kawashima, R, Mochida, S, Matsui, A, YouLuTuz, ZY, Ishikawa, K, Toshima, K, Yamanobe, F, Inao, M, Ikeda, H, Ohno, A, Nagoshi, S, Uede, T, & Fujiwara, K. (1999). Expression of osteopontin in Kupffer cells and hepatic macrophages and stellate cells in rat liver after carbon tetrachloride intoxication: a possible factor for macrophage migration into hepatic necrotic areas. Biochem Biophys Res Commun, 256, 527-31[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Kim, TH, Mars, WM, Stolz, DB, Petersen, BE, & Michalopoulos, GK. (1997). Extracellular matrix remodeling at the early stages of liver regeneration in the rat. Hepatology, 26, 896-904[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Kodali, P, Wu, P, Lahiji, PA, Brown, EJ, & Maher, JJ. (2006). ANIT toxicity toward mouse hepatocytes in vivo is mediated primarily by neutrophils via CD18. Am J Physiol Gastrointest Liver Physiol, 291, 355-63[CrossRef] Kon, K, Kim, JS, Jaeschke, H, & Lemasters, JJ. (2004). Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes. Hepatology, 40, 1170-1179[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Lawson, JA, Farhood, A, Hopper, RD, Bajt, ML, & Jaeschke, H. (2000). The hepatic inflammatory response after acetaminophen overdose: role of neutrophils. Toxicol Sci, 54, 509-16 Lawson, JA, Fisher, MA, Simmons, CA, Farhood, A, & Jaeschke, H. (1998). Parenchymal cell apoptosis as a signal for sinusoidal sequestration and transendothelial migration of neutrophils in murine models of endotoxin and Fas-antibody induced liver injury. Hepatology, 28, 761-7[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Lee, WM. (2004). Acetaminophen and the US acute liver failure study group: lowering the risks of hepatic failure. Hepatology, 40, 6-9[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Lentsch, AB, Yoshidome, H, Cheadle, WG, Miller, FN, & Edwards, MJ. (1998). Chemokine involvement in hepatic ischemia/reperfusion injury in mice: roles for macrophage inflammatory protein-2 and Kupffer cells. Hepatology, 27, 507-12[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Lieber, CS. (2000). Hepatic, metabolic, and nutritional disorders of alcoholism: from pathogenesis to therapy. Crit Rev Clin Lab Sci, 37, 551-84[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Limaye, P, Apte, U, Shankar, K, Bucci, T, Warbritton, A, & Mehendale, H. (2003). Calpain released from dying hepatocytes mediates progression of acute liver injury induced by model hepatotoxicants. Toxicol Appl Pharmacol, 191, 211-26[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Limaye, PB, Bhave, VS, Palkar, PS, Apte, UM, Sawant, SP, Yu, S, Latendresse, JR, Reddy, JK, & Mehendale, HM. (2006). Upregulation of calpastatin in regenerating and developing rat liver: role in resistance against hepatitoxicity. Hepatology, 44, 379-88[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Liu, P, McGuire, GM, Fisher, MA, Farhood, A, Smith, CW, & Jaeschke, H. (1995). Activation of Kupffer cells and neutrophils for reactive oxygen formation is responsible for endotoxin-enhanced liver injury after hepatic ischemia. Shock, 3, 56-62[Web of Science][Medline] [Order article via Infotrieve] Liu, J, Liu, Y, Hartley, D, Klaassen, CD, Shehin-Johnson, SE, Lucas, A, & Cohen, SD. (1999). Metallothionein-I/II knockout mice are sensitive to acetaminophen-induced hepatotoxicity. J Pharmacol Exp Ther, 289, 580-586 Liu, ZX, Govindaranjan, S, & Kaplowitz, N. (2004). Innate immune system plays a critical role in determining the progression and severity of acetaminophen hepatotoxicity. Gastroenterology, 127, 1760-1774[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Liu, ZX, Han, D, Gunawan, B, & Kaplowitz, N. (2006). Neutrophil depletion protects against murine acetaminophen hepatotoxicity. Hepatology, 43, 1220-30[CrossRef][Web of Science][Medline] [Order article via Infotrieve] MacSween, RN, & Burt, AD. (1986). Histological spectrum of alcoholic liver disease. Semin Liver Dis, 6, 221-32[Web of Science][Medline] [Order article via Infotrieve] Maher, JJ, Scott, MK, Saito, JM, & Burton, MC. (1997). Adenovirus-mediated expression of cytokine-induced neutrophil chemoattractant in rat liver induces a neutrophilic hepatitis. Hepatology, 25, 624-30[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Maher, JJ. (2002). Alcoholic steatosis and steatohepatitis. Semin Gastrointest Dis, 13, 31-9 Mehendale, HM, & Limaye, PB. (2005). Calpain: a death protein that mediated progression of death injury. Trends Pharmacol Sci, 26, 232-6[CrossRef][Medline] [Order article via Infotrieve] Murohisa, G, Kobayashi, Y, Kawasaki, T, Nakamura, S, & Nakamura, H. (2002). Involvement of platelet-activating factor in hepatic apoptosis and necrosis in chronic ethanol-fed rats given endotoxin. Liver, 22, 394-403[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Nagy, L. (2003). Recent insights into the role of the innate immune system in the development of alcoholic liver disease. Exp Biol Med, 228, 882-90 Nanji, A. In Zakim, D, & Boyer, TD (Eds.). (2002). Alcoholic liver disease. Hepatology, A Text Book of Liver Disease (pp.839-922). Philadelphia: W. B. Saunders Nanji, AA, Zhao, S, Lamb, RG, Dannenberg, AJ, Sadrzadeh, SM, & Waxman, DJ. (1994). Changes in cytochromes P-450, 2E1, 2B1, and 4A and phospholipases A and C in the intragastric feeding rat model for alcoholic liver disease: relationship to dietary fats and pathologic liver injury. Alcohol Clin Exp Res, 18, 902-8[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Napirei, M, Basnakian, AG, Apostolov, EO, & Mannherz, HG. (2006). Deoxyribonuclease 1 aggravates acetaminophen-induced liver necrosis in male CD-1 mice. Hepatology, 43, 297-305[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Nelson, SD, & Bruschi, SA. In Kaplowitz, N, & Deleve, LD (Eds.). (2003). Mechanism of acetaminophen-induced liver disease. Drug-Induced Liver Disease (pp.287-325). New York: Marcel-Dekker, Inc Niehorster, M, Tiegs, G, Schade, UF, & Wendel, A. (1991). In vivo evidence for protease-catalysed mechanism providing bioactive tumor necrosis factor alpha. Biochem Pharmacol, 40, 1601-3[CrossRef][Web of Science] Nitti, M, Domenicotti, C, d’Abramo, C, Asserto, S, Cottalasso, D, Melloni, E, Poli, G, Biasi, F, Marinari, UM, & Prozanto, MA. (2002). Activation of PKC-β isoforms mediate HNE-induced MCP-1 release by macrophages. Biochem Biophys Res Commun, 294, 547-52[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Okaya, T, & Lentsch, AB. (2003). Cytokine cascades and the hepatic inflammatory response to ischemia and repurfusion. J Invest Surg, 16, 141-7[Web of Science][Medline] [Order article via Infotrieve] O’Regan, A, & Berman, JS. (2000). Osteopontin: a key cytokine in cell-mediated and granulomatous inflammation. Int J Exp Pathol, 81, 373-90[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Pennington, HL, Wilce, PA, & Worrall, S. (1998). Chemokine and cell adhesion molecule mRNA expression and neutrophil infiltration in lipopolysaccharide-induced hepatitis in ethanol-fed rats. Alcohol Clin Exp Res, 22, 1713-8[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Ramaiah, SK, Rivera, C, & Arteel, GE. (2004). Early-phase alcoholic liver disease: An update on animal models, pathology and pathogenesis. Internat J Toxicol, 23, 217-31[CrossRef] Rose, R, Banerjee, A, & Ramaiah, SK. (2006). Calpain inhibition attenuates iNOS production and midzonal hepatic necrosis in a repeat dose model of endotoxemia in rats. Toxicol Pathol, 34, 785-94 Sahai, A, Malladi, P, Melin-Aldana, H, Green, RM, & Whittington, PF. (2004). Upregulation of osteopontin expression is involved in the development of nonalcoholic steatohepatitis in a dietary murine model. Am J Physiol Gastrointest Liver Physiol, 287, G264-73 Saito, JM, & Maher, JJ. (2000). Bile duct ligation in rats induces biliary expression of cytokine-induced neutrophil chemoattractant. Gastroenterology, 118, 1157-68[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Scaffidi, P, Misteli, T, & Bianchi, ME. (2002). Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature, 418, 191-5[CrossRef][Medline] [Order article via Infotrieve] Schlayer, HJ, Laaff, H, Peters, T, Woort-Menker, M, Estler, HC, Karck, U, Schaefer, HE, & Decker, K. (1988). Involvement of tumor necrosis factor in endotoxin-triggered neutrophil adherence to sinusoidal endothelial cells of mouse liver and its modulation in acute phase. J Hepatol, 7, 239-49[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Shen, W, Kamendulis, LM, Ray, SD, & Corcoran, GB. (1992). Acetaminophen-induced cytotoxicity in cultured mouse hepatocytes: effects of Ca(2+)-endonuclease, DNA repair, and glutathione depletion inhibitors on DNA fragmentation and cell death. Toxicol Appl Pharmacol, 112, 32-40[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Shi, J, Fujieda, H, Kokubo, Y, & Wake, K. (1996). Apoptosis of neutrophils and their elimination by Kupffer cells in rat liver. Hepatology, 24, 1256-63[Web of Science][Medline] [Order article via Infotrieve] Simonet, WS, Hughes, TM, Nguyen, HQ, Trebasky, LD, Danilenko, DM, & Medlock, ES. (1994). Long-term impaired neutrophil migration in mice overexpressing human interleukin-8. J Clin Invest, 94, 1310-9[Web of Science][Medline] [Order article via Infotrieve] Smith, GS, Nadig, DE, Kokoska, ER, Solomon, H, Tiniakos, DG, & Miller, TA. (1998). Role of neutrophils in hepatotoxicity induced by oral acetaminophen administration in rats. J Surg Res, 80, 252-8[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Sodek, J, Zhu, B, Huynh, MH, Brown, TJ, & Ringuette, M. (2002). Novel functions of the matricellular proteins osteopontin and osteonectin/SPARC. Connect Tissue Res, 43, 308-19[Web of Science][Medline] [Order article via Infotrieve] Sweet, MJ, & Hume, DA. (1996). Endotoxin signal transduction in macrophages. J Leukoc Biol, 60, 8-26[Abstract] Takada, H, Mawet, E, Shiratori, Y, Hikiba, Y, Nakata, R, Yoshida, H, Okano, K, Kamii, K, & Omata, M. (1995). Chemotactic factors released from hepatocytes exposed to acetaminophen. Dig Dis Sci, 40, 1831-6[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Thurman, RG, Bradford, BU, Iimuro, Y, Knecht, KT, Arteel, GE, Yin, M, Connor, HD, Wall, C, Raleigh, JA, Frankenberg, MV, Adachi, Y, Forman, DT, Brenner, D, Kaiiska, M, & Mason, RP. (1998). The role of gut-derived bacterial toxins and free radicals in alcohol-induced liver injury. J Gastroenterol Hepatol, 13, S39-50[Web of Science][Medline] [Order article via Infotrieve] Tsukamoto, H, Horne, W, Kamimura, S, Niemela, O, Parkkila, S, Yla-Herttuala, S, & Brittenham, GM. (1995). Experimental liver cirrhosis induced by alcohol and iron. J Clin Invest, 96, 620-30[Web of Science][Medline] [Order article via Infotrieve] Tsung, A, Hoffman, RA, Izuishi, K, Critchlow, ND, Nakao, A, Chan, MH, Lotze, MT, Geller, DA, & Billiar, TR. (2005a). Hepatic ischemia/reperfusion injury involves functional TLR4 signaling in non-parenchymal cells. J Immunol, 175, 7661-8 Tsung, A, Sahai, R, Tanaka, H, Nakao, A, Fink, MP, Lotze, MT, Yang, H, Li, J, Tracey, KJ, Geller, DA, & Billiar, TR. (2005b). The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion. J Exp Med, 201, 1135-43 Uesugi, T, Froh, M, Artell, G, Bradford, B, Wheeler, M, Gabele, E, Isayama, F, & Thurman, R. (2002). Role of lipopolysaccharide-binding protein in early alcohol-induced injury in mice. J Immunol, 168, 2963-9 Uesugi, T, Yin, M, Bradford, BU, Wheeler, MD, Uesugi, T, Froh, M, Goyert, SM, & Thurman, RG. (2001). Toll-Like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice. Hepatology, 34, 101-8[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Wagner, JG, & Roth, RA. (1999). Neutrophil migration during endotoxemia. J Leukoc Biol, 66, 10-24[Abstract] Welty, SE, Smith, CV, Benzick, AE, Montgomery, CA, & Hansen, TN. (1993). Investigation of possible mechanisms of hepatic swelling and necrosis caused by acetaminophen in mice. Biochem Pharmacol, 45, 449-58[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Wiedow, O, & Meyer-Hoffert, U. (2005). Neutrophil serine proteases: potential key regulators of cell signalling during inflammation. J Intern Med, 257, 319-28[Web of Science][Medline] [Order article via Infotrieve] Witthaut, R, Farhood, A, Smith, CW, & Jaeschke, H. (1994). Complement and tumor necrosis factor-alpha contribute to Mac-1 (CD11b-CD18) up-regulation and systemic neutrophil activation during endotoxemia in vivo. J Leukoc Biol, 55, 105-11[Abstract] Xu, J, Lee, G, Wang, H, Vierling, JM, & Maher, JJ. (2004). Limited role for CXC chemokines in the pathogenesis of Yamaguchi, Y, Ohshiro, H, Nagao, Y, Odawara, K, Okabe, K, Hidaka, H, Ishihara, K, Uchino, S, Furuhashi, T, Yamada, S, Mori, K, & Ogawa, M. (2000). Urinary trypsin inhibitor reduces C-X-C chemokine production in rat liver ischemia/reperfusion. J Surg Res, 94, 107-15[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Ziol, M, Tepper, M, Lohez, M, Arcangeli, G, Ganne, N, Christidis, C, Trinchet, JC, Beaugrand, M, Guillet, JG, & Guettier, C. (2001). Clinical and biological relevance of hepatocyte apoptosis in alcoholic hepatitis. J Hepatol, 34, 254-60[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
Toxicologic Pathology, Vol. 35, No. 6,
757-766 (2007) This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
|
|
 |
|
Sign In to gain access to subscriptions and/or personal tools.
Top
Abstract
Introduction
B, the upregulation of ICAM-1 on liver cells (
gene knockout mice and NK and NKT cell-depleted animals show less liver injury and a lower number of neutrophils in the liver after APAP overdose (
