* Department of Pharmacology, Pharmacia & Upjohn, Inc., Kalamazoo, Michigan 49007;
Department of Pathology, University of Texas Health Science Center, Houston, Texas 77030; and
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205
Received September 16, 1999; accepted December 8, 1999
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ABSTRACT |
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Key Words: cytokines; chemokines; adhesion molecules; inflammation, liver necrosis; Mac-1 (CD11b/CD18); L-selectin (CD62L).
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INTRODUCTION |
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Neutrophils have been shown to be involved in a number of liver disease processes including hepatic ischemia-reperfusion injury (Jaeschke, et al., 1990), endotoxemia (Hewett et al., 1992
; Jaeschke et al., 1991
), sepsis (Molnar et al., 1997
), alcoholic hepatitis (Bautista, 1997
) and after exposure to certain chemicals such as
-naphthylisothiocyanate (Dahm et al. 1991
). Neutrophil-induced liver injury is a multistep process that includes the activation and recruitment of these inflammatory cells into the liver vasculature, transendothelial migration, and adherence to parenchymal cells (Jaeschke et al., 1996
; Jaeschke and Smith, 1997
). Members of the C-X-C chemokine family are potent chemoattractants for neutrophils and have been shown to contribute to hepatic neutrophil recruitment and injury during endotoxemia and ischemia-reperfusion (Colletti et al., 1996
; Maher et al., 1997
; Zhang et al., 1995
). In addition, a number of adhesion molecules, particularly members of the ß2 integrin family (CD11/CD18), are required for neutrophil-induced cell killing (Jaeschke, 1997
). One member, Mac-1 (CD11b/CD18), proved to be essential for the adherence-dependent oxidant burst and cell injury (Shappell et al., 1990
). Consequently, antibodies against CD11b and CD18 (Jaeschke et al., 1991
, 1993b
; Liu et al., 1995
), which functionally inactivated neutrophils in vivo, effectively protected against a neutrophil-mediated injury. Therefore, the aims of our study were to characterize and quantify hepatic neutrophil sequestration during AAP overdose in mice and to test whether liver injury can be attenuated by a monoclonal antibody against CD18. In addition, we determined the formation of C-X-C chemokines after AAP to evaluate if these chemoattractants could be responsible for the recruitment of neutrophils into the liver.
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MATERIALS AND METHODS |
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Experimental protocol.
Groups of animals (n = 56) were treated with AAP. At different time points (024 h), animals were anesthetized with pentobarbital (60 mg/kg). Blood was collected from the vena cava into a syringe; 0.1 ml of the blood was heparinized and the rest was allowed to coagulate on ice. All samples were centrifuged and the plasma was used for determination of alanine aminotransferase (ALT) activity with Sigma test kit DG 159-UV. The serum samples were aliquoted and stored at 80°C until analysis. Livers were sectioned transversely across the midportion of each lobe; parts were fixed in phosphate-buffered formalin for histologic analysis, and the rest was frozen in liquid nitrogen for hemoglobin analysis and RNA isolation.
Histology.
Formalin-fixed portions of the liver were paraffin-embedded and 5-µm thick sections were cut. Cell damage was evaluated in parallel sections stained with hematoxylin-eosin. The percentage of necrosis was estimated by evaluating the number of medium power microscopic fields (x 10) with necrosis compared to the entire histologic section. Parallel sections were stained with naphthol AS-D chloroacetate esterase as described in detail (Jaeschke et al., 1996). Neutrophils were counted in 50 high-power fields (x 400) using a Nikon Labophot Microscope. The pathologist (AF) performing the histologic evaluation was blinded as to the treatment of animals.
Biochemical and immunologic analyses.
Serum samples were analyzed for TNF-, KC, and MIP-2 with the respective ELISA kits, i.e., Factor-TestTM Mouse TNF ELISA Kit (Genzyme, Inc., Cambridge, MA), Quantikine Mouse KC (R&D Systems, Inc., Minneapolis, MN). and Quantikine Mouse MIP-2 (R&D Systems, Inc.). Tissue hemoglobin as indicator for hemorrhage was determined with the Total Hemoglobin Kit (Sigma Diagnostics, St. Louis, MO). Briefly, a 20% liver homogenate was prepared in 50 mM Na-phosphate buffer (120 mM NaCl, 10 mM EDTA). After centrifugation at 16,000 x g for 10 min at 4°C, the supernatant was diluted in Drabkin's reagent and the absorbance measured at 550 nm. To account for different background absorbance, the absorbance at 550 nm was obtained from a spectrum (400700 nm). The hemoglobin (Hb) concentration was determined with a calibration curve and calculated as milligrams hemoglobin/gram liver tissue.
Ribonuclease protection assay (RPA).
Total cellular RNA was isolated from mouse liver tissue according to the method of Chomczynski and Sacchi (1987) as described in detail (Essani et al., 1997). For the RPAs, all protocols followed the instructions of the RiboQuant Multi-Probe RNase Protection Assay System (PharMingen, San Diego, CA). Using the In Vitro Transcription Kit and a customized template set containing mouse MIP-2, mouse KC, and L32, a radiolabeled probe set was synthesized using [
-32P]UTP. These probes were hybridized with total RNA isolated from liver tissue for 16 h. After digestion of nonhybridized RNA with RNase, the protected probes were separated on a denaturing acrylamide gel. The gel was dried and then exposed to X-ray film (Kodak X-OMatTM, Fisher Scientific, Pittsburgh, PA) for 12 h at 80°C. The developed X-ray films were scanned using a Bio-Rad GS-710 Calibrated Imaging Densitometer (Bio-Rad Laboratories, Hercules, CA). The images were labeled and printed using Adobe Photoshop 4.0.
Flow cytometric analysis (Essani et al., 1997).
Peripheral blood neutrophils were stained using Coulter Immunology's (Hialeah, FL) whole blood lysis kit according to the manufacturer's instructions. Briefly, 100 µl of whole blood was washed three times with phosphate-buffered saline containing 0.1% bovine serum albumin (PBS/BSA). Cells were resuspended with 100 µl of PBS/BSA containing 1 µg of fluorescein isothiocyanate (FITC)-conjugated RB6-8C5 (anti-GR-1) and phycoerythrin (PE)-conjugated M1/70 (anti-CD11b), or PE-conjugated Mel-14 (anti-L-selectin) antibodies (Pharmingen, San Diego, CA). Following incubation for 30 min on ice, cells were pelleted by centrifugation and washed twice with PBS. Cells were lysed with 1 ml Immuno-Lyse (Coulter) for 2 min at room temperature and fixed with 250 µl of Coulter Clone fixative. Cells were then pelleted by centrifugation, washed twice with PBS, and resuspended in PBS. Two-color analysis of antibody binding to cells was conducted by flow cytometry using a FACScan flow cytometer (Becton Dickinson, San Diego, CA). Peripheral blood neutrophils were gated by the forward and light angle scatter and Gr-1 FITC fluorescence. Nonspecific fluorescence was determined on cells incubated with isotype and cytochrome-matched control antibodies.
Statistics.
Data are given as mean ± SE. Comparisons between multiple groups were performed with one-way ANOVA followed by Bonferroni t test. p < 0.05 was considered significant.
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RESULTS |
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DISCUSSION |
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Further support for the conclusion that neutrophils may not be sufficiently activated to cause additional injury during AAP toxicity comes from the observation that there was neither Mac-1 (CD11b/CD18) upregulation nor L-selectin (CD62L) shedding on circulating neutrophils after AAP administration. Enhanced Mac-1 expression and L-selectin shedding are characteristic for activation of neutrophils (Jutila et al., 1989). In all models where neutrophils accumulated in the liver and contributed to the injury process, upregulation of Mac-1 was observed on circulating neutrophils. This includes hepatic ischemia-reperfusion injury (Jaeschke et al., 1993b
), galactosamine (Gal)/endotoxin (Essani et al., 1995
), Gal/TNF (Essani et al., 1995
), and high doses of endotoxin (Spitzer et al., 1994
; Witthaut et al., 1994
). In contrast, hepatic neutrophil accumulation without Mac-1 upregulation, as seen after Gal/IL-1 administration, did not result in injury (Essani et al., 1995
). The activation status of circulating neutrophils closely reflects those accumulated in the liver vasculature (Spitzer et al., 1994
). Therefore, it can be concluded that there was no relevant systemic activation of neutrophils during AAP intoxication. A potential local activation in the liver, which may be not reflected on circulating cells, appears less likely, because the anti-CD18 antibody had no effect. Previous experience showed that in all models with Mac-1 upregulation on neutrophils, antibodies against CD11b and/or CD18 were highly protective (Jaeschke et al., 1991
, 1993b
; Liu et al., 1995
). Moreover, transcriptional upregulation of ICAM-1 was observed and ICAM-1 antibodies were also beneficial (Essani et al., 1995
; Farhood et al., 1995
). However, toxic doses of AAP did not induce ICAM-1 mRNA expression in the liver (Welty et al., 1993
) suggesting that this important counterreceptor for ß2 integrins is not upregulated on liver cells. Although we can not exclude an involvement of neutrophils at a later stage, the delay between accumulation and the injury was never longer than 57 h. The fact that neutrophils were present in the liver for more than 20 h without involvement in the injury process suggests that neutrophils may not contribute to AAP-induced liver injury unless additional chemotactic factors are generated at later times.
A recent manuscript appears to contradict the findings of our study. Smith et al. (1998) showed a protective effect of an antineutrophil polyclonal antiserum against AAP toxicity in the rat. A limitation of this study is the use of a neutropenia-inducing antiserum. Previous experiments with monoclonal antibodies and antisera, which cause neutropenia, showed that the majority of neutrophils will be accumulating in the liver after treatment (Bautista et al., 1994). These neutrophils are functionally inactivated and are phagocytosed by Kupffer cells (Bautista et al., 1994
). This results in the initial activation and priming of Kupffer cells, as demonstrated by enhanced release of superoxide (Bautista et al., 1994
) and TNF-
(Hewett et al., 1993
). Consequently, prolonged pretreatment, as done in the AAP study (Smith et al., 1998
), may cause inactivation of Kupffer cells. Recent studies showed that inactivation of Kupffer cells has a profound protective effect in the AAP model (Laskin et al., 1995
; Michael et al., 1999
). Thus, without further clarification it is unclear if the protective effect of a neutropenia-inducing antiserum was due to neutrophil or Kupffer cell inactivation. Because of these problems, we used a monoclonal antibody that does not cause neutropenia.
Quantitatively, the number of neutrophils accumulating in the liver after AAP (200250 PMNs/50 HPF) is approximately 5070% of the cell numbers seen after endotoxemia (Chosay et al., 1997), which involves massive formation of proinflammatory cytokines and chemokines (Colletti et al., 1996
; Schlayer et al., 1988
; Zhang et al., 1995
). Consistent with previous observations of TNF-
and IL-1 mRNA and protein formation after AAP (Blazka et al., 1995
), we observed low levels of TNF-
in blood at the time of injury between 4 and 24 h. However, peak plasma levels of 100150 pg/ml were less than 5% of the concentrations measured after endotoxemia (Essani et al., 1995
; Schlayer et al., 1988
). TNF-
and IL-1 are the major cytokines responsible for hepatic neutrophil sequestration after low doses of endotoxin (Essani et al., 1995
; Schlayer et al., 1988
). In addition, TNF-
is responsible for neutrophil activation, as indicated by increased Mac-1 expression (Essani et al., 1995
; Witthaut et al., 1994
). In these experiments, endogenously generated TNF resulted in peak serum levels of 35 ng/ml (Witthaut et al., 1994
). Consistent with these in vivo observations, TNF-mediated upregulation of Mac-1 on neutrophils in vitro requires
1 ng/ml for any effect and 510 ng/ml for maximal expression of Mac-1 (Thompson and Matsushima, 1992
; von Asmuth et al., 1991
). Thus, the minor increase of TNF-
formation after AAP treatment is consistent with the lack of Mac-1 upregulation (Fig. 2
) and ICAM-1 mRNA expression (Welty et al., 1993
). Consequently, it appears unlikely that this very limited cytokine formation could be responsible for neutrophil recruitment into the liver during AAP-induced injury.
Other potential mediators of hepatic neutrophil sequestration could be C-X-C chemokines. Members of this family are potent neutrophil chemoattractants and have been shown to be involved in the neutrophil pathophysiology during ischemia-reperfusion (Colletti et al., 1996; Lentsch et al., 1998
). In addition, transgenic mice that overexpress the human IL-8 gene (Simonet et al., 1994
) or rats transfected with an adenovirus containing the rat chemokine gene CINC (Maher et al., 1997
) have increased numbers of neutrophils in the liver. These observations suggest that a general or local overproduction of C-X-C chemokines can cause neutrophil accumulation in the liver. If this chemokine formation occurs selectively in hepatocytes, neutrophils can transmigrate and attack parenchymal cells, leading to liver damage (Maher et al., 1997
). Our data with AAP showed that both KC and MIP-2 are generated during the injury phase. The fact that mRNA levels of these chemokines increased in the liver indicates that at least some of these peptides were generated in the liver. However, when KC and MIP-2 levels obtained with AAP treatment are compared to those during endotoxemia (KC: 60,00070,000 pg/ml; MIP-2: 12,00015,000 pg/ml) (Lawson and Jaeschke, unpublished), the increase is only less than 5%. Although there is evidence that chemokines may contribute to some degree to hepatic neutrophil recruitment during endotoxemia in a rat model (Zhang et al., 1995
), it seems unlikely that the relative moderate formation of KC and MIP-2 could have a major effect on AAP-induced neutrophil accumulation. This conclusion is supported by our results that intravenous injection of KC and MIP-2 had very little or no effect on neutrophil sequestration in the hepatic vasculature. Thus, neither cytokines nor C-X-C chemokines formed after AAP overdose appear to be generated in sufficient quantities to recruit neutrophils into the liver. This leaves complement factors as potential mediators of hepatic neutrophil sequestration. Cell injury and the substantial release of cell contents can activate complement. Complement factors, e.g., C5a, are potent activators and chemoattractants for neutrophils (Perez, 1984
) and have been shown to be at least partially responsible for hepatic neutrophil accumulation during ischemia-reperfusion (Jaeschke et al., 1993a
) and endotoxemia (Witthaut et al., 1994
). However, more detailed studies are necessary to confirm this hypothesis.
In summary, our study showed an inflammatory response in the liver after AAP overdose with cytokine/chemokine formation and sequestration of neutrophils in the hepatic vasculature. However, neither TNF- nor the C-X-C chemokines KC and MIP-2 are generated in large enough quantities to be able to account for the substantial neutrophil accumulation in the liver. In addition, neutrophils appear to be only moderately activated and interference with ß2 integrins on neutrophils did not prevent injury. Because of the critical importance of ß2 integrins for neutrophil cytotoxicity, these results suggest that neutrophils do not contribute to the initiation or progression of AAP-induced liver during the first 24 h. The moderate inflammatory response after AAP-induced liver injury may be sufficient to remove necrotic cell debris but is not severe enough to cause additional damage.
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ACKNOWLEDGMENTS |
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NOTES |
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