| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
-Inducible Protein-10 (CXCL10) Is Hepatoprotective During Acute Liver Injury Through the Induction of CXCR2 on Hepatocytes1
*
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109; and
Department of Pulmonary and Critical Care Medicine, University of California, Los Angeles, CA 90095-1922
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-inducible protein-10 (IP-10/CXCL10) is a non-ELR-CXC
chemokine that is present during various forms of acute and chronic
liver injury. The purpose of this study was to explore the role of
IP-10 during acute liver injury induced by acetaminophen (APAP). After
a 400 mg/kg APAP challenge in fasted CD-1 mice, immunoreactive levels
of IP-10 were dramatically elevated in the serum within 8 h.
CXCR3, the receptor for IP-10, was up-regulated in the liver. Mice that
received an i.v. injection of rIP-10 10 h after APAP challenge
exhibited a dramatic reduction in alanine aminotransferase 8 h
later. Histologic analysis confirmed that the delayed IP-10 therapy
dramatically improved the appearance of the liver when examined 48
h after APAP. The therapeutic effect of IP-10 was associated with a
marked increase in CXCR2 expression on hepatocytes.
Neutralization of CXCR2 during IP-10 therapy resulted in an
abrogation of the hepatoprotective effect of IP-10. Furthermore, IP-10
treatment of cultured hepatocytes stimulated a CXCR2-dependent
proliferative response. In conclusion, IP-10 has a hepatoregenerative
effect in a murine model of acute liver injury that is dependent on its
up-regulation of CXCR2 on hepatocytes. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Chemokines are chemotactic cytokines that can be divided into four
families dependent on the location of the conserved cysteine residues.
For example, the CXC chemokines contain two conserved cysteine residues
separated by a nonconserved amino acid. The CXC chemokines can be
further divided dependent on which amino acids precede the CXC motif.
The NH2 terminus of some of the CXC chemokines
contains a 3-aa motif (Glu-Leu-Arg: the ELR motif) immediately adjacent
to the CXC motif. The ELR-CXC chemokines, such as IL-8,
macrophage-inflammatory protein (MIP)-2, and epithelial cell-derived
neutrophil-activating protein-78, which bind to CXCR2, have
previously been shown to have a therapeutic role in acute liver injury
after APAP challenge, and after APAP challenge in combination with an
adenovirus (7, 8, 9). The roles of the non-ELR-CXC
chemokines, including IFN--inducible protein-10 (IP-10), monokine
induced by IFN-, and IFN-inducible T cell 
chemoattractant, which bind to CXCR3 and are inducible by the
IFNs, are controversial in liver injury. While some studies have shown
that IP-10 (also known as CXCL10) levels correspond to liver injury
(10, 11), IP-10 has been shown to have hepatoprotective
effects (12), and recent studies have shown that its
elevation correlates to the peak of DNA synthesis (13).
Therefore, the aim of the current study was to elucidate the role of
IP-10 during APAP-induced liver injury. To this end, we examined the
expression pattern of IP-10 and its receptor CXCR3 during an APAP
challenge and found that it was elevated in the serum correlating to
the peak of alanine aminotransferase (ALT), a measurement of liver
injury. Maintaining the elevated IP-10 levels 10 h after an APAP
challenge proved to be quite beneficial by reducing liver injury and
promoting the expression of CXCR2, the receptor for MIP-2, which
appeared to be absolutely necessary for this protective effect.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Female CD-1 (6–8 wk of age) were purchased from Charles River Breeding Laboratories (Portage, MI) and maintained under specific pathogen-free conditions with free access to water and food before each experiment. Fresh suspensions of APAP (Sigma-Aldrich, St. Louis, MO) were made daily by dissolving the compound in PBS warmed to 50°C. In all experiments, mice were deprived of food, but not water, for 18 h before an APAP challenge. APAP was given to each mouse by i.p. injection at a dose of 400 mg/kg, as described previously in detail (9).
Experimental protocols
In preliminary experiments, mice were fasted for 18 h and
received 400 mg/kg APAP. Liver and serum samples were removed from each
mouse at 0 (immediately before APAP challenge), 4, 8, 24, and 48 h
after APAP challenge (Fig. 1
A). In a second set of
experiments, fasted mice received either PBS (0.5 ml) as control or 1
µg of murine rIP-10 (PeproTech, Rocky Hill, NJ) dissolved in
0.5 ml of PBS via an i.v. injection at 10 h after the APAP
challenge. Liver and serum samples were removed from each mouse at 4,
8, 26, 34, 40, and 48 h after PBS or murine rIP-10 therapy (Fig. 1B).
|
B, filled arrows). Immediately after IP-10 treatment, mice
received 0.5 mg of either anti-CXCR2 or goat IgG (i.p.), and then
received another dose 2 h later (Fig. 1B, open arrows).
Liver and serum samples were removed from the mice 8 h after PBS
or IP-10 treatment. Protein detection by ELISA
Murine IP-10 was quantified using a modification of a double ligand method, as previously described. Briefly, flat-bottom 96-well microtiter plates (Nunc Immuno-Plate I 96-F; Nunc, Roskilde, Denmark) were coated with 50 ml/well anti-mouse cytokine Ab (1 mg/ml in 0.6 M NaCl, 0.26 M H3BO4, and 0.08 M NaOH, pH 9.6) for 16 h at 4°C and then washed with wash buffer (PBS, pH 7.5, 0.05% Tween 20). Nonspecific binding sites in each plate were blocked with 2% BSA in PBS and incubated for 90 min at 37°C. Plates were rinsed four times with wash buffer and diluted (neat and 1/10) serum (50 ml) in duplicate was added to each plate and incubated for 1 h at 37°C. Plates were washed four times, followed by the addition of 50 ml/well biotinylated rabbit Abs against the specific cytokines (3.5 mg/ml in PBS, pH 7.5, 0.05% Tween 20, and 2% FCS), and incubated for 30 min at 37°C. After washing, streptavidin-peroxidase conjugate (Bio-Rad, Richmond, CA) was added and the plates were incubated for 30 min at 37°C. After washing again, chromagen substrate (Bio-Rad) was added. The plates were incubated at room temperature to the desired extinction, and the reaction was terminated with 50 ml/well 3 M H2SO4 solution. Plates were read at 490 nm in an ELISA reader. Standards were one-half log dilutions of LPS-free recombinant murine cytokines (R&D Systems, Minneapolis, MN, or PeproTech) from 1 pg/ml to 100 ng/ml. This ELISA method consistently detected murine cytokine concentrations above 25 pg/ml, and ELISA specificity was confirmed for each cytokine and chemokine measured.
Real-time PCR analysis to monitor hepatic IP-10 gene expression
Total RNA was isolated from whole liver samples before and at 4 and 8 h after APAP challenge. A total of 0.5 µg of total RNA was reverse transcribed to yield cDNA, and IP-10 gene expression was analyzed by real-time quantitative RT-PCR procedure using an ABI PRISM 7700 Sequence Detection System (Applied Biosystems, Foster City, CA). GAPDH was analyzed as an internal control. All primers and probes were purchased from Applied Biosystems. IP-10 gene expression was normalized to GAPDH before the fold change in IP-10 was calculated. The fold increase in IP-10 gene expression in APAP-challenged livers was calculated via the comparison of gene expression of this chemokine after the APAP challenge to that detected before the APAP challenge (i.e., t = 0). IP-10 mRNA levels before APAP were assigned an arbitrary value of 1.
RT-PCR to assess hepatic CXCR3 expression
mRNA expression in the liver of APAP-challenged mice was examined using RT-PCR. Briefly, total RNA was isolated from liver homogenates, and 5 µg of total RNA was reverse transcribed to yield cDNA using techniques previously described in detail (14). The following sense and antisense primers, respectively, were used in the PCR reaction: cyclophilin sense 5'-CATCTGCACTGCCAAGACTG-3' and antisense 5'-CTGCAATCCAGCTAGGCATG-3', and CXCR3 sense 5'-ATCAGCGCTTCAATGCCAC-3' and antisense 5'-TGGCTTTCTCGACCACAGTT-3'.
PCR samples were initially incubated for 94°C for 5 min and then cycled 30 times through denaturation at 95°C for 30 s, annealing at 55°C for 45 s, and extension at 72°C for 75 s. PCR products were then separated on 2% agarose gels containing 0.3% ethidium bromide, and the bands corresponding to the intended products were photographed under UV illumination.
Serum ALT measurement
Serum levels of ALT were determined at various times after APAP challenge by Clinical Pathology at the University of Michigan Medical School (Ann Arbor, MI) using standardized techniques.
Histology and immunohistochemistry
A portion of resected liver from each mouse was immediately fixed in 4% paraformaldehyde for a minimum of 12 h. Fixed liver samples were subsequently processed, embedded in paraffin, thin sectioned, and placed on L-lysine-coated slides. H&E staining was used to reveal morphometric differences among groups of mice. Additional slides containing unstained liver sections were used for immunohistochemical analysis. To reveal the presence of CXCR2 in liver sections, other slides were deparaffinized, microwaved for approximately 20 min in 10 mM citric acid buffer, and then allowed to cool to room temperature. Slide-mounted liver sections were blocked using normal goat serum (blocking solution) for 1 h. Tissue sections were treated with purified polyclonal anti-mouse CXCR2 Ab or rabbit IgG for control. All were diluted at 1/25 with TBS containing blocking solution (1/100) and incubated overnight at 4°C. After incubation, slides were washed twice for 5 min in TBS. A 1/35 dilution of biotinylated goat anti-rabbit Ab (BioGenex, San Ramon, CA) was placed on the slides for 2 h at 37°C in a humidified chamber. Slides were again washed twice in TBS and incubated with a 1/35 dilution of streptavidin conjugated to HRP (BioGenex) for 45 min. Following two washes in TBS with 50 mM levamisole, Fast Red chromagen (BioGenex) was placed on each slide, and staining was visualized at low power until color development was complete. The staining reaction was terminated in sterile water, and each slide was counterstained with Mayer’s hematoxylin (0.1%; Sigma-Aldrich).
Cytoplasmic extractions
Preparation of cytoplasmic extracts from liver was conducted as follows. Briefly, liver samples were rapidly homogenized in PBS containing Complete protease inhibitor (10 mg/ml; Boehringer Mannheim, Indianapolis, IN) on ice and washed with fresh PBS. Homogenates were then suspended in buffer A (10 mM HEPES, 10 mM KCl, 0.5 mM DTT, 1% Nonidet P-40) for 10 min and centrifuged for 10 min at 14,000 x g, and the supernatant containing cytoplasmic components was removed.
Western blot analysis
After cytoplasmic protein levels were determined using a Bradford assay (Bio-Rad), 50 µg of liver cytoplasmic extracts were electrophoresed on a 12% polyacrylamide gel and then transferred to a polyvinylidene difluoride (PVDF) membrane (Bio-Rad). Equal protein loading was reconfirmed by Coomassie blue staining of the gel after transfer. PVDF membranes were blocked for 1 h at room temperature in 5% dry milk. CXCR2 Abs were diluted to 1/500 and incubated with PVDF membranes overnight at 4°C. HRP-linked secondary Ab (Pierce, Rockford, IL) were then added at a 1/3000 dilution for 2 h at room temperature, and protein bands were visualized by chemiluminescence (Bio-Rad).
Statistical analysis
Results are expressed as means ± SEM of 5–10 mice per
group at each time point after treatment. All statistical calculations
were performed using GraphPad Prism 2.0 computer software (GraphPad,
San Diego, CA); for all analyses, a Student’s t test was
used to test for significance. p 
0.05 was considered
statistically significant.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
IP-10 protein levels in the serum and IP-10 mRNA levels in the
liver of APAP-challenged mice were examined before challenge and at 4,
8, and 24 h after challenge. As shown in Fig. 2A, immediately prior (i.e.,
0 h) to an i.p. challenge of 400 mg/kg APAP and 4 h after
this challenge, there were no detectable levels of IP-10 in the serum.
In contrast, 8 h after APAP challenge, levels of IP-10 were
dramatically increased (p = 0.01). These
elevated levels are not sustained throughout recovery from APAP
toxicity, and IP-10 levels begin to fall by 24 h after challenge.
Because the regulation of IP-10 in the serum after APAP challenge was
quite dramatic, we next determined whether there was a quantitative
change in IP-10 mRNA in the liver and found that the levels of IP-10 in
the liver were significantly increased at 4 and 8 h after APAP
challenge (Fig. 2B). Thus, an APAP challenge in mice was
associated with systemic and local increases in IP-10 protein and gene
expression.
|
A, RT-PCR analysis revealed
that constitutive CXCR3 mRNA was expressed in liver homogenates before
APAP challenge and increased following the challenge (Fig. 3B). Four hours following the APAP challenge, there was an
almost 2-fold increase in CXCR3 mRNA expression as compared with time 0
as determined by densitometry, and at 8 h following the challenge
there was almost three times more mRNA expressed. Thus, IP-10 and its
receptor CXCR3 were both up-regulated following a sublethal APAP
challenge in mice, which correlates to the time when ALTs, a marker of
acute hepatocellular injury, are at their peak levels (Fig. 4). Therefore, IP-10 levels were not
regulated in the liver, but levels of its receptor were markedly
increased at the gene level corresponding to the time of peak liver
injury.
|
|
Given the marked increase in liver levels of CXCR3 in the
APAP-challenged mice, we next assessed the effect of endogenously
administered IP-10. Given that the greatest increases in CXCR3 were
observed at 8 h after APAP, rIP-10 was administered to mice at
10 h after the APAP challenge. When animals were treated with
rIP-10 or control (PBS) 10 h after a 400-mg/kg dose of APAP (see
protocol outlined in Fig. 1B), IP-10 dramatically
decreased hepatic injury 2 days after challenge. When control animals
were treated with PBS, there is dramatic reduction in centrilobular
hepatocyte necrosis and hemorrhagic injury (Fig. 5A). In contrast, when animals
were treated with rIP-10, there is maintenance of hepatic architecture
and little evidence of hepatocyte injury (Fig. 5B). As shown
in Fig. 6, IP-10 significantly decreased
liver injury at 8 h after administration by 
3-fold
(p = 0.0078). Taken together, these data
demonstrate that IP-10 has a dramatic therapeutic effect 10 h
after an APAP challenge. Subsequent experiments were designed to
address the mechanisms for this therapeutic application.
|
|
Previous studies in our laboratory have shown that MIP-2 and its
receptor CXCR2 have a tremendous therapeutic effect in acute liver
injury due to their hepatoprotective effect (9). To assess
whether CXCR2 mediated the therapeutic effect of IP-10, we examined the
expression of CXCR2 in the presence and absence of exogenous IP-10. As
shown in Fig. 7, IP-10 dramatically
enhanced the expression of CXCR2 protein, as assessed by
immunohistochemistry. Fig. 7A depicts low CXCR2 expression
on hepatocytes after an i.p. challenge with 400 mg/kg APAP and i.v.
injections of PBS 10 h later. In contrast, histological liver
sections from mice that received 1 µg of IP-10 exhibited strong
expression of CXCR2 on hepatocytes at the same time after treatment
(Fig. 7C). Depicted in Fig. 7, B and
D, are the negative controls of Fig. 7, A and
C, respectively.
|
). Although
there was similar expression in both groups of mice at 4 h after
treatment, by 26 h there was a dramatic divergence in CXCR2
expression. For example, mice treated with exogenous IP-10 expressed
much greater levels of CXCR2 protein (as indicated by the 42- and
84-kDa bands) at all subsequent time points examined compared with
controls. The monomeric form of CXCR2 is represented by the 42-kDa
band, and the 84-kDa band represents a SDS-resistant CXCR2 dimer
similar to other G protein-coupled receptors (15, 16).
Thus, IP-10 treatment increased the protein levels of CXCR2 in the
liver.
|
Since IP-10 appeared to up-regulate CXCR2 on hepatocytes within
the liver, we next examined whether this effect accounted for the
therapeutic effect of IP-10. To this end, fasted mice received 400
mg/kg APAP and 1 µg of IP-10 (i.v.) 10 h later. Immediately
after the IP-10 treatment, mice were given 0.5 mg of either
anti-CXCR2 or goat IgG (i.p.) and then received another dose 2
h later. The IP-10 and goat IgG treatment dramatically reduced ALT
levels at 8 h following treatment as compared with control animals
that received PBS and goat IgG (Fig. 9).
In contrast, CXCR2 immunoneutralization strikingly abrogated the
therapeutic effect of IP-10, resulting in 3-fold higher ALT levels than
IP-10 treatment alone. These data strongly suggested that IP-10
mediated its hepatoregenerative effects via CXCR2. Further evidence for
this was observed in histological samples from mice that received
anti-CXCR2 and IP-10 after an APAP challenge (Fig. 10).
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
treatment, there was less injury in an
ischemia-reperfusion model, as shown by a decrease in ALT values
(12). Additionally, more recent data suggest that IP-10
expression correlates with a regenerative response in the liver
(13). In the present study, we examined the role of IP-10
in an acute liver injury model initiated by APAP overdose. While other
chemokines, notably monocyte chemoattractant protein-1 and MIP-2, have
been shown to exert protective and regenerative roles in this model of
liver toxicity (9, 18), the role of IP-10 has not been
previously examined. IP-10 levels were elevated in the serum, while its
receptor, CXCR3, was elevated in the liver after APAP challenge.
Importantly, CXCR3 levels were increased at a time when liver injury
was maximal (8 h), as assessed by serum ALTs. While the cellular source
of the systemically elevated IP-10 was not examined, it is likely that
it is being released from the damaged hepatocytes, similar to that seen
in autoimmune liver diseases (19) and hepatitis
(20). Furthermore, primary murine hepatocytes can release
IP-10 after isolation (20). The presence of increased
CXCR3 expression in the liver prompted us to investigate the potential
effects that this chemokine had on liver injury. When exogenous IP-10
was given 10 h after APAP challenge (corresponding to the time of
maximal CXCR3 expression and liver injury), there was a marked
improvement in liver function, and the histological appearance of the
liver was dramatically improved. This therapeutic effect was striking
in light of the fact that the standard of care in APAP poisoning,
N-acetylcysteine, is no longer effective (6).
Further exploration of this therapeutic application is needed to assess
the potential clinical relevance of this chemokine.
The therapeutic effect of IP-10 appeared to be dependent on the
up-regulation of CXCR2 on hepatocytes, the receptor for MIP-2, while
not having a significant effect on the levels of MIP-2 (data not
shown). MIP-2 and its receptor CXCR2 have previously been shown to play
a central role in recovery from APAP-induced toxicity (9).
These unanticipated results are striking because of the dichotomous
roles that ELR vs non-ELR-CXC chemokines play in other biological
events, particularly angiogenesis (21, 22). While members
of the ELR-CXC chemokine family have been shown to induce endothelial
cell chemotaxis, proliferation, and angiogenesis in vivo
(23), the non-ELR-CXC chemokines are angiostatic
(24). Furthermore, studies on hepatocyte proliferation
have shown that the ELR-CXC chemokines promote hepatocyte
proliferation, but the non-ELR-CXC chemokines are able to block this
proliferative effect (8). Although these results seem to
conflict, similar results have been seen in angiogenesis. For example,
while the ligands for CXCR3, including IP-10, IFN-inducible T cell
chemoattractant, and monokine induced by IFN-, induced
chemotaxis of human microvascular dermal endothelial cells at high
concentrations, they are still capable of inhibiting the chemotactic
response of human microvascular dermal endothelial cells to the ELR-CXC
chemokines (25). While it is known that ELR-CXC
chemokines, including IL-8 and MIP-2, can exist as homodimers
(26, 27), it is possible that cotreatment with IP-10 and
MIP-2 results in the formation of heterodimers (28)
similar to the heterodimer formed by MIP-1 and MIP-1
(29), which may prevent the binding of the chemokine to
its receptor.
Thus, in this study, we have found that IP-10 protein and mRNA levels were increased following APAP challenge, along with up-regulation of its receptor CXCR3 in the liver. These levels began to decline after 8 h, and maintenance of these levels with a 10-h post-treatment of rIP-10 resulted in a dramatic recovery of liver injury due to hepatocyte regeneration. This effect was dependent on CXCR2, which was up-regulated in the liver following APAP challenge. In conclusion, the therapeutic effect of IP-10 post-treatment at a time when conventional treatment is no longer effective was striking and suggests that IP-10 plays a role as a regulator of hepatocyte proliferation.
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Steven L. Kunkel, Department of Pathology, University of Michigan Medical School, 5214 Med. Sci. I, 1301 Catherine Road, Ann Arbor, MI 48109-0602. E-mail address: slkunkel{at}umich.edu
3 Abbreviations used in this paper: APAP, acetaminophen; ALT, alanine aminotransferase; IP-10, IFN--inducible protein-10; MIP, macrophage-inflammatory protein; PVDF, polyvinylidene difluoride.
Received for publication July 13, 2001. Accepted for publication October 4, 2001.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
2-adrenergic receptor transmembrane domain inhibits both receptor dimerization and activation. J. Biol. Chem. 271:16384.-inducible protein 10 (IP-10) is an angiostatic factor that inhibits human non-small cell lung cancer (NSCLC) tumorigenesis and spontaneous metastases. J. Exp. Med. 184:981. and 1 as a native secreted heterodimer. J. Biol. Chem. 276:12404.This article has been cited by other articles:
|
|
 |
|
  K. B. Walsh, R. A. Edwards, K. M. Romero, M. V. Kotlajich, S. A. Stohlman, and T. E. Lane Expression of CXC Chemokine Ligand 10 from the Mouse Hepatitis Virus Genome Results in Protection from Viral-Induced Neurological and Liver Disease J. Immunol., July 15, 2007; 179(2): 1155 - 1165. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. C Henderson, K. J Pollock, J. Frew, A. C Mackinnon, R. A Flavell, R. J Davis, T. Sethi, and K. J Simpson Critical role of c-jun (NH2) terminal kinase in paracetamol- induced acute liver failure Gut, July 1, 2007; 56(7): 982 - 990. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. L. Hokeness, E. S. Deweerd, M. W. Munks, C. A. Lewis, R. P. Gladue, and T. P. Salazar-Mather CXCR3-Dependent Recruitment of Antigen-Specific T Lymphocytes to the Liver during Murine Cytomegalovirus Infection J. Virol., February 1, 2007; 81(3): 1241 - 1250. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Donahower, S. S. McCullough, R. Kurten, L. W. Lamps, P. Simpson, J. A. Hinson, and L. P. James Vascular endothelial growth factor and hepatocyte regeneration in acetaminophen toxicity Am J Physiol Gastrointest Liver Physiol, July 1, 2006; 291(1): G102 - G109. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. P. James, P. M. Simpson, H. C. Farrar, G. L. Kearns, G. S. Wasserman, J. L. Blumer, M. D. Reed, J. E. Sullivan, J. A. Hinson, and The Pediatric Pharmacology Research Unit Network Cytokines and Toxicity in Acetaminophen Overdose J. Clin. Pharmacol., October 1, 2005; 45(10): 1165 - 1171. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Stefanovic, D. A. Brenner, and B. Stefanovic Direct Hepatotoxic Effect of KC Chemokine in the Liver Without Infiltration of Neutrophils Experimental Biology and Medicine, September 1, 2005; 230(8): 573 - 586. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Jaruga, F. Hong, W.-H. Kim, and B. Gao IFN-{gamma}/STAT1 acts as a proinflammatory signal in T cell-mediated hepatitis via induction of multiple chemokines and adhesion molecules: a critical role of IRF-1 Am J Physiol Gastrointest Liver Physiol, November 1, 2004; 287(5): G1044 - G1052. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Ellinger-Ziegelbauer, B. Stuart, B. Wahle, W. Bomann, and H.-J. Ahr Characteristic Expression Profiles Induced by Genotoxic Carcinogens in Rat Liver Toxicol. Sci., January 1, 2004; 77(1): 19 - 34. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. S. Younis, A. R. Parrish, and I. Glenn Sipes The Role of Hepatocellular Oxidative Stress in Kupffer Cell Activation during 1,2-Dichlorobenzene-Induced Hepatotoxicity Toxicol. Sci., November 1, 2003; 76(1): 201 - 211. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. Miller, R. M. Strieter, A. D. Gruber, S. B. Ho, and N. W. Lukacs CXCR2 Regulates Respiratory Syncytial Virus-Induced Airway Hyperreactivity and Mucus Overproduction J. Immunol., March 15, 2003; 170(6): 3348 - 3356. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
