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Abstract |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Acute lung injury (ALI), a severe respiratory syndrome, develops in response to numerous insults and responds poorly to
therapeutic intervention. Recently, cDNA microarray analyses
were performed that indicated several pathogenic responses
during nickel-induced ALI, including marked macrophage activation. Macrophage activation is mediated, in part, via the receptor tyrosine kinase Ron. To address the role of Ron in ALI,
the response of mice deficient in the cytoplasmic domain of
Ron (Ron tk
/) were assessed in response to nickel exposure. Ron tk/ mice succumb to nickel-induced ALI earlier,
express larger, early increases in interleukin-6, monocyte
chemoattractant protein-1, and macrophage inflammatory protein-2, display greater serum nitrite levels, and exhibit earlier onset of pulmonary pathology and augmented pulmonary
tyrosine nitrosylation. Increases in cytokine expression and
cellular nitration can lead to tissue damage and are consistent
with the differences between genotypes in the early onset of
pathology and mortality in Ron tk/ mice. These analyses
indicate a role for the tyrosine kinase receptor Ron in ALI.
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Introduction |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Although initially described over 30 years ago, mortality from acute lung injury (ALI) remains high (35-50%) with an estimated 150,000 cases annually. The principal clinical manifestations of the syndrome include pulmonary edema, cellular infiltration, and airway collapse with hypoxia and multiple organ failure commonly leading to death. The pathogenesis of ALI is complex and typically involves epithelial and macrophage activation, enhanced proteolysis, increased expression of inflammatory mediators, and generation of reactive oxygen and nitrogen species (1, 2). However, questions remain regarding the factors regulating the initiation and progression of this complex response.
Exposure of mice to nickel models the initiation and progression of ALI with the development of pulmonary and perivascular edema, epithelial damage, and cellular infiltration (3, 4). Analysis from cDNA microarrays revealed temporal expression patterns of genes during the progression of nickel-induced ALI consistent with increased macrophage activation, excess nitric oxide (NO) production, and enhanced proteolysis (5).
Many of the responses that were noted with the cDNA microarray analysis, including marked macrophage activation, suggested that receptor tyrosine kinases may be important in the regulation of this complex syndrome. To begin to examine these proteins, we initially focused on the tyrosine kinase domain of Ron. Binding of the ligand hepatocyte growth factor-like protein/macrophage stimulating protein (HGFL/MSP) initiates phosphorylation of specific tyrosine residues within the intracellular catalytic domain of Ron (6). With phosphorylation, docking sites are created for interaction with intracellular signaling molecules, including phosphatidylinositol-3 (PI-3) kinase (7), that modulate several cellular responses, including inhibition of NO synthesis by peritoneal macrophage (8). Because overproduction of NO is damaging to tissue (9), we postulated that through inhibition of NO synthesis, Ron may be important in nickel-induced ALI. To determine the significance of Ron during ALI, mice deficient in the tyrosine kinase domain of this receptor were used. Mice lacking this domain are viable (10), but demonstrate susceptibility to endotoxin with increased lethality in vivo and the overproduction of NO metabolites from isolated macrophage in vitro. In the present study, mice deficient in the tyrosine kinase domain of Ron were assessed for survival, pulmonary cytokine expression, NO synthesis, pulmonary tyrosine nitration, and tissue damage in response to nickel-induced ALI.
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Materials and Methods |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Experimental Design
We proposed that disruption of the Ron signaling pathway would
increase sensitivity to nickel-induced ALI. Therefore, survival time of Ron tk/ mice was monitored relative to Ron tk+/+
mice during continuous exposure to nickel. Disruption of the Ron
signaling pathway could disrupt regulation of cytokine expression,
therefore, we next examined expression of interleukin (IL)-6,
macrophage inflammatory protein (MIP)-2, monocyte chemotactic protein (MCP)-1, tumor necrosis factor (TNF)-
, macrophage
migration inhibitory factor (MIF), IL-1
, regulated upon activation, normal T cells expressed and secreted (RANTES), transforming growth factor (TGF)-, inducible NO synthase (iNOS),
IL-10, IL-12, granulocyte macrophage-colony stimulating factor
(GM-CSF), and interferon (IFN)-
. Because Ron inhibits NO
synthesis, serum nitrite, a stable NO metabolite, was measured
and tyrosine nitration was examined using immunohistochemistry. Lung pathology was evaluated by histology and by lung wet-to-dry weight ratios before exposure and at death.
Mice and Exposure
Mice (6-10 wk; sex matched) containing a deletion of the tyrosine kinase domain of the mouse Ron gene were generated as described (10). Briefly, loxP sites were incorporated into introns
flanking exons 13 and 18 of the Ron gene by homologous recombination into embryonic stem cells, creating a floxed allele (11).
Mice homozygous for the floxed Ron allele were generated by
standard techniques. To delete sequences encompassed by the
loxP sites, mice homozygous for the floxed Ron allele were
mated to mice heterozygous for Cre recombinase driven by the
endogenous hepatocyte nuclear factor 3 gene sequence. Mice
heterozygous for both the floxed Ron allele and Cre recombinase
were backcrossed to mice homozygous for the floxed Ron allele.
In offspring from this cross, Cre mediated deletion of exons 13 through 18 was verified by Southern, PCR, and Western analyses. This deletion occurred at 100% efficiency before embryonic
Day 9.0 due to early systemic Cre expression. The Ron tyrosine
kinase deficient mice express a truncated form of Ron, verified
by Western blot analysis, which, when translated, produces a protein comprised of the entire extracellular and transmembrane domains and 5 amino acids of the cytoplasmic domain (10). For this
study, control mice are designated as Ron tk+/+ and tyrosine kinase deficient mice are designated as Ron tk/. The Ron tk/ mice and Ron tk+/+ mice used in this study were generated
from crosses of hybrid mice (admixture of CD-1, Swiss Black,
and 129). The genetic contribution from this admixture could
contribute to the phenotype of the Ron tk/ mice.
Mice were exposed to aerosolized NiSO4 (115 ± 7 µg/m3) and characterized as previously described (0.2 mm mass median aerodynamic diameter, 1.85 geometric standard deviation) (4) and survival monitored.
Pulmonary Cytokine Analysis
To assess lung cytokine transcript levels, mice (n = 3/time) were
removed from nickel exposure, anaesthetized, exsanguinated, and the lobes of lung removed by incision at the major bronchi and immediately frozen in liquid nitrogen. Total RNA was isolated from homogenized lung (TRIZOL; Life Technologies, Gaithersburg, MD; Tissumizer, Tekmar-Dohrmann, Cincinnati, OH) and
RNase protection assays were performed by modifying protocols
from RiboQuant (PharMingen, San Diego, CA) and RPA III
(Ambion, Austin, TX) (12). Template-sets (PharMingen) contained
the following murine cDNA sequences: IL-6, MIP-2, MCP-1,
TNF-, MIF, IL-1, RANTES, TGF-, iNOS, IL-10, IL-12, GM-CSF, IFN-, and ribosomal protein L32. Antisense, radiolabeled RNA probes were generated from each template-set, 1 µL of
template-set was incubated (37°C, 1 h) with 40 U RNasin, 0.14 mM each GTP/CTP/ATP, 0.003 mM UTP, 10 mM dithiothreitol,
1× Transcription Buffer (PharMingen), 0.1 mCi -32P-uridine
5'-triphosphate (NEN, Boston, MA), and 20 U T7 RNA polymerase. The reaction was terminated by incubation with 2 U RNase-free DNase (37°C, 30 min). Following addition of 2 µg tRNA and
4 µL of 5× stop buffer (5× stop: 1 M ethylenediaminetetraacetic
acid [EDTA], 10% Ficoll, 0.1% bromophenol blue), the radiolabeled probes were column purified (Roche, Indianapolis, IN).
Total RNA (10 µg) was denatured (95°C, 5 min) and hybridized
with 32P-labeled probe diluted to 200,000 cpm/µl (56°C, 16 h) in
16 µL deionized formamide (SigmaUltra) and 0.4 M NaCl, 2.0 mM
EDTA, 0.04 M PIPES, pH 6.6. Following hybridization, single-stranded, unprotected RNA was digested using 3.8 U RNase A/152
U RNase T1/µl RNase Digestion III Buffer (Ambion) (37°C, 1 h).
Protected fragments were precipitated using 225 µL RNase Inactivation/Precipitation III Solution (Ambion) and 100 µL 100%
ethanol, resuspended in 95% formamide, 0.025% xylene cyanol
and bromophenol blue, 18 mM EDTA, 0.025% sodium dodecyl
sulfate, separated by denaturing electrophoresis (6% polyacrylamide gel containing 8 M urea), and quantified by PhosphorImager
analysis (ImageQuant; Molecular Dynamics PhosphorImager, Sunnyvale, CA). The level of expression of each cytokine was
normalized to the intensity of the L32 band.
Serum Nitrite Analyses
To assess serum nitrite levels, mice (n=4/time) were removed from exposure and anesthetized (3.3 mg ketamine; 0.165 mg xylazine; Phoenix, St.Joseph, MO; 0.085 mg acepromazine; Boehringer Ingelheim, Ingelheim, Germany). Blood was collected via the inferior vena cava, allowed to coagulate (30 min, RT), serum separated, and nitrite measured as previously described (13).
Pathology
To assess lung pathology, mice were anesthetized (5 mg Nembutal, Abbott, intraperitoneal), exsanguinated (by severing the descending aorta), and their tracheae exposed and cannulated using 0.58 mm-ID polyethylene tubing (Clay Adams, Parsippany, NJ) inserted through a slit below the larynx. The diaphragm was punctured and the lung infused (1.0 ml 3.7% paraformaldehyde in phosphate buffered saline; infusion pressure = 30 cm H2O). After infusion, the chest wall was opened, trachea ligated, heart, lung, and trachea removed en bloc and immersed in fixative (16 h; 4°C). At 24, 36, 48 h and at death, liver, kidney, and intestine were dissected and immediately placed into 10% buffered formalin (3.7% formaldehyde, pH = 7.4). Tissues were paraffin embedded, sectioned (5 µm), stained with hematoxylin and eosin, and examined by light microscopy. Additional analysis of the lung for nitrotyrosine deposition was performed on paraffin-embedded tissue sections as previously described (10). To assess pulmonary edema, lung wet-to-dry weight ratios were determined for unexposed mice and at death as described previously (4).
Statistical Analysis
The Mantel-Cox rank test was used for survival curve analysis and the t test statistic was used to compare mean survival times. For analysis of lung cytokine expression, serum nitrite, anti-nitrotyrosine stained cells, and lung wet-to-dry weight ratios, means were compared by two-way analysis of variance (ANOVA) followed by Student-Newman-Keuls method for multiple comparisons. When data was not normally distributed (failed the Kolmogorov-Smirnov test), log transformation was performed before ANOVA. Values are presented as means ± SEM. Significance was accepted for values of P < 0.05.
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Results |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Deletion of the Tyrosine Kinase Domain of Ron Increases Sensitivity to Nickel-Induced ALI
To directly test whether disruption of the Ron signaling pathway would increase sensitivity to nickel-induced ALI, Ron
tk/ and Ron tk+/+ mice were monitored for survival
during continuous exposure to nickel. Survival time was decreased for Ron tk/ mice compared with Ron tk+/+ mice
(Figure 1). Although both Ron tk/ and Ron tk+/+ mice
succumbed to nickel-induced ALI, the mean survival time of
Ron tk/ mice preceded Ron tk+/+ mice by 16 h.
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Early Pulmonary Cytokine Expression Is Greater in Ron
tk/ Mice
To explore whether loss of Ron signaling would disrupt
regulation of cytokine expression in response to nickel-induced ALI, RNA levels of 13 inflammatory mediators
were measured. Before exposure, baseline cytokine expression was not different between genotypes. At 12 h,
IL-6, MCP-1, and MIP-2, expression in the lung of Ron
tk/ mice was greater than in Ron tk+/+ mice (Figure 2). By 24 h, IL-6 expression remained greater (4-fold) in
Ron tk/ mice compared with Ron tk+/+ mice, yet
MCP-1 and MIP-2 expression was similar between genotypes. By 36 h, expression of IL-6, MCP-1, and MIP-2 was
similar in Ron tk/ and Ron tk+/+ mice, increasing (> 14-fold) over baseline (data not shown).
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Of the other cytokines measured, a large (3- to 6-fold),
early increase was noted in MIF expression (Table 1). However, MIF expression did not differ between Ron tk/
and Ron tk+/+ mice. Ron tk/ and Ron tk+/+ mice
displayed a similar, late increase in IL-1, and with no significant change in TNF-, TGF-, IL-10, IL-12, iNOS,
RANTES, or GM-CSF. Expression of IFN- was undetectable (Table 1).
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Deletion of the Tyrosine Kinase Domain of Ron Augments Serum Nitrite Levels in Response to Nickel-Induced ALI
To assess whether deletion of the tyrosine kinase domain
of Ron reduces inhibition of NO synthesis, serum nitrite
was measured during nickel-induced ALI. Before exposure, baseline levels of serum nitrite were similar in Ron
tk/ and Ron tk+/+ mice. However, by 24 h, Ron tk/
serum nitrite levels were ~ 2-fold those of Ron tk+/+
mice. Serum nitrite levels increased at 36 and 48 h in both
genotypes with Ron tk/ levels consistently remaining 2-fold more than Ron tk+/+ levels (Figure 3).
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Pulmonary Tyrosine Nitration Is More Pronounced in Ron
tk/ Mice
To assess whether the increase in serum nitrite in Ron
tk/ mice corresponded to enhanced tyrosine nitration
in the lung, the degree of nitrotyrosine deposition was
evaluated by immunohistochemistry. After 24 h of nickel
exposure, the number of antinitrotyrosine stained cells
was greater in Ron tk/ mice than in Ron tk+/+ mice
(Figure 4; Table 2). Antinitrotyrosine staining was distributed throughout the lung, localizing primarily to type II
cells. By 36 h, the number of antinitrotyrosine stained cells
was similar between genotypes.
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Deletion of the Tyrosine Kinase Domain of Ron Hastens Development of Perivascular Edema
Ron tk/ mice displayed an earlier onset of pulmonary
pathology in response to nickel-induced ALI (Figure 5).
By 36 h, perivascular edema had developed primarily in
Ron tk/ mice. At death, pulmonary pathology and pulmonary edema were similar in Ron tk/ and Ron tk+/+
mice, indicated by histology and a lung wet-to-dry weight ratio that increased 1.5-fold in both genotypes (Figure 6).
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Kidney, liver, and intestine histology was also assessed. In the kidney, mild periglomerular cellular infiltration and focal tubular necrosis were apparent in experimental mice at death. In the liver, hepatocyte enlargement was observed in experimental mice at death. The kidney and hepatic pathologies were consistent with hypoxia, most likely resulting from the severe lung injury. Histology of the intestine was unremarkable.
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Discussion |
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Abstract
Introduction
Materials and Methods
Results
Discussion
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These analyses indicate that deletion of tyrosine kinase activity of Ron augments the response to nickel-induced
ALI. Ron tk/ mice succumb earlier to nickel-induced
ALI, express a larger, early increase in IL-6, MCP-1, and
MIP-2, generate increased levels of nitrite, and display an
earlier onset of pulmonary pathology and enhanced tyrosine nitrosylation. Thus, the tyrosine kinase domain of
Ron regulates, in part, the response to nickel-induced ALI.
To examine the enhanced sensitivity of Ron tk/
mice in response to nickel-induced ALI, pulmonary cytokine expression was evaluated. Early increases in the expression of IL-6, MCP-1, and MIP-2 were greater in Ron
tk/ mice than in Ron tk+/+ mice. Elevation of these
cytokines is indicative of epithelial injury and macrophage activation during lung injury. In addition, these cytokines
act in a paracrine fashion to activate resident macrophage
and epithelial cells. This activation accelerates pathogenesis, in part, by augmenting the synthesis of reactive oxygen
and nitrogen species and proteolytic enzymes.
IL-6 can act as an anti-inflammatory mediator (14), yet
IL-6 knockout mice develop less NO formation in response to lung injury (15). The increase in IL-6 expression
at 12 h may have contributed to the increased NO synthesis observed in the Ron tk/ mice. In addition to IL-6,
the increase in MCP-1 expression at 12 h in Ron tk/
mice exceeded that of Ron tk+/+ mice. MCP-1 is a potent
monocyte chemoattractant capable of stimulating monocyte respiratory burst and release of lysosomal enzymes
(16). Along with IL-6 and MCP-1, the increase in MIP-2
was greater in Ron tk/ mice at 12 hours. MIP-2 mediates neutrophilic infiltration (17) and contributes to the
pathogenesis of inflammatory lung disease (18). In addition to the early increase in the expression of IL-6, MCP-1,
and MIP-2, earlier (< 12 h) increases in other cytokines
may have been missed because the first time assessed was at
12 h and these increases likewise could have contributed to
the accelerated onset of pathogenesis and mortality.
Expression of IL-6, MCP-1, and MIP-2 was stimulated
in the Ron tk/ mice as early as 12 h. Evidence from our
previous microarray analysis suggested that activation of
resident alveolar macrophage and epithelial cells is an
early response (3-8 h) to nickel-induced ALI (5). While
Ron has been found to be expressed in airway epithelial
cells (19), expression in resident alveolar macrophage is
uncertain (20, 21). This suggests that epithelial expression of Ron may downregulate select pulmonary cytokine expression in response to ALI.
Recently, the cytokine MIF has emerged as a mediator
in acute respiratory distress syndrome, a severe form of
ALI (22). Recombinant MIF increases sepsis-induced mortality (23) and neutrophilic infiltration (24). Treatment
with a neutralizing anti-MIF antibody is protective, resulting in decreased mortality and diminished neutrophilic infiltration. In response to nickel-induced ALI, MIF expression increased similarly in Ron tk/ and Ron tk+/+ mice. Ron signaling may serve as a downstream inhibitor of
MIF activity with loss of Ron signaling in Ron tk/ mice
accelerating pulmonary pathogenesis and mortality due to
aberrant downstream regulation by this cytokine.
One function of Ron is to inhibit NO synthesis in peritoneal macrophages (10, 13, 25). Whereas the mechanism of
this inhibition is not fully understood, PI-3 kinase activation and NF-
B inhibition have been shown to be important
determinants (8, 26). Synthesis of nanomolar concentrations of NO is requisite for physiologic signal transduction,
yet at micromolar concentrations, NO is damaging to tissue and is associated with mortality (9). Previously, several
genes known to be altered by reactive oxygen species and
the excess production of NO (e.g., glutathione-S-transferase, metallothionein, heme oxygenase) were found increased in response to nickel-induced ALI (5). When reactive oxygen species, such as superoxide, are abundant, they
can react with excess NO to produce peroxynitrite (27).
Peroxynitrite is capable of nitrating biologic molecules, including tyrosine residues, thiol groups, nucleic acids, and
lipids, thereby impairing cellular function. In addition to
elevated serum nitrite levels in Ron tk/ mice, pulmonary tyrosine nitration exceeded that of Ron tk+/+ mice. Excess NO contributes to enhanced vascular permeability
in response to ALI (28). Possibly the larger early increase
in NO and enhanced tyrosine nitration in Ron tk/ induced the earlier onset of perivascular edema and lethality
in response to nickel-induced ALI.
In response to nickel-induced ALI, iNOS gene expression remained unchanged in either genotype. In macrophages, Ron signaling via PI-3 kinase decreases iNOS gene expression. However, when PI-3 kinase is blocked using wortmannin, NO levels are still attenuated, suggesting that Ron is capable of inhibiting NO synthesis separate from the inhibition of iNOS (8). Because macrophage also express constitutive NO synthases (29, 30), it is possible that the regulation of NO by Ron in response to nickel- induced ALI is through the modulation of NO synthesis by constitutive isoforms.
Notably, Ron tk/ mice succumb to nickel-induced
ALI earlier than any inbred strain previously examined (4).
The sensitive mouse strain, A, succumbs to nickel-induced
ALI hours earlier than the resistant C57BL/6 strain, and
death in Ron tk/ mice precedes that of A mice. At
death, Ron tk/, A, and C57Bl/6, mice develop pulmonary edema (increased lung wet-to-dry weight ratio). Although unique factors such as genetic determinants, including those that regulate signaling pathways, may determine sensitivity, pulmonary edema is a consistent end stage response. The early increase in cytokine expression, large increase in NO, early onset of perivascular edema, pulmonary nitration, and death in Ron tk/ mice suggests that
Ron regulates critical responses to nickel-induced ALI.
In summary, our studies indicate that deletion of the
tyrosine kinase domain of Ron increases sensitivity to
nickel-induced ALI. Decreased survival time in Ron tk/
mice, larger, early increases in IL-6, MCP-1, and MIP-2,
augmented serum nitrite levels, earlier onset of pulmonary
pathology, and enhanced tyrosine nitration indicate the
critical role of Ron in regulation of the response to ALI
and suggest targets for therapeutic intervention.
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Footnotes |
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Address correspondence to: Susan E. Waltz, Ph.D., Division of Developmental Biology, Children's Hospital Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229. E-mail: swaltz{at}chmcc.org
(Received in original form May 3, 2001 and in revised form August 31, 2001).
Abbreviations: acute lung injury, ALI; granulocyte macrophage-colony stimulating factor, GM-CSF; hepatocyte growth factor-like protein/macrophage stimulating protein, HGFL/MSP; interferon-, IFN-; interleukin, IL; inducible NO synthase, iNOS; monocyte chemotactic protein,
MCP; macrophage migration inhibitory factor, MIF; macrophage inflammatory protein, MIP; nitric oxide, NO; phosphatidylinositol-3, PI-3; regulated upon activation, normal T cells expressed and secreted, RANTES;
transforming growth factor, TGF; tumor necrosis factor, TNF.
Acknowledgments: This study was supported by the Marion Merrel Dow Foundation (S.E.W.), the March of Dimes Organization (S.E.W.), the American Heart Association (S.E.W.), a Board of Trustees grant from the Children's Hospital Research Foundation (S.E.W.), by grants HD-36888 (S.E.W.), DK-47003 (S.J.F.D.), DK-58182 (S.J.F.D.), ES10562 (G.D.L.), HL-65612 (G.D.L.), ES06096 (G.D.L.), HL-65613 (G.D.L.), from the National Institutes of Health, and by the Health Effects Institute (G.D.L.). The Health Effects Institute is an organization jointly funded by the US Environmental Protection Agency, Assistance Agreement X-812059, and automotive manufacturers. The contents of this article do not necessarily reflect the views of the Health Effects Institute or the policies of the US Environmental Protection Agency or automotive manufacturers. S.M. is a recipient of the US Environmental Protection Agency Science to Achieve Results Graduate Fellowship and the Albert J. Ryan Fellowship, and this work was conducted in partial fulfillment of the requirements for the Ph.D. degree at the University of Cincinnati.
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References |
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Materials and Methods
Results
Discussion
References
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1. Pittet, J. F., R. C. Mackersie, T. R. Martin, and M. A. Matthay. 1997. Biological markers of acute lung injury: prognostic and pathogenetic significance. Am. J. Respir. Crit. Care Med. 155: 1187-1205 [Medline].
2. Jobe, A. H., and M. Ikegami. 1998. Surfactant and acute lung injury. Proc. Assoc. Am. Physicians 110: 489-495 . [Medline]
3. Benson, J. M., I. Y. Chang, Y. S. Cheng, F. F. Hahn, C. H. Kennedy, E. B. Barr, K. R. Maples, and M. B. Snipes. 1995. Particle clearance and histopathology in lungs of F344/N rats and B6C3F1 mice inhaling nickel oxide or nickel sulfate. Fundam. Appl. Toxicol. 28: 232-244 [Medline].
4.
Wesselkamper, S. C.,
D. R. Prows,
P. Biswas,
K. Willeke,
E. Bingham, and
G. D. Leikauf.
2000.
Genetic susceptibility to irritant-induced acute lung
injury in mice.
Am. J. Physiol. Lung Cell Mol. Physiol.
279:
L575-L582
5.
McDowell, S. A.,
K. Gammon,
C. J. Bachurski,
J. S. Wiest,
J. E. Leikauf,
D. R. Prows, and
G. D. Leikauf.
2000.
Differential gene expression in the
initiation and progression of nickel-induced acute lung injury.
Am. J. Respir. Cell Mol. Biol.
23:
466-474
6.
Wang, M. H.,
A. Iwama,
A. Skeel,
T. Suda, and
E. J. Leonard.
1995.
The murine stk gene product, a transmembrane protein tyrosine kinase, is a receptor
for macrophage-stimulating protein.
Proc. Natl. Acad. Sci. USA
92:
3933-3937
7. Iwama, A., N. Yamaguchi, and T. Suda. 1996. STK/RON receptor tyrosine kinase mediates both apoptotic and growth signals via the multifunctional docking site conserved among the HGF receptor family. Embo J. 15: 5866-5875 [Medline].
8.
Chen, Y. Q.,
J. H. Fisher, and
M. H. Wang.
1998.
Activation of the RON receptor tyrosine kinase inhibits inducible nitric oxide synthase (iNOS) expression by murine peritoneal exudate macrophages: phosphatidylinositol-3 kinase is required for RON-mediated inhibition of iNOS expression.
J.
Immunol.
161:
4950-4959
9. MacMicking, J. D., C. Nathan, G. Hom, N. Chartrain, D. S. Fletcher, M. Trumbauer, K. Stevens, Q. W. Xie, K. Sokol, and N. Hutchinson. 1995. Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell 81: 641-650 [Medline].
10. Waltz, S. E., L. Eaton, K. Toney-Earley, K. A. Hess, B. E. Peace, J. R. Ihlendorf, M.-H. Wang, K. H. Kaestner, and S. J. F. Degen. 2001. Ron- mediated cytoplasmic signaling is dispensable for viability but is required to limit inflammatory responses. J. Clin. Invest. 108: 567-576 [Medline].
11. Waltz, S. E., C. L. Toms, S. A. McDowell, L. A. Clay, R. S. Muraoka, E. L. Air, W. Y. Sun, M. B. Thomas, and S. J. Degen. 1998. Characterization of the mouse Ron/Stk receptor tyrosine kinase gene. Oncogene 16: 27-42 [Medline].
12.
Bachurski, C. J.,
G. S. Pryhuber,
S. W. Glasser,
S. E. Kelly, and
J. A. Whitsett.
1995.
Tumor necrosis factor-alpha inhibits surfactant protein C gene
transcription.
J. Biol. Chem.
270:
19402-19407
13. Muraoka, R. S., W. Y. Sun, M. C. Colbert, S. E. Waltz, D. P. Witte, J. L. Degen, S. J. Friezner, and Degen. 1999. The Ron/STK receptor tyrosine kinase is essential for peri-implantation development in the mouse. J. Clin. Invest. 103: 1277-1285 [Medline].
14. Meng, Z. H., K. Dyer, T. R. Billiar, and D. J. Tweardy. 2000. Distinct effects of systemic infusion of G-CSF vs. IL-6 on lung and liver inflammation and injury in hemorrhagic shock. Shock 14: 41-48 [Medline].
15.
Cuzzocrea, S.,
L. Sautebin,
G. De Sarro,
G. Costantino,
L. Rombola,
E. Mazzon,
A. Ialenti,
A. De Sarro,
G. Ciliberto,
M. Di Rosa,
A. P. Caputi, and
C. Thiemermann.
1999.
Role of IL-6 in the pleurisy and lung injury
caused by carrageenan.
J. Immunol.
163:
5094-5104
16.
Rollins, B. J.,
A. Walz, and
M. Baggiolini.
1991.
Recombinant human MCP-1/JE induces chemotaxis, calcium flux, and the respiratory burst in human
monocytes.
Blood
78:
1112-1116
17.
Wolpe, S. D.,
B. Sherry,
D. Juers,
G. Davatelis,
R. W. Yurt, and
A. Cerami.
1989.
Identification and characterization of macrophage inflammatory
protein 2.
Proc. Natl. Acad. Sci. USA
86:
612-616
18. Driscoll, K. E., D. G. Hassenbein, J. Carter, J. Poynter, T. N. Asquith, R. A. Grant, J. Whitten, M. P. Purdon, and R. Takigiku. 1993. Macrophage inflammatory proteins 1 and 2: expression by rat alveolar macrophages, fibroblasts, and epithelial cells and in rat lung after mineral dust exposure. Am. J. Respir. Cell Mol. Biol. 8: 311-318 .
19. Sakamoto, O., A. Iwama, R. Amitani, T. Takehara, N. Yamaguchi, T. Yamamoto, K. Masuyama, T. Yamanaka, M. Ando, and T. Suda. 1997. Role of macrophage-stimulating protein and its receptor, RON tyrosine kinase, in ciliary motility. J. Clin. Invest. 99: 701-709 [Medline].
20.
Iwama, A.,
M.-H. Wang,
N. Yamaguchi,
K. Okano,
T. Sudo,
F. Gervais,
C. Morissette,
E. J. Leonard, and
T. Suda.
1995.
Terminal differentiation of
murine resident peritoneal macrophages is characterized by expression of
the STK protein tyrosine kinase, a receptor for macrophage-stimulating
protein.
Blood
86:
3394-3403
21.
Waltz, S. E.,
S. A. McDowell,
R. S. Muraoka,
E. L. Air,
L. M. Flick,
Y. Q. Chen,
M. H. Wang, and
S. J. Degen.
1997.
Functional characterization of
domains contained in hepatocyte growth factor-like protein.
J. Biol. Chem.
272:
30526-30537
22. Donnelly, S. C., C. Haslett, P. T. Reid, I. S. Grant, W. A. Wallace, C. N. Metz, L. J. Bruce, and R. Bucala. 1997. Regulatory role for macrophage migration inhibitory factor in acute respiratory distress syndrome. Nat. Med. 3: 320-323 [Medline].
23. Calandra, T., B. Echtenacher, D. L. Roy, J. Pugin, C. N. Metz, L. Hultner, D. Heumann, D. Mannel, R. Bucala, and M. P. Glauser. 2000. Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nat. Med. 6: 164-170 [Medline].
24.
Bozza, M.,
A. R. Satoskar,
G. Lin,
B. Lu,
A. A. Humbles,
C. Gerard, and
J. R. David.
1999.
Targeted disruption of migration inhibitory factor gene
reveals its critical role in sepsis.
J. Exp. Med.
189:
341-346
25.
Wang, M. H.,
G. W. Cox,
T. Yoshimura,
L. A. Sheffler,
A. Skeel, and
E. J. Leonard.
1994.
Macrophage-stimulating protein inhibits induction of nitric
oxide production by endotoxin- or cytokine-stimulated mouse macrophages.
J. Biol. Chem.
269:
14027-14031
26.
Liu, Q. P.,
K. Fruit,
J. Ward, and
P. H. Correll.
1999.
Negative regulation of
macrophage activation in response to IFN-gamma and lipopolysaccharide
by the STK/RON receptor tyrosine kinase.
J. Immunol.
163:
6606-6613
27. Eiserich, J. P., R. P. Patel, and V. B. O'Donnell. 1998. Pathophysiology of nitric oxide and related species: free radical reactions and modification of biomolecules. Mol. Aspects Med. 19: 221-357 [Medline].
28. Matsuo, N.. 1999. The role of intrapulmonary nitric oxide generation in the development of adult respiratory distress syndrome. Surg. Today 29: 1068-1074 [Medline].
29. van Straaten, J. F., D. S. Postma, W. Coers, J. A. Noordhoek, H. F. Kauffman, and W. Timens. 1998. Macrophages in lung tissue from patients with pulmonary emphysema express both inducible and endothelial nitric oxide synthase. Mod. Pathol. 11: 648-655 [Medline].
30.
Miles, P. R.,
L. Bowman,
A. Rengasamy, and
L. Huffman.
1998.
Constitutive nitric oxide production by rat alveolar macrophages.
Am. J. Physiol.
Lung Cell Mol. Physiol.
274:
L360-L368
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