| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* Meakins Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec, Canada; and
Merck Frosst Centre for Therapeutic Research, Dorval, Quebec, Canada
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The airway responses to allergen challenge are complex phenomena that
involve mast cells, eosinophils, and T cells, in particular
CD4+ T cells of the Th2 phenotype (6).
PGE2 has been shown to have effects on all of these cell
types in vitro, although some effects are likely to promote allergic
inflammation, whereas others may act to suppress it. PGE2
may induce IL-6 but suppress TNF-
synthesis by mast cells
(7). It also promotes histamine and GM-CSF release from
mast cells (8). PGE2 inhibits IgE production
by human B cells (9), but it may also affect T cell help
for Ab synthesis so as to favor IgE synthesis and allergic-type
inflammation (10). A similar role in Th2 biasing of T cell
responses has been shown in BALB/c mice through inhibition of IFN-
(11).
The diverse biological effects of PGE2 are attributable to the presence of four receptors (EP1–4), of which two are positively coupled to adenylate cyclase (EP2 and EP4) and two (EP1 and EP3) act by stimulating phosphoinositide-specific phospholipase C and inhibit adenylate cyclase (reviewed in Ref. 12). It is difficult to predict the nature of the in vivo effects of PGE2 on allergic airway responses because of the complexity of its cellular effects. We hypothesized, however, that PGE2 would inhibit Th2 cytokine expression and cys-LT synthesis in the airways after allergen challenge and in so doing would inhibit allergic bronchoconstriction. The aim of this study was to examine the effects of PGE2 on both allergen-induced early (EAR) and late bronchoconstriction and allergic inflammation in a well-characterized model of allergic asthma. To investigate the mechanism of these effects, we measured Th1 and Th2 cell markers, cys-LT levels in BALF, and the distribution of PGE2 receptor subtypes in the lung.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Male BN rats between 7 and 9 wk of age were purchased from Harlan Sprague Dawley U.K. (Blackthorn, U.K.) and maintained in a conventional animal facility at McGill University (Montreal, Canada). All rats were actively sensitized with a s.c. injection of 1 mg of OVA (grade V; Sigma-Aldrich, St. Louis, MO) precipitated in 4.28 mg of aluminum hydroxide gel (Anachemia Chemicals, Montreal, Canada) in 1 ml of normal saline. Simultaneously, 0.5 ml of Bordetella pertussis vaccine containing 6 x 109 heat-killed bacilli/ml (Institut Armand Frappier, Laval-Des-Rapides, Canada) was injected i.p. as an adjuvant. A booster sensitization was performed at 7 days. Animals were anesthetized with pentobarbital (35 mg/kg i.p.), intubated, and exposed to an aerosol of 5% OVA (w/v) for 5 min.
For the evaluation of the effects of PGE2 on the EAR, LAR, and airway inflammation, four groups of sensitized rats were studied. The first group was challenged with aerosolized OVA after administration of the vehicle saline (100 µl) intratracheally by insufflation. The second group was challenged with aerosolized OVA after an intratracheal insufflation of PGE2 (1 µg). The third group was challenged with aerosolized OVA after an intratracheal insuffation of PGE2 (3 µg), and the fourth group was challenged with aerosolized BSA after an intratracheal insufflation of saline (100 µl).
Measurement of airway responses to Ag challenge
Two weeks after sensitization, animals were anesthetized with
urethan (1.25 g/kg i.p.) for measurements of allergen-induced airway
responses. Animals were intubated endotracheally with polyethylene
tubing (PE240; Commercial Plastics, Montreal, Canada) and placed on a
heating pad to maintain a rectal temperature of 36°C. Airflow was
measured by placing the tip of the endotracheal tube inside a Plexiglas
box (
250 ml). A pneumotachograph (Fleisch No. 0; Bionetics,
Montreal, Canada) coupled to a differential transducer (PX 170-14DV;
Omega Engineering, Stamford, CN) was connected to the other end of the
box to measure airflow. A water-filled catheter connected to a pressure
transducer (Transpac II; Sorenson, Abbott, IL) was advanced into the
lower end of the esophagus to measure changes in transpulmonary
pressure. Pulmonary resistance (RL) was
determined by multiple linear regression from transpulmonary pressure
and airflow using commercial software (RHT Infodat, Montreal, Canada)
(13).
Animals were challenged for 5 min with an aerosol of either OVA or BSA (5% w/v). A disposable nebulizer (Hudson model 1400; Hudson, Temecula, CA) was used with an output of 0.15 ml/min. RL was measured every 5 min for 30 min after challenge and subsequently at 15-min intervals for a total period of 8 h. The EAR was defined as the maximal value of RL, expressed as percent baseline RL, in the first 30 min after challenge. The LAR was calculated as the area under the curve of RL against time (cm H2O · ml-1 · s min) from 3 to 8 h after challenge, after correction of RL for the baseline value. Animals were then sacrificed for bronchoalveolar lavage (BAL).
Bronchoalveolar lavage
BAL was performed 8 h after challenge with five
instillations of 5 ml of saline. The first 5-ml aliquot was spun, and
the supernatant was used for analysis of cys-LTs. Approximately 22 ml
of fluid were recovered with each BAL, and the volume did not differ
significantly among treatment groups. The total cell count and cell
viability were estimated using a hemacytometer and trypan blue stain.
Slides were prepared using a Cytospin model II (Shandon, Pittsburgh,
PA). The differential cell count was assessed with
May-Grünwald-Giemsa staining, eosinophil counts by
immunocytochemistry, and IL-4, IL-5, and IFN- mRNA by in situ
hybridization.
Immunocytochemistry and in situ hybridization for eosinophils and T cell cytokines
Cytospin slides were prepared on poly-L-lysine-coated glass slides, fixed in 4% paraformaldehyde, and washed with PBS before processing. BAL cells were immunostained with an Ab, BMK13 mAb (kindly provided by Dr. R. Moqbel (University of Alberta, Edmonton, Canada), directed against major basic protein (MBP) using the alkaline phosphatase anti-alkaline phosphatase method. MBP-positive cells were counted by an investigator blinded to group status. A minimum of 500 BAL cells was counted, and the percentage of cells expressing MBP immunoreactivity was evaluated.
In situ hybridization was performed as previously described
(14) on cytospins from rats in experimental groups 1, 3,
and 4. Antisense and sense riboprobes were prepared from cDNAs coding
for rat IL-4, IL-5, and IFN- mRNA. cDNAs were first inserted into a
pGEM vector and linearized with appropriate enzymes. In vitro
transcription was conducted in the presence of [35S]-UTP
and the T7 or SP6 RNA polymerases. After permeabilization and
prehybridization steps, the preparations were incubated with antisense
or sense probes (106 cpm/section). Posthybridization
washing was performed in decreasing concentrations of standard saline
citrate at 40°C. Unhybridized single-strand RNA was removed by RNase
A (20 mg/ml). After dehydration, the slides were immersed in NBT2
emulsion and exposed for 10 days. The autoradiographs were developed in
Kodak D-19, fixed, and counterstained with hematoxylin. Slides were
coded, and positive cells were counted blindly. For negative controls,
cytospins were hybridized with sense probes or pretreated with RNase
before the application of probes.
EP receptor distribution in pulmonary tissues
We examined the distribution of EPR mRNA in the lungs of two sensitized and two naive rats. Fourteen days after sensitization, the lungs were removed, fixed, and sectioned in 4-µm-thin slices on silane-coated slides. Hybridization was performed using digoxigenin-labeled RNA probes. The probes were constructed using PCR amplification and cloning into the PCR-II vector (Invitrogen, San Diego, CA). The cRNA probe for the EP1 receptor mRNA was obtained from a 226-bp fragment from 715 to 941 of the rEP1 coding sequence. For the EP2 receptor, we used a 192-bp cRNA probe hybridizing to a segment corresponding to positions 683–875. For the EP3 receptor, we used a 242-bp cRNA probe hybridizing to positions 765–1007. This particular probe hybridizes with all EP3 splice variants. Finally, for the EP4 receptor, we used a 321-bp cRNA probe hybridizing to positions 812–1133. The plasmids were linearized, and digoxigenin-labeled cRNA sense and antisense probes were synthesized using the DIG-RNA labeling kit from Boehringer Mannheim (Laval, Canada). For in situ hybridization, a standard protocol was used as previously described (15). Detection of the digoxigenin-labeled cRNA probe was performed using HRP-linked Abs (Boehringer Mannheim) and diaminobenzidine substrate (Pierce, Rockford, IL). The tissues were counterstained with hematoxylin (Fisher, Nepean, Canada).
Analysis of BAL cys-LTs
The levels of cys-LTs in BALF were measured using an enzyme immunoassay following the manufacturer’s instructions (Cayman Chemical, Ann Arbor, MI). The antiserum is reported to have cross-reactivity for leukotrienes (LT) C4 (100%), D4 (100%), and E4 (67%). Methanol was added to each BALF sample (500 µl), and the precipitated protein was removed by centrifugation. A solid phase extraction cartridge (Cayman Chemical) was used to extract cys-LTs that were eluted with HPLC grade hexane. The samples were then dried by vacuum centrifugation and reconstituted in enzyme immunoassay buffer. Samples were placed in 96-well plates in duplicate and incubated for 18 h at room temperature with acetylcholinesterase tracer and cys-LT antiserum. Ellman’s reagent was then added and developed for 60–90 min. The plates were read at 405 nm. A standard curve was constructed using concentrations of LTD4 ranging from 7.8 to 1000 pg/ml. Results were not corrected for extraction efficiency.
Statistical analysis
Comparisons among several means were performed by ANOVA, and post hoc testing was done with a Tukey test or a Fisher least significant difference test. Values of p < 0.05 were considered significant.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Sensitized rats undergoing challenge with OVA showed rapid albeit
minor increases in RL (Fig. 1
). The increase in
RL was sustained throughout most of the 8-h
period of observation after challenge. There were further superimposed
peaks in RL 200 and 350 min after
challenge. Rats challenged with BSA had values of
RL that were slightly below the baseline,
whereas rats challenged with OVA after PGE2 pretreatment (3
µg) had also markedly attenuated responses to OVA challenge (Fig. 1).
A lower dose of PGE2 (1 µg) had a similar inhibitory
effect (the data have been omitted from the figure for clarity). There
was a significant EAR in the OVA-sensitized and OVA-challenged rats
compared with the OVA-sensitized and BSA-challenged controls
(p = 0.04). The EAR showed a dose-dependent
reduction with PGE2 pretreatments of 1 and 3 µg
intratracheally (Fig. 2). The inhibition
reached significance after the 3 µg dose (p =
0.01). The LAR after OVA challenge was statistically significantly
inhibited by PGE2, 1 µg (p =
0.02) and 3 µg (p = 0.002), and was different
from the BSA-challenged controls (p = 0.004;
Fig. 3).)
|
|
|
The total cell counts were significantly higher in the
OVA-challenged rats with or without PGE2 (3 µg)
pretreatment compared with the BSA-challenged rats
(p = 0.04; Fig. 4). The differential cell counts obtained
using the May-Grünwald-Giemsa stain did not show any
statistically significant differences. Although granulocyte numbers
tended to be lower in the PGE2-pretreated rats, these
differences were not significant. No attempt was made to distinguish
between neutrophils and eosinophils using May-Grünwald-Giemsa
staining because of previous observations that this stain tends to lead
to an underestimate of eosinophil numbers in OVA-challenged BN rats
(16). For this reason, eosinophils were analyzed using
immunochemical staining instead. There was a substantial eosinophilia
after OVA challenge (10%; p < 0.001). After 3 µg
PGE2 pretreatment, there was a substantial reduction in
eosinophil numbers to <2% of BAL cells (p =
0.001; Fig. 5). This latter value was not
different from eosinophil numbers in the BALF of the
BSA-challenged rats.
|
|
mRNA-positive cells in BALF
Cytokine expression in BAL cells from OVA- or BSA-challenged and
saline-pretreated rats was compared with OVA-challenged and
PGE2-pretreated animals. Only rats pretreated with
PGE2 3 µg intratracheally were studied because this dose
seemed to produce a maximal inhibitory effect on the LAR. Approximately
10% of BAL cells of OVA-challenged rats were positive for IL-5 mRNA by
in situ hybridization (Fig. 6A). This number was reduced
to 3% by PGE2 (p < 0.001)
which was comparable with the BSA-challenged rats (2%;
p = NS). IL-4 mRNA-positive cells were 8% of the
BAL cells in OVA-challenged rats (Fig. 6B), and there was a
small but significant reduction in this number to 6% after
PGE2 pretreatment (p = 0.012).
About 3% of BAL cells were IL-4 positive in the BSA-challenged group,
which was significantly less than in the PGE2-pretreated
group (p = 0.003) and in the OVA-challenged
group (p < 0.001). IFN- expression was very
low in saline-pretreated and OVA-challenged rats and was higher in
BSA-challenged controls (p = 0.012; Fig. 6C). PGE2-treated animals had intermediate
numbers of IFN- cells that were not significantly different from
either of the other groups.
|
There was a significant difference in BALF levels of cys-LTS among
the OVA-challenged/saline-pretreated,
OVA-challenged/PGE2-pretreated and BSA-challenged groups of
rats (p = 0.02 by ANOVA). The
increase in cys-LTs in the BALF of OVA-challenged rats was
significantly higher than in rats after BSA challenge
(p = 0.047; Fig. 7). Animals treated with PGE2
before challenge had substantial and significant inhibition of
cys-LTs (p = 0.007 compared with OVA-challenged
and saline-pretreated rats).
|
The distribution of EP receptors was examined by in situ
hybridization. There were no obvious differences between naive and
sensitized animals. The most abundant receptor mRNA found was that of
the EP4 subtype (Fig. 8).
There was detectable expression on the alveolar epithelium, on vascular
endothelial cells, and on inflammatory cells within the interstitium
and air spaces. The expression of the EP1 and
EP2 receptor subtypes was virtually undetectable. There was
weak staining for the EP3 receptor on the alveolar
epithelium. There was no detectable mRNA for any of the EP receptors on
airway smooth muscle cells.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Because PGE2 has been shown to induce bronchodilation in mice through interaction with EP2 receptors (20), it is possible that a direct effect on airway smooth muscle cells could have contributed to the inhibitory response to this PG. However, the paucity of expression of EP receptors on airway smooth muscle cells in the BN rat would suggest that the allergic airway responses may not have been mediated primarily by a direct effect of PGE2 on airway smooth muscle. However, such an effect is not excluded by the current study because the inhibition of the EAR that was observed may have been the result of either inhibition of airway smooth muscle contraction or inhibition of mast cell degranulation. The extent to which direct actions of PGE2 on airway smooth muscle account for any of its salutary effects on allergic airway responses in the current study or in any of the published studies is unclear. There are several studies of the effects of PGE2 on the mast cell. It has been reported to both enhance IgE-dependent mast cell degranulation (histamine release) in vitro (7, 8) and inhibit Ag-induced histamine release (21). Although PGE2 has been shown to reduce the early response in human subjects, it appears to do so predominantly through an effect on PGD2 synthesis (3). In this latter study, the effect of PGE2 on cys-LTs was not significant, suggesting a differential effect on the inhibition of these two arachidonate-derived mediators synthesized by the mast cell. The inhibition of the late response in the current study can also be accounted for by inhibition of mediator release.
In vitro experiments have provided substantial evidence of the
potential for PGE2 to have anti-inflammatory and
immunomodulatory actions. PGE2 has been shown to alter mast
cell cytokine synthesis; it induces IL-6 (7, 8) and GM-CSF
(8), whereas it suppresses TNF- synthesis
(7). Several other targets of the actions of
PGE2 warrant mention, in particular B and T lymphocytes.
Our data using in situ hybridization indicate that T cell cytokine
expression was reduced by PGE2, indicating an effect on T
cell function. Because T cell activation is presumably caused by
presentation of Ag to T cells in the airway wall, then PGE2
could exert effects on the T cell through actions either on the T cell
itself or on APCs. Mitogen-stimulated CD4+ T cells have
been shown to undergo a change in phenotype in vitro on exposure to
PGE2 with a reduction in IFN- and an increase in IL-5
expression (10). Differences in the sensitivity of APCs to
the inhibitory properties of PGE2 have also been invoked as
an explanation for Th2 biasing in BALB/c mice (11). Our
results indicate that the net result of the complex actions of
PGE2 in vivo is a selective inhibition of Th2 cytokines
whereas IFN-, representative of Th1 cytokines, is unchanged.
PGE2 has effects that are of interest in the consideration
of this substance as a therapeutic agent for allergic asthma. It
inhibits IL-4-induced production of IgE by human B cells
(9). There is contrary evidence indicating that
PGE2 may also affect T cell help for Ab synthesis so as to
favor IgE synthesis and allergic type inflammation. PGE2
has been shown to suppress the Th1 type cytokines IL-2 and IFN-
cells and to stimulate Th2 cells (10, 22). A similar role
in Th2 biasing of T cell responses has been shown in BALB/c mice
through inhibition of IFN- (11). This effect seems to
be in part mediated by an inhibition of IL-12p70 heterodimer production
by Ag APCs to PGE2 in this mouse strain
(11). Other reports have shown that murine B cells
may respond to PGE2 analogs with an enhancement of
IL-4-induced IgE production (23).
PGE2 inhibited airway eosinophilia by 80%. There are
several potential mechanisms for this observation. IL-5 is a central
cytokine involved in the induction of eosinophilia by allergen
challenge (24, 25, 26) interacting with other protein
chemoattractants such as eotaxin (27). Ab-neutralizing
experiments on models of allergic asthma as well as knockout mice show
a clear dependence of eosinophilia on IL-5 (26, 28). It is
quite plausible that the inhibition of IL-5 by PGE2 is
responsible, at least in part, for the reduction of eosinophilia. It is
also possible that PGE2-induced inhibition of
PGD2 release by mast cells could have contributed to the
inhibitory effect on eosinophil infiltration as PGD2 has
been shown to be a potent chemoattractant for these cells
(29). Cys-LTs were also strikingly reduced in BALF and,
although not potently chemotactic, they have also been shown to be
involved in the induction of eosinophilia by OVA challenge in
sensitized mice (30) and rats (31). This
finding provides another potential mechanism for the reduction in
eosinophils. Eosinophilia perhaps could be reduced also by effects of
PGE2 on the eosinophil itself. Interestingly,
cyclooxygenase-deficient mice have exaggerated airway inflammation
after sensitization and challenge, indicating that cyclooxygenase
products produced endogenously are in sufficient concentrations to
modulate allergic airway responses (32). Indomethacin
treatment has similar effects in mice (33).
The results of the current experiments clearly indicate sensitivity to PGE2 of the cells synthesizing cys-LTs during the late response. The inhibition of cys-LTs in the BAL fluid of OVA-challenged animals in the current experiments was substantial. The observed inhibition exceeded the effects of a single administration of either topical or systemic corticosteroids on cys-LTs in the rat (34, 35). The mechanism by which cys-LTs were inhibited is not known. Although unproven, eosinophils are considered to be a probable source of cys-LTs in human asthmatic subjects. In rodents, however, eosinophils do not synthesize significant amounts of cys-LTs (36, 37). Mast cells or macrophages are alternative sources (37), but to date their implication in cys-LT synthesis in vivo in rats has not been confirmed. Inhibition by PGE2 of the synthesis of LTB4, another product of 5-lipoxygenase, by polymorphonuclear leukocytes has also been reported (38). If this occurred in the current experiment, it may have contributed to the reduction in BAL eosinophilia, that has been shown to inhibited by antagonists of LTB4 in this animal model (39).
In conclusion, PGE2 is a potent inhibitor of allergic airway responses in the BN rat model of allergic asthma. The effects are likely exerted at several sites, but the current study clearly shows effects on T cell cytokine expression and on the control of eosinophilia. The synthesis of cys-LTs is also inhibited by PGE2. These findings support the notion that PGE2 could be a useful anti-inflammatory treatment for asthma. However PGE2 has complex immunomodulatory properties in vitro so that elucidation of the pertinence of these effects in vivo would be important preceding the application of this molecule as a therapeutic agent.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. James G. Martin, Meakins Christie Laboratories, Department of Medicine, McGill University, 3626 St. Urbain Street, Montreal, H2X2P2 Quebec, Canada. E-mail address: james.martin{at}mcgill.ca
3 Abbreviations used in this paper: AHR, airway hyperresponsiveness; LT, leukotriene; cys-LT, cysteinyl-LT; LAR, late allergic airway response; BAL, bronchoalveolar lavage; BALF, BAL fluid; EAR, allergen-induced early response; MBP, major basic protein.
Received for publication December 7, 2001. Accepted for publication July 22, 2002.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
and and prostaglandin E2. Proc. Natl. Acad. Sci. USA 85:6880.This article has been cited by other articles:
|
|
 |
|
  Y. Shiraishi, K. Asano, K. Niimi, K. Fukunaga, M. Wakaki, J. Kagyo, T. Takihara, S. Ueda, T. Nakajima, T. Oguma, et al. Cyclooxygenase-2/Prostaglandin D2/CRTH2 Pathway Mediates Double-Stranded RNA-Induced Enhancement of Allergic Airway Inflammation J. Immunol., January 1, 2008; 180(1): 541 - 549. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Y. Park and J. W. Christman Involvement of cyclooxygenase-2 and prostaglandins in the molecular pathogenesis of inflammatory lung diseases Am J Physiol Lung Cell Mol Physiol, May 1, 2006; 290(5): L797 - L805. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Carey, J. A. Bradbury, J. M. Seubert, R. Langenbach, D. C. Zeldin, and D. R. Germolec Contrasting Effects of Cyclooxygenase-1 (COX-1) and COX-2 Deficiency on the Host Response to Influenza A Viral Infection J. Immunol., November 15, 2005; 175(10): 6878 - 6884. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. F. Chung Evaluation of Selective Prostaglandin E2 (PGE2) Receptor Agonists as Therapeutic Agents for the Treatment of Asthma Sci. Signal., September 27, 2005; 2005(303): pe47 - pe47. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. L. Bannenberg, N. Chiang, A. Ariel, M. Arita, E. Tjonahen, K. H. Gotlinger, S. Hong, and C. N. Serhan Molecular Circuits of Resolution: Formation and Actions of Resolvins and Protectins J. Immunol., April 1, 2005; 174(7): 4345 - 4355. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Offer, S. Yedgar, O. Schwob, M. Krimsky, H. Bibi, A. Eliraz, Z. Madar, and D. Shoseyov Negative feedback between secretory and cytosolic phospholipase A2 and their opposing roles in ovalbumin-induced bronchoconstriction in rats Am J Physiol Lung Cell Mol Physiol, March 1, 2005; 288(3): L523 - L529. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Monneret, R. Boumiza, S. Gravel, C. Cossette, J. Bienvenu, J. Rokach, and W. S. Powell Effects of Prostaglandin D2 and 5-Lipoxygenase Products on the Expression of CD203c and CD11b by Basophils J. Pharmacol. Exp. Ther., February 1, 2005; 312(2): 627 - 634. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Hashimoto, J. R. Sheller, J. D. Morrow, R. D. Collins, K. Goleniewska, J. O'Neal, W. Zhou, S. Ji, D. B. Mitchell, B. S. Graham, et al. Cyclooxygenase Inhibition Augments Allergic Inflammation through CD4-Dependent, STAT6-Independent Mechanisms J. Immunol., January 1, 2005; 174(1): 525 - 532. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Okunishi, M. Dohi, K. Nakagome, R. Tanaka, and K. Yamamoto A Novel Role of Cysteinyl Leukotrienes to Promote Dendritic Cell Activation in the Antigen-Induced Immune Responses in the Lung J. Immunol., November 15, 2004; 173(10): 6393 - 6402. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. P. J. Hofer, E. Bitterle, I. Beck-Speier, K. L. Maier, M. Frankenberger, J. Heyder, and L. Ziegler-Heitbrock Diesel exhaust particles increase LPS-stimulated COX-2 expression and PGE2 production in human monocytes J. Leukoc. Biol., May 1, 2004; 75(5): 856 - 864. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
