| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
,
Departments of
*
Experimental Internal Medicine,
Internal Medicine,
Pathology, and
Infectious Diseases, Tropical Medicine, and AIDS, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and
¶ Center for Transgene Technology and Gene Therapy, Flemish Interuniversity Institute for Biotechnology, Leuven, Belgium
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
2
integrin CD11b/CD18. Indeed, an essential role of uPAR in neutrophil
recruitment during pulmonary infection has been demonstrated for
2 integrin-dependent respiratory pathogens. We
investigated the role of uPAR and urokinase plasminogen activator (uPA)
during pneumonia caused by a 2 integrin-independent
respiratory pathogen, Streptococcus pneumoniae.
uPAR-deficient (uPAR-/-), uPA-deficient
(uPA-/-), and wild-type (Wt) mice were intranasally
inoculated with 105 CFU S. pneumoniae.
uPAR-/- mice showed reduced granulocyte accumulation in
alveoli and lungs when compared with Wt mice, which was associated with
more S. pneumoniae CFU in lungs, enhanced dissemination
of the infection, and a reduced survival. In contrast,
uPA-/- mice showed enhanced host defense, with more
neutrophil influx and less pneumococci in the lungs compared with Wt
mice. These data suggest that uPAR is necessary for adequate
recruitment of neutrophils into the alveoli and lungs during pneumonia
caused by S. pneumoniae, a pathogen eliciting a
2 integrin-independent inflammatory response. This
function is even more pronounced when uPAR is unoccupied by
uPA. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
2 integrin CD11b/CD18, thereby modulating the
migration-promoting activity (16, 17). Treatment with
saccharides disrupted this uPAR-CD11b/CD18 coupling and inhibited
chemotaxis (12). Neutrophil emigration from the pulmonary circulation is unique in that it appears to be mediated by two pathways: one that requires CD11b/CD18 and one that does not, varying with the stimulus used to induce pulmonary inflammation. In general, Gram-negative bacterial stimuli are CD11b/CD18 dependent, while Gram-positive stimuli elicit a CD11b/CD18-independent emigration of leukocytes (18, 19, 20). The essential role of uPAR in host defense against pulmonary infection has in particular been demonstrated for Pseudomonas aeruginosa, a CD11b/CD18-dependent respiratory pathogen (21). Mice deficient in uPAR showed increased susceptibility as well as less recruitment of inflammatory cells. We investigated to which extent uPAR deficiency would influence host defense during pneumonia caused by Streptococcus pneumoniae, a CD11b/CD18-independent stimulus, responsible for >50% of community-acquired pneumonias (22, 23).
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Mice with a targeted deletion in the gene for uPAR or uPA, resulting in a complete deficiency of uPAR (uPAR-/-) or uPA (uPA-/-), respectively, were generated as previously described (24, 25). All mice were on a mixed C57BL/6J (75%) x 129 (25%) background. The respective wild types of the uPAR-/- and uPA-/- mice were derived from original littermates of the knockout mice and were bred separately in different colonies (under identical circumstances as their corresponding knockout strain) within the animal institution of the Flemish Interuniversity Institute for Biotechnology (Leuven, Belgium). For the experiments mice were transported to the Academic Medical Center (Amsterdam, The Netherlands). All experiments were approved by the Committee on Use and Care of Animals of the Academic Medical Center.
Induction of pneumonia
Pneumonia was induced as described previously (26).
Briefly, S. pneumoniae, serotype 3, obtained from American
Type Culture Collection (ATCC 6303; Rockville, MD), were grown for
6 h to midlogarithmic phase at 37°C in 5%
CO2 using Todd-Hewitt broth (Difco, Detroit, MI),
harvested by centrifugation at 1500 x g for 15 min,
and washed twice in sterile isotonic saline. Bacteria were then
resuspended in sterile isotonic saline at 
106
CFU/ml, as determined by plating serial 10-fold dilutions onto
sheep-blood agar plates. Mice were lightly anesthetized by inhalation
of isoflurane (Abott, Queensborough, Kent, U.K.), and 50 µl of
bacterial suspension was inoculated intranasally.
Bronchoalveolar lavage
At 24 and 48 h after inoculation mice were anesthetized by i.p. injection with Hypnorm (Janssen Pharmaceutica, Beerse, Belgium) and midazolam (Roche, Mijdrecht, The Netherlands), and blood was collected from the inferior caval vein. The trachea was exposed through a midline incision and cannulated with a sterile 22-gauge Abbocath-T catheter (Abbott, Sligo, Ireland). Bronchoalveolar lavage (BAL) was performed by instilling two 0.5-ml aliquots of sterile isotonic saline. A total of 0.9–1 ml of lavage fluid was retrieved per mouse, and total cell numbers were counted from each sample in a hemocytometer. BAL fluid (BALF) differential cell counts were determined on cytospin preparations stained with modified Giemsa stain (Diff-Quick; Baxter, McGraw Park, IL).
Histologic examination
After a 24-h fixation of lungs in 10% buffered formalin and embedding in paraffin, 4-µm-thick sections were stained with H&E. All slides were coded and scored by a pathologist without knowledge of the type of mice and treatment. For granulocyte staining, slides were deparaffinized and rehydrated. Slides were then digested by a solution of pepsin 0.25% (Sigma-Aldrich, St. Louis, MO) in 0.01 M HCl. After being rinsed, the sections were incubated in 10% normal goat serum (DAKO, Glostrup, Denmark) and then exposed to FITC-labeled anti-mouse Ly-6-G mAb (BD PharMingen, San Diego, CA). Endogenous peroxidase activity was quenched by a solution of 0.1% NaN3/0.03% H2O2 (Merck, Darmstadt, Germany). After washes, slides were incubated with a rabbit anti-FITC Ab (DAKO) followed by further incubation with a biotinylated swine anti-rabbit Ab (DAKO), rinsed again, incubated in a streptavidin-ABC solution (DAKO), and developed using 1% H2O2 and 3,3'-diaminobenzidine tetrahydrochloride (Sigma-Aldrich) in Tris-HCl. The sections were mounted in glycerin gelatin without counter staining and analyzed.
Preparation of lung homogenates
Whole lungs were harvested and homogenized at 4°C in five volumes of sterile isotonic saline with a tissue homogenizer (Biospect Products, Bartlesville, OK), which was carefully cleaned and disinfected with 70% ethanol after each homogenization. Serial 10-fold dilutions in sterile isotonic saline were made from these homogenates (and blood), and 50-µl volumes were plated onto sheep-blood agar plates and incubated at 37°C and 5% CO2. CFU were counted after 16 h. For cytokine measurements lung homogenates were lysed in lysis buffer (300 mM NaCl, 15 mM Tris, 2 mM MgCl, 2 mM Triton X-100, pepstatin A, leupeptin, aprotinin (20 ng/ml), pH 7.4) and spun at 1500 x g at 4°C for 15 min; the supernatant was frozen at -20°C until cytokine measurement.
Assays
Cytokine and chemokine levels were measured by using
commercially available ELISAs, in accordance with the manufacturer’s
recommendations: IL-6 (BD PharMingen), IL-1, macrophage-inflammatory
protein 2 (MIP-2), and KC (R&D Systems, Abingdon, U.K.). Detection
limits were 37 (IL-6), 47 (MIP-2), and 12 (KC) pg/ml. uPA activity was
measured by an amidolytical assay as previously described
(27). Briefly, diluted lung homogenates were incubated
with 0.3 mmol/L S-2251 (Chromogenix, Mölndal, Sweden), 0.13 mol/L
plasminogen, and 0.12 mg/ml cyanogen bromide fragments of
fibrinogen (Chromogenix). Conversion of plasminogen to plasmin was
assessed by subsequent conversion of the chromogenic substrate S-2251
and was detected with a spectrophotometer. The fraction of the lysis
due to uPA activity was determined by including in the assay 50 µg/ml
polyclonal neutralizing rabbit anti-murine uPA-specific IgGs. A
standard curve for uPA activity was obtained by incubating different
amounts of purified murine uPA to the assay system.
Statistical analysis
Data were analyzed using the SPSS statistical package. Data are expressed as means ± SEM, unless indicated otherwise. Comparisons between groups were conducted using the Mann-Whitney U test. Survival curves were compared by log-rank test. A value of p < 0.05 was considered to represent a statistically significant difference.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Intranasal administration of S. pneumoniae increased
the concentrations of uPA in lung homogenates obtained 24 and 48 h
after inoculation (at baseline 88.5 ± 9.1 µg/ml; peak at
48 h: uPA 182.7 ± 8.6 µg/ml; p < 0.05 vs
control) (Fig. 1
). Hence, these data
demonstrate that pneumococcal pneumonia results in locally elevated
levels of the ligand of uPAR.
|
Recently it has been reported that uPAR is an important
regulator of integrin-dependent cellular migration (16, 17). Cell recruitment to the site of infection is an important
part of host defense during pneumonia. For this reason we compared cell
influx in the alveolar spaces of uPAR-/- mice
and wild-type (Wt) mice after inoculation with S.
pneumoniae. uPAR-/- mice had significantly
fewer cells in their BALF when compared with Wt mice
(p = 0.004), which was mainly caused by a
diminished recruitment of neutrophils (Table I).
|
At 48 h after inoculation, the lungs of
uPAR-/- mice showed patchy and dense
inflammatory infiltrates (Fig. 2A), predominantly composed of
monocytes and lymphocytes with relatively few granulocytes (Fig. 2, A and C). In contrast, Wt mice had a mild
interstitial inflammation (Fig. 2B) composed of granulocytes
and monocytes corresponding to a clearance phase (Fig. 2D).
|
To investigate the role of uPAR in the pulmonary clearance
of S. pneumoniae, we determined the numbers of CFU in lungs
24 and 48 h after inoculation. At both time points
uPAR-/- mice had significantly more CFU in
their lungs than Wt mice (p < 0.05) (Fig. 3). Furthermore, S. pneumoniae
could be cultured from the blood of 12.5% of the Wt mice after 48
h, whereas 87.5% of the blood cultures obtained from the
uPAR-/- mice were positive for S.
pneumoniae at this time point. At 24 h blood cultures were
negative in all mice.
|
To investigate whether uPAR influences survival, we assessed
survival twice daily in uPAR-/- and Wt mice
after intranasal inoculation with 105 CFU
S. pneumoniae. uPAR-/- mice
succumbed much earlier than Wt mice (p = 0.004)
(Fig. 4).
|
Because the localized production of cytokines and chemokines
is an important part of host defense (28), we measured the
concentrations of these mediators in lung homogenates. All cytokines
and chemokines measured (IL-1, IL-6, KC, and MIP-2) were higher in
uPAR-/- mice, in particular at 48 h
postinoculation (Table II). Thus, a
reduced production of protective proinflammatory cytokines or
chemokines could not explain the impaired host defense in
uPAR-/- mice.
|
Having established that uPAR is important for host defense against
pneumococcal pneumonia, we next determined the role of the ligand for
uPAR, uPA, in this model of Gram-positive respiratory tract infection
(Fig. 5). In contrast to
uPAR-/- mice, uPA-/-
mice had more neutrophils (p = 0.08) and less
pneumococci in their lungs at 48 h postinoculation
(p = 0.027). There was no significant
difference in mortality between uPA-/- and
Wt mice.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
uPAR can form a functional complex with the
2 integrin CD11b/CD18. The CD11b/CD18 complex
is necessary for cell recruitment in nearly every organ system.
However, there is a difference between neutrophil adhesion within the
pulmonary compartment and in the systemic circulation, i.e., leukocytes
can migrate out of the lung capillaries by either a
CD11b/CD18-dependent or -independent mechanism. IL-1, PMA, and
Gram-negative bacterial stimuli elicit migration via pathways
mediated by CD11b/CD18. Conversely, the cellmigration in
response to Gram-positive bacteria, hydrochloric acid, and C5a occurs
independent of CD11b/CD18 (18, 19, 20, 29, 30). Treatment with
anti-CD18 Ab had no effect on the leukocyte emigration in the lung
induced by S. pneumoniae (18). Furthermore, the
combined absence of P-selectin and ICAM-1, the ligand for CD11b/CD18,
had no effect on neutrophil recruitment to the inflammatory site in
response to S. pneumoniae (31). Thus, S.
pneumoniae elicits a CD11b/CD18-independent inflammatory response
in the lungs, while Gram-negative bacteria need CD11b/CD18 to recruit
cells to the inflammatory site.
Accordingly, during P. aeruginosa pneumonia,
uPAR-/- mice demonstrated a reduced
neutrophilic influx in the lung associated with an enhanced bacterial
outgrowth (21). However, Wt mice treated with a blocking
anti-CD11b mAb also had less accumulation of neutrophils in the
lung after P. aeruginosa inoculation, similar to
uPAR-/- mice. Furthermore, anti-CD11b mAb
did not influence the recruitment of neutrophils in
uPAR-/- mice, indicating that uPAR and CD11b
act on neutrophils by a common mechanism in this
2 integrin-dependent model. Interestingly, we
found that during pneumonia caused by a CD11b/CD18-independent
pathogen, S. pneumoniae, uPAR is also necessary for adequate
neutrophil recruitment, as documented by fewer neutrophils in BALF and
lung parenchyma in uPAR-/- mice. This finding
at least in part can explain the impaired antipneumococcal defense of
uPAR-/- mice in this model of respiratory tract
infection, considering that neutrophils are critical for effective
eradication of bacteria from the lungs (32). We did not
investigate whether the absence of uPAR influences opsonization or
phagocytosis by neutrophils. However, to our knowledge no data are
available to indicate that uPAR is involved in either of these
processes.
uPA, as the ligand for uPAR, also influences cell migration. On the one hand it promotes cell invasion due to proteolysis, causing a conformational change in uPAR that uncovers a chemotactic epitope, while on the other hand uPA negatively influences the migratory function of uPAR in vitro (33, 34, 35, 36, 37, 38). Our results demonstrate that uPA deficiency leads to increased neutrophil influx and an enhanced antibacterial host defense, although not to a reduced mortality. In line with our results, uPA had no effect, or even an inhibitory effect, on the adhesive capacity of monocytes and neutrophils (35, 39). In vivo, intratracheal KC (a murine CXC chemokine) administration to uPA-/- and Wt mice reduced the neutrophil influx after engagement of uPAR by nonproteolytic uPA, while uPAR-/- mice showed no difference in cell accumulation (33). In addition, uPA-/- mice showed no difference in neutrophil recruitment during pneumonia caused by Gram-negative bacteria or fungi (21, 40, 41). This demonstrates that uPA exerts opposite influences on neutrophil migration in different models. In our in vivo model of acute bacterial pneumonia, uPA seems to influence the function of uPAR as a chemotactic receptor in a negative way.
It should be noted that the number of S. pneumoniae CFUs measured in Wt mice of uPA-/- mice was considerably higher than the number of CFUs found in Wt mice of uPAR-/- mice, despite the fact that both mouse strains were on the same C57BL/6J (75%) x 129 (25%) background. The explanation for this finding is not clear, although several possibilities exist. First, in retrospect the bacterial inoculum was slightly higher in the experiments with uPA-/- and Wt mice than in the experiments with uPAR-/- and Wt mice (i.e., 3 x 105 vs 1 x 105 CFU). Second, the experiments with uPAR-/- and corresponding Wt mice, and those with uPA-/- and Wt mice, were done with an interval of several months. Our experience is that even with Wt mice purchased from commercial suppliers a certain degree of biological variation in the bacterial clearance exists between experiments and between different "shipments" of mice. Third, the respective Wt of the uPAR-/- and uPA-/- mice were derived from original littermates of the knockout mice and were bred separately in different colonies (under identical circumstances as their corresponding knockout strain); thus, slight (nongenetic) differences may have contributed to the different behavior of Wt mice in separate experiments. However, we would like to emphasize that our studies were performed under adequately controlled conditions; i.e., knockout and Wt mice were not only on the same genetic background but were also bred under identical circumstances and inoculated at the same time with exactly the same inoculum on each occasion.
uPAR was found to be important for cell-mediated immunity against
P. aeruginosa, a 2
integrin-dependent respiratory pathogen (21). Our data
demonstrate that deficiency of uPAR is associated with an impaired host
defense against pneumococcal pneumonia, a model that does not need
2 integrin for the inflammatory response. In
contrast, uPA-/- mice showed enhanced host
defense. Together these data suggest that uPAR is necessary for
adequate recruitment of cells and that this chemotactic function is
even more pronounced when uPAR is unbound. These findings not only add
to our understanding of the role of uPAR and uPA in pneumonia but also
warrant caution for treatment concerning modulation of the fibrinolytic
system in different infectious diseases.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Anita W. Rijneveld, Academic Medical Center, University of Amsterdam, G2-105, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail address: a.w.rijneveld{at}amc.uva.nl
3 Abbreviations used in this paper: uPAR, uPA receptor; uPA, urokinase plasminogen activator; Wt, wild type; BAL, bronchoalveolar lavage; BALF, BAL fluid; MIP-2, macrophage-inflammatory protein 2.
Received for publication August 15, 2001. Accepted for publication January 30, 2002.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
M2' CD11b/CD18) during neutrophil polarization. J. Immunol. 156:297.[Abstract]
2 integrin CD18 in the local accumulation of neutrophils in pulmonary and cutaneous inflammation in the rabbit. Am. J. Respir. Cell Mol. Biol. 10:391.[Abstract]
2 integrins in vivo. J. Exp. Med. 188:1029.This article has been cited by other articles:
|
|
 |
|
  M. Schouten, W. J. Wiersinga, M. Levi, and T. van der Poll Inflammation, endothelium, and coagulation in sepsis J. Leukoc. Biol., March 1, 2008; 83(3): 536 - 545. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I-M. Wang, S. Stepaniants, Y. Boie, J. R. Mortimer, B. Kennedy, M. Elliott, S. Hayashi, L. Loy, S. Coulter, S. Cervino, et al. Gene Expression Profiling in Patients with Chronic Obstructive Pulmonary Disease and Lung Cancer Am. J. Respir. Crit. Care Med., February 15, 2008; 177(4): 402 - 411. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Suelves, B. Vidal, A. L. Serrano, M. Tjwa, J. Roma, R. Lopez-Alemany, A. Luttun, M. M. de Lagran, M. A. Diaz, M. Jardi, et al. uPA deficiency exacerbates muscular dystrophy in MDX mice J. Cell Biol., September 7, 2007; 178(6): 1039 - 1051. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. C. Bryer and T. J. Koh The urokinase-type plasminogen activator receptor is not required for skeletal muscle inflammation or regeneration Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2007; 293(3): R1152 - R1158. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. T. Keller, K. F. van der Sluijs, M. D. de Kruif, V. E. A. Gerdes, J. C. M. Meijers, S. Florquin, T. van der Poll, E. C. M. van Gorp, D. P. M. Brandjes, H. R. Buller, et al. Effects on Coagulation and Fibrinolysis Induced by Influenza in Mice With a Reduced Capacity to Generate Activated Protein C and a Deficiency in Plasminogen Activator Inhibitor Type 1 Circ. Res., November 24, 2006; 99(11): 1261 - 1269. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X.-Q. Wang, K. Bdeir, S. Yarovoi, D. B. Cines, W. Fang, and E. Abraham Involvement of the Urokinase Kringle Domain in Lipopolysaccharide-Induced Acute Lung Injury J. Immunol., October 15, 2006; 177(8): 5550 - 5557. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Renckens, J. J. T. H. Roelofs, S. A. J. ter Horst, C. van 't Veer, S. R. Havik, S. Florquin, G. T. M. Wagenaar, J. C. M. Meijers, and T. van der Poll Absence of Thrombin-Activatable Fibrinolysis Inhibitor Protects against Sepsis-Induced Liver Injury in Mice J. Immunol., November 15, 2005; 175(10): 6764 - 6771. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Xiao, Y.-P. Hsu, A. Ishizaka, T. Kirikae, and R. B. Moss Sputum Cathelicidin, Urokinase Plasminogen Activation System Components, and Cytokines Discriminate Cystic Fibrosis, COPD, and Asthma Inflammation Chest, October 1, 2005; 128(4): 2316 - 2326. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-H. Kwak, S. Mitra, K. Bdeir, D. Strassheim, J. S. Park, J. Y. Kim, S. Idell, D. Cines, and E. Abraham The kringle domain of urokinase-type plasminogen activator potentiates LPS-induced neutrophil activation through interaction with {alpha}V{beta}3 integrins J. Leukoc. Biol., October 1, 2005; 78(4): 937 - 945. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Shushakova, G. Eden, M. Dangers, J. Zwirner, J. Menne, F. Gueler, F. C. Luft, H. Haller, and I. Dumler The Urokinase/Urokinase Receptor System Mediates the IgG Immune Complex-Induced Inflammation in Lung J. Immunol., September 15, 2005; 175(6): 4060 - 4068. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. East, D. Baker, G. Pryce, H. R. Lijnen, M. L. Cuzner, and D. Gveric A Role for the Plasminogen Activator System in Inflammation and Neurodegeneration in the Central Nervous System during Experimental Allergic Encephalomyelitis Am. J. Pathol., August 1, 2005; 167(2): 545 - 554. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Degryse, M. Resnati, R.-P. Czekay, D. J. Loskutoff, and F. Blasi Domain 2 of the Urokinase Receptor Contains an Integrin-interacting Epitope with Intrinsic Signaling Activity: GENERATION OF A NEW INTEGRIN INHIBITOR J. Biol. Chem., July 1, 2005; 280(26): 24792 - 24803. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. L. Yershov, B. S. Jordan, C. H. Guymon, and M. A. Dubick Relationship between the inoculum dose of Streptococcus pneumoniae and pneumonia onset in a rabbit model Eur. Respir. J., April 1, 2005; 25(4): 693 - 700. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. W. Wieland, S. Knapp, S. Florquin, A. F. de Vos, K. Takeda, S. Akira, D. T. Golenbock, A. Verbon, and T. van der Poll Non-Mannose-capped Lipoarabinomannan Induces Lung Inflammation via Toll-like Receptor 2 Am. J. Respir. Crit. Care Med., December 15, 2004; 170(12): 1367 - 1374. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. E. Bosinger, K. A. Hosiawa, M. J. Cameron, D. Persad, L. Ran, L. Xu, M. R. Boulassel, M. Parenteau, J. Fournier, E. W. Rud, et al. Gene Expression Profiling of Host Response in Models of Acute HIV Infection J. Immunol., December 1, 2004; 173(11): 6858 - 6863. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. de Paulis, N. Montuori, N. Prevete, I. Fiorentino, F. W. Rossi, V. Visconte, G. Rossi, G. Marone, and P. Ragno Urokinase Induces Basophil Chemotaxis through a Urokinase Receptor Epitope That Is an Endogenous Ligand for Formyl Peptide Receptor-Like 1 and -Like 2 J. Immunol., November 1, 2004; 173(9): 5739 - 5748. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Arredouani, Z. Yang, Y. Ning, G. Qin, R. Soininen, K. Tryggvason, and L. Kobzik The Scavenger Receptor MARCO Is Required for Lung Defense against Pneumococcal Pneumonia and Inhaled Particles J. Exp. Med., July 19, 2004; 200(2): 267 - 272. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Levi, T. van der Poll, and H. R. Buller Bidirectional Relation Between Inflammation and Coagulation Circulation, June 8, 2004; 109(22): 2698 - 2704. [Full Text] [PDF]
|
|
|
|
|
|
S. Knapp, C. W. Wieland, C. van 't Veer, O. Takeuchi, S. Akira, S. Florquin, and T. van der Poll Toll-Like Receptor 2 Plays a Role in the Early Inflammatory Response to Murine Pneumococcal Pneumonia but Does Not Contribute to Antibacterial Defense J. Immunol., March 1, 2004; 172(5): 3132 - 3138. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. W. Rijneveld, S. Weijer, S. Florquin, C. T. Esmon, J. C. M. Meijers, P. Speelman, P. H. Reitsma, H. Ten Cate, and T. van der Poll Thrombomodulin mutant mice with a strongly reduced capacity to generate activated protein C have an unaltered pulmonary immune response to respiratory pathogens and lipopolysaccharide Blood, March 1, 2004; 103(5): 1702 - 1709. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Leemans, A. A. te Velde, S. Florquin, R. J. Bennink, K. de Bruin, R. A. W. van Lier, T. van der Poll, and J. Hamann The Epidermal Growth Factor-Seven Transmembrane (EGF-TM7) Receptor CD97 Is Required for Neutrophil Migration and Host Defense J. Immunol., January 15, 2004; 172(2): 1125 - 1131. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Beaufort, D. Leduc, J.-C. Rousselle, V. Magdolen, T. Luther, A. Namane, M. Chignard, and D. Pidard Proteolytic Regulation of the Urokinase Receptor/CD87 on Monocytic Cells by Neutrophil Elastase and Cathepsin G J. Immunol., January 1, 2004; 172(1): 540 - 549. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. H. Dockrell, H. M. Marriott, L. R. Prince, V. C. Ridger, P. G. Ince, P. G. Hellewell, and M. K. B. Whyte Alveolar Macrophage Apoptosis Contributes to Pneumococcal Clearance in a Resolving Model of Pulmonary Infection J. Immunol., November 15, 2003; 171(10): 5380 - 5388. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Coleman and J. L. Benach The Urokinase Receptor Can Be Induced by Borrelia burgdorferi through Receptors of the Innate Immune System Infect. Immun., October 1, 2003; 71(10): 5556 - 5564. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Sato, J. Schorey, V. A. Ploplis, E. Haalboom, L. Krahule, and F. J. Castellino The Fibrinolytic System in Dissemination and Matrix Protein Deposition During a Mycobacterium Infection Am. J. Pathol., August 1, 2003; 163(2): 517 - 531. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. W. Rijneveld, S. Florquin, P. Bresser, M. Levi, V. de Waard, R. Lijnen, J. S. Van der Zee, P. Speelman, P. Carmeliet, and T. van der Poll Plasminogen activator inhibitor type-1 deficiency does not influence the outcome of murine pneumococcal pneumonia Blood, August 1, 2003; 102(3): 934 - 939. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Abraham, M. R. Gyetko, K. Kuhn, J. Arcaroli, D. Strassheim, J. S. Park, S. Shetty, and S. Idell Urokinase-Type Plasminogen Activator Potentiates Lipopolysaccharide-Induced Neutrophil Activation J. Immunol., June 1, 2003; 170(11): 5644 - 5651. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Knapp, J. C. Leemans, S. Florquin, J. Branger, N. A. Maris, J. Pater, N. van Rooijen, and T. van der Poll Alveolar Macrophages Have a Protective Antiinflammatory Role during Murine Pneumococcal Pneumonia Am. J. Respir. Crit. Care Med., January 15, 2003; 167(2): 171 - 179. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Montuori, M. V. Carriero, S. Salzano, G. Rossi, and P. Ragno The Cleavage of the Urokinase Receptor Regulates Its Multiple Functions J. Biol. Chem., November 27, 2002; 277(49): 46932 - 46939. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
) and uPAR-/-
mice (
). Mortality was assessed twice daily for 10 days
(n = 12 per group).