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Compensates for the Impaired Host Defense of IL-1 Type I Receptor-Deficient Mice During Pneumococcal Pneumonia1
Departments of
*
Experimental Internal Medicine,
Infectious Diseases, Tropical Medicine, and AIDS, and
Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-1
mRNA and protein levels in the lungs. Survival
rates did not differ between IL-1R-/- and Wt mice after
inoculation with 5 x 104 or 2 x 105
CFU. At early time points (24 and 48 h) IL-1R-/-
mice had 2-log more S. pneumoniae CFU in lungs than Wt
mice; at 72 h bacterial outgrowth in lungs was similar in both
groups. Upon histopathologic examination IL-1R-/- mice
displayed a reduced capacity to form inflammatory infiltrates at
24 h after the induction of pneumonia. IL-1R-/- mice
also had significantly less granulocyte influx in bronchoalveolar
lavage fluid at 24 h after inoculation. Since TNF is known to
enhance host defense during pneumonia, we determined the role of
endogenous TNF in the early impairment and subsequent recovery of
defense mechanisms in IL-1R-/- mice. All
IL-1R-/- mice treated with anti-TNF rapidly died (no
survivors (of 14 mice) after 4 days), while 10-day survival in
IL-1R-/- mice (control Ab), Wt mice (anti-TNF), and
Wt mice (control Ab) was 7 of 13, 3 of 14, and 12 of 13, respectively.
These data suggest that TNF is more important for host defense against
pneumococcal pneumonia than IL-1, and that the impaired early host
defense in IL-1R-/- mice is compensated for by TNF at a
later phase. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Activation of the cytokine network plays an important role in the early
response to severe infection (6). In models of systemic
infection TNF is the first cytokine that becomes detectable in the
circulation, followed shortly thereafter by IL-1
(7, 8, 9). TNF and IL-1 have highly overlapping biological
activities and synergize in inducing systemic toxicity in animals in
vivo (10, 11). Elimination of either TNF or IL-1 activity
during severe bacteremia in baboons largely prevents lethality,
suggesting that excessive systemic production of these cytokines is of
pivotal importance for the development of organ injury during the
sepsis syndrome (12, 13). However, evidence indicates that
the local production of proinflammatory cytokines is crucial for the
clearance of bacterial infections from the lung. Indeed, passive
immunization against TNF impairs host defense during pneumococcal,
Legionella, and Klebsiella pneumonia in mice
(14, 15, 16). The role of IL-1 during bacterial pneumonia is
less well defined.
IL-1 is a pleiotropic proinflammatory cytokine, mainly produced by
mononuclear phagocytes, which affects nearly all cell types. The IL-1
family consists of three members, namely, IL-1, IL-1, and IL-1R
antagonist (IL-1Ra)3
(17, 18). IL-1 can bind to two receptors, IL-1R types I
and II. Type I receptors are found on most cell types, whereas
expression of type II receptors is limited to blood neutrophils,
monocytes, bone marrow progenitor cells, and B lymphocytes. IL-1R type
II is not able to transduce a signal and is therefore generally
referred to as a decoy receptor (19, 20). The type I IL-1R
has equal affinities for IL-1, IL-1, and IL-1Ra. After binding of
IL-1 to IL-1R type I, IL-1-IL-1R type I forms a complex with the IL-1R
accessory protein, which results in signal transduction and biological
effects, including induction of an acute phase response to sterile
inflammation, fever, and synthesis of other proinflammatory cytokines
and chemokines, such as IL-6, TNF, and IL-8 (17, 21).
To determine the role of IL-1 in the pathogenesis of pneumococcal pneumonia, IL-1R type I gene-deficient (IL-1R-/-) mice were compared with wild-type (Wt) mice after induction of pneumonia with S. pneumoniae (22). In addition, the possible interaction between endogenous IL-1 and TNF during pneumonia was evaluated by treatment of IL-1R-/- and Wt mice with a neutralizing anti-TNF Ab.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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All experiments were approved by the institutional animal care and use committee of the Academic Medical Center (Amsterdam, The Netherlands). IL-1R-/- mice back-crossed six times to a C57BL/6 background (provided by Immunex, Seattle, WA) and normal C57BL/6 Wt mice (Harlan Sprague Dawley, Horst, The Netherlands) were used. Male (10–12 wk old) mice were used in all experiments. IL-1R-/- mice are normal in size, weight, and fertility and display no abnormalities in leukocyte subsets (22).
Induction of pneumonia
Pneumonia was induced as described previously (16, 23). Briefly, S. pneumoniae serotype 3 was obtained from American Type Culture Collection (ATCC 6303, Manassas, VA). Pneumococci were grown in Todd-Hewitt broth (Difco, Detroit, MI) for 6 h to midlogarithmic phase at 37°C in 5% CO2, 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 different concentrations (2 x 105 to 4 x 106 CFU/ml), as determined by plating serial 10-fold dilutions onto sheep-blood agar plates. Mice were lightly anesthetized by inhalation of isoflurane (Abbott, Queensborough, U.K.), and 50 µl bacterial suspension or an equal volume of sterile isotonic saline as a control was inoculated intranasally.
Antibodies
Rat anti-mouse TNF mAb was provided by D. Shealy (Centocor, Malvern, PA). Rat IgG2a (clone R7D4) was used as the control Ab. Abs were given i.p. in two doses of 0.5 mg, 2 h before and 24 h after induction of pneumonia.
RT-PCR
Mouse lungs were harvested and snap-frozen in liquid nitrogen 24 and 48 h after inoculation with S. pneumoniae and 48 h after saline inoculation. Total RNA was isolated from mouse lungs using TRIzol reagents (Life Technologies, Berlin, Germany). Briefly, cells were lysed in TRIzol reagents, and RNA was isolated following chloroform extraction and isopropanol precipitation. RT was performed using 2 µg total cellular RNA and 0.5 µg oligo(dT) (Life Technologies) and incubating the solution (12 µl) for 10 min at 72°C. The final 20-µl reaction mixture contained the following components at the indicated final concentrations: 1x first-strand buffer (Life Technologies), 10 mM DTT, 1.25 mM each of dNTPs, and 100 U Superscript RNase H reverse transcriptase (Life Technologies). The reaction was incubated for 60 min at 42°C, followed by 72°C for 10 min. Finally, 180 µl H2O was added to the reaction mixture, and samples were stored at -20°C.
For PCR, cDNA from three mice were pooled, and 5 µl RT product was
used in a total volume of 25 µl of a solution containing 0.5 U
AmpliTaq polymerase (PerkinElmer, Norwalk, CT), 1.25 mM dNTPs, 2.5 µl
10x Pol buffer (0.67 M Tris-HCl (pH 8.8), 67 mM
MgCl2, 0.1 M 2-ME, 67 µM EDTA, and 0.166
M
(NH4)2SO4),
1% DMSO, 0.5 mg/ml BSA, and 200 ng of each primer. The following
sequence was performed on a thermocycler (PerkinElmer) for each PCR
reaction: 94°C for 5 min (one cycle), followed immediately by 94°C
for 1 min, 55°C for 1 min, and 72°C for 1 min (with variable
numbers of cycles), and a final extension phase of 72°C for 10 min. A
variable number of cycles was used to ensure that amplification
occurred in the linear phase and that differences between control and
experimental conditions were maintained by adopting a limited number of
cycles. To insure that differences between samples were not a result of
unequal concentrations of cDNA, a PCR using -actin as an internal
standard was performed on each sample. -Actin was shown to be linear
at 27 amplification cycles; IL-1 and IL-1 were linear at 30
amplification cycles. The primer sequences are as follows: -actin
(forward), 5'-GTCAGAAGGACTCCTATGTG-3'; -actin (reverse),
3'-GCTCGTTGCCAATAGTGATG-5'; IL-1 (forward),
5'-CTCTAGAGCACCATGCTACAGAC-3'; IL-1 (reverse),
3'-TGGAATCCAGGGGAAACACTG-5'; IL-1 (forward),
5'-TCATGGGATGATGATAACCTGCT-3'; and IL-1 (reverse),
3'-CCCATACTTTAGGAAGACACGGAT-5'. The PCR products were separated on a
1.5% agarose gel and visualized by UV illumination.
Histologic examination
After 24-h fixation of lungs in 4% paraformaldehyde in PBS and embedding in paraffin, 4-µm thick sections were stained with H&E. All slides were coded and semiquantitatively scored by a pathologist without knowledge of the type of mice and treatment.
Preparation of lung homogenates
Mice were anesthetized with Hypnorm (Janssen Pharmaceutica, Beerse, Belgium) and midazolam (Roche, Meidrecht, The Netherlands), and blood was collected from the inferior vena cava. Whole lungs were harvested and homogenized at 4°C in 5 vol sterile isotonic saline with a tissue homogenizer (Biospect Products, Bartlesville, OK), which was carefully cleaned and disinfected with 70% alcohol 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, and 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.
Bronchoalveolar lavage (BAL)
The trachea was exposed through a midline incision and cannulated with a sterile 22-gauge Abbocath-T catheter (Abbott, Sligo, Ireland). BAL was performed by instilling two 0.5-ml aliquots of sterile isotonic saline. Lavage fluid (0.9–1 ml/mouse) was retrieved, and total cell numbers were counted from each sample in a hemocytometer. BAL fluid (BALF) differential cell counts were conducted on cytospin preparations stained with modified Giemsa stain (Diff-Quick; Baxter, McGraw Park, IL).
Pulmonary cell influx
Single-cell suspensions were obtained by crushing lungs through a 40-µm cell strainer (BD Biosciences, Mountain View, CA). Erythrocytes were lysed with ice-cold isotonic NH4Cl solution (155 mM NH4Cl, 10 mM KHCO3, and 100 mM EDTA, pH 7.4), and the remaining cells were washed. Total leukocyte count was determined using a hemocytometer. The number of polymorphonuclear cells was calculated from these totals, using cytospin preparations stained with modified Giemsa stain (Diff-Quick).
Cytokine and chemokine determinations
Cytokine and chemokine levels were measured using commercially
available ELISAs in accordance with the manufacturer’s
recommendations: IL-1, IL-1, IL-1Ra, TNF, IFN-
, MIP-2, and
KC (all from R&D Systems, Minneapolis, MN).
Statistical analysis
Data were analyzed using the SPSS statistical package (SPSS, Chicago, IL). Data are expressed as the mean ± SEM unless indicated otherwise. Comparisons between groups were conducted using the Mann-Whitney U test. For survival studies the log-rank test was used. p < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, IL-1, and TNF in lungs
Administration of S. pneumoniae induced an increased
production of IL-1 and IL-1 in lungs at both mRNA and protein
levels. Control mice inoculated with saline showed only vague IL-1
and IL-1 mRNA bands, whereas pneumonia was associated with clear
bands at both 24 and 48 h postinoculation (Fig. 1
). High IL-1 and IL-1 protein
levels were detected in lung homogenates of mice with pneumonia at
these same time points (peak levels: IL-1, 4.1 ± 0.3; IL-1,
5.0 ± 0.3 ng/g lung; at 48 h; both p < 0.05
vs control). IL-1Ra did not increase in lungs of mice with pneumonia
(data not shown). In line with previous findings in this model of
pneumococcal pneumonia (16), induction of pneumonia in Wt
mice resulted in a sustained increase in TNF concentrations in lung
homogenates, which reached a plateau between 12 and 72 h (233
± 27 ng/g at 72 h; p < 0.05 vs control).
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Once we had established that IL-1 and IL-1 are produced in
lungs during pneumococcal pneumonia, we wanted to evaluate the
contributions of these cytokines to survival after inoculation with
S. pneumoniae (Fig. 2)
. Survival did not significantly differ between
IL-1R-/- and Wt mice up to 10 days after
inoculation with 5 x 104 CFU (7-day
survival, 64 and 73%, respectively) or 2 x
105 CFU (0 and 15%, respectively). Mice
surviving for 10 days postinoculation appeared to be permanent
survivors. Additional experiments were performed with
105 CFU S. pneumoniae.
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To determine the role of IL-1 in the early host defense against
pneumonia we assessed the outgrowth of pneumococci in the lungs of
IL-1R-/- and Wt mice 24, 48, and 72 h
after intranasal inoculation with 105 CFU
S. pneumoniae (Fig. 3) .
At early time points (24 and 48 h)
IL-1R-/- mice had more S. pneumoniae
CFU in lungs than Wt mice (p < 0.05), but at
72 h the numbers of CFU recovered from lungs were similar in the
two groups. S. pneumoniae could not be cultured from the
blood of any Wt mice. On the other hand, 25 and 50% of the blood
cultures obtained from the IL-1R-/- mice at 24
and 48 h, respectively, were positive for S.
pneumoniae. These results are in accordance with the survival
study, which did not show a difference in the eventual survival, and
thus suggest that while endogenous IL-1 activity is important for the
early antibacterial host defense, a defect in IL-1 signaling does not
influence survival in this model.
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Twenty-four hours after inoculation with S. pneumoniae,
Wt mice displayed more inflammatory infiltrates than
IL-1R-/- mice (Fig. 4) . Wt mice suffered from
bronchopneumonia involving 5–20% of the lung parenchyma. As
illustrated in Fig. 4A, the inflammation was
characterized by extensive vasculitis and diapedesis of inflammatory
cells through small and medium-sized vessels. At this stage neutrophils
were dominant and filled bronchi, bronchioles, and adjacent alveolar
spaces. Necrosis was locally present, leading to the formation of small
abscesses. On the other hand, IL-1R-/- mice
displayed slight inflammatory infiltrates at 24 h postinoculation,
predominantly composed of lymphocytes concentrated around bronchioles
and small vessels, but without signs of bronchopneumonia (Fig. 4B). After 48 h all Wt mice presented interstitial
inflammatory infiltrates composed of lymphocytes, monocytes, and a few
granulocytes, compatible with clearance of the inflammation (see Fig. 4C). At this time point 80% of
IL-1R-/- mice showed accumulation of foamy
cells in alveolar spaces (alveolar macrophages) together with
interstitial inflammatory infiltrates, as depicted in Fig. 4D.
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Granulocytes play an essential role in antibacterial host defense
during pneumonia (Fig. 5). In a first
attempt to obtain insight into the mechanism by which IL-1 exerts a
protective effect in the early phase of pneumococcal pneumonia, we
compared cell influx in BALF in IL-1R-/- and Wt
mice. Wt mice had fewer granulocytes in their BALF at 24 h
(p < 0.05) than
IL-1R-/- mice. On the other hand, at 48 h
postinoculation IL-1R-/- mice demonstrated a
3.5-fold higher influx of granulocytes in BALF than Wt mice
(p < 0.05). Hence, these data suggest that the
recruitment of granulocytes to the inflammatory site is delayed in
IL-1R-/- mice.
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Local production of specific cytokines and chemokines plays an
important role in the pathogenesis of pneumonia. Mediators that have
been found to improve host defense include the cytokines TNF and
IFN- and the chemokines KC and MIP-2 (15, 16, 24, 25, 26).
To determine whether alterations in the local expression of these
mediators could contribute to the relatively impaired antibacterial
defense in IL-1R-/- mice, we measured their
concentrations in lung homogenates of IL-1R-/-
and Wt mice. We found that the lung concentrations of all these
protective cytokines and chemokines were similar or higher in
IL-1R-/- mice compared with those in Wt mice
(data not shown). Thus, these data suggest that IL-1 does not enhance
host defense by inducing protective cytokines or chemokines during
pneumococcal pneumonia.
Both IL-1 and TNF are necessary for effective host defense during
pneumococcal pneumonia (Fig. 6)
Since TNF is known to enhance host defense during pneumonia
(15, 16), and IL-1 and TNF can exert synergistic
proinflammatory effects in vivo (10, 11), we next
determined the role of endogenous TNF in the early impairment and
subsequent recovery of host defense in IL-1R-/-
mice. All IL-1R-/- mice treated with
anti-TNF rapidly died after inoculation with
105 CFU S. pneumoniae (0% survivors
after 4 days), while 10-day survival rates in
IL-1R-/- mice (control Ab), Wt mice
(anti-TNF), and Wt mice (control Ab) were 62, 29, and 92%,
respectively (Fig. 6, upper panel). Mice surviving for 10
days appeared to be permanent survivors. To obtain further insight into
the concerted action of IL-1 and TNF in the protective immune response
to pneumococcal pneumonia, we compared bacterial outgrowth in
IL-1R-/- mice treated with anti-TNF or
control Ab at 48 h postinfection. Treatment with anti-TNF was
associated with more S. pneumoniae CFUs in lung homogenates
(p < 0.05 vs control Ab; Table I) and an enhanced dissemination of the
infection, as reflected by the fact that all anti-TNF-treated
IL-1R-/- mice had positive blood cultures vs
40% of IL-1R-/- mice treated with control Ab.
Anti-TNF tended to increase the influx of neutrophils into lungs (Table I), whereas IL-6 and KC concentrations were lower, and MIP-2
concentrations were higher in anti-TNF-treated
IL-1R-/- mice (p <
0.05 vs IL-1R-/- mice for KC and MIP-2). The
histopathology showed that all IL-1R-/- mice
treated with anti-TNF suffered from severe pneumonia 48 h
after inoculation. The lungs showed dense and diffuse infiltration of
granulocytes, destruction of alveolar septae, and pronounced edema
around the vessels (Fig. 6, lower panel).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-1 are both produced in the lung and that
deficiency of the functional receptor for these cytokines impairs the
early pulmonary defense. Pretreatment of
IL-1R-/- mice with a neutralizing anti-TNF
Ab resulted in strongly diminished survival, suggesting that the
combined actions of endogenous IL-1 and TNF are required for an
effective pulmonary defense against S. pneumoniae.
IL-1 has been shown to be locally produced during pneumonia in
humans. In patients with unilateral community-acquired pneumonia, the
inflammatory reaction within the lung was limited to the site of
infection, as reflected by higher IL-1 concentrations in BALF from
the involved lung than BALF from the noninvolved lung or in serum
(27). Furthermore, alveolar macrophages recovered from the
involved lung spontaneously released more IL-1 than alveolar
macrophages from the noninvolved lung (27). Patients with
pleural empyema showed a significant elevation of IL-1 in the
pleural fluid when compared with patients with pleural fluid due to
other etiologies (28). Children with bacterial pulmonary
infection had significantly higher levels of IL-1 and IL-1 activity
in BALF than children without such an infection (29).
However, knowledge of the role of IL-1 in host defense against
pneumonia is limited. An earlier study suggested a protective role for
IL-1 during Pneumocystis carinii pneumonia. Reconstitution
of SCID mice with immunocompetent spleen cells resulted in clearance of
the naturally acquired pulmonary infection with P. carinii
(30). Treatment of these mice with anti-IL-1R type I
Abs at 2 days postreconstitution inhibited this clearance
(30). In addition, IL-1-deficient mice were more
sensitive to pneumonia caused by influenza virus (31).
Together with our present results, these data suggest that locally
produced IL-1 contributes to defense mechanisms during bacterial,
protozoal, and viral lung infections.
The results of the present study suggest that endogenous IL-1 is mainly
required in the early stage of the inflammatory response. At early time
points (24 and 48 h) IL-1R-/- mice showed
enhanced bacterial outgrowth in the lungs, while at 72 h
postinoculation the number of pneumococci in the lungs was similar in
the two groups. This is in accordance with the fact that survival
curves for 10 days postinoculation did not reveal marked differences
between IL-1R-/- and Wt mice. It
should be noted that the number of S. pneumoniae CFUs
measured at 72 h was considerably lower than the number of CFUs
found at 48 h. The 24 and 48 h data were obtained in one
experiment using the same inoculum. The 72 h data were generated
in a subsequent experiment in which, in retrospect, the bacterial
inoculum was slightly lower (i.e., 8 x 104
CFU vs 1 x 105 CFU in the earlier
experiment). This together with the fact that some biological variation
between mouse experiments separated in time exists may have caused the
difference between the 48 and 72 h values. The impaired
antibacterial defense in IL-1R-/- mice can at
least in part be explained by their apparently reduced capacity to
mount an inflammatory response in the pulmonary compartment, as
reflected by histopathology and an attenuated recruitment of
granulocytes shortly after infection. The local production of
protective cytokines was not reduced in
IL-1R-/- mice. The finding that the influx of
granulocytes in BALF was delayed in IL-1R-/-
mice is in keeping with previous observations that IL-1 and IL-1
can induce granulocyte recruitment to lungs after intratracheal
administration to rodents (32, 33, 34), and that inhibition of
IL-1 activity reduces endotoxin-induced neutrophil influx in BALF
(35, 36).
It should be noted that in the final survival studies (Fig. 6
),
IL-1R-/- mice had a slightly reduced survival
compared with normal Wt mice, while in the first two survival
experiments IL-1R-/- mice tended to have
increased mortality (Fig. 2). These findings suggest that the absence
of an intact IL-1 signal results in a diminished early antibacterial
defense that, at most, influences survival in a modest way.
Nonetheless, it is clear that anti-TNF has a more profound
detrimental effect in this model (this study and Ref. 16),
indicating that endogenous TNF is more important than IL-1 for host
defense against pneumococcal pneumonia. Moreover, our data show that
TNF and IL-1 act synergistically to combat pneumococci in the lung.
Indeed, neutralization of endogenous TNF rendered
IL-1R-/- mice highly susceptible to
pneumococcal pneumonia. In this respect the acutely fatal outcome of
IL-1R-/- mice treated with anti-TNF
relative to Wt mice treated with anti-TNF was striking, suggesting
that during the early phase of murine pneumococcal pneumonia endogenous
IL-1 can compensate in part for the absence of TNF. Considering the
different survival curves of IL-1R-/- mice
treated with either anti-TNF or control Ab, endogenous TNF can
compensate for the absence of an intact IL-1 signal at later stages of
infection.
IL-1 and TNF are potent proinflammatory cytokines that play a pivotal role in organ failure and death in animal models of severe sepsis induced by i.v. administration of high doses of bacteria (12, 13). However, the clinical relevance of such models is doubtful in light of the acute and fulminant course and the lack of a local infectious source. In addition, clinical trials in patients with sepsis failed to show any beneficial effect of IL-1- or TNF-neutralizing strategies (37). Evidence is accumulating that the local activity of proinflammatory cytokines is required for an adequate antibacterial response at the site of an infection (6, 23, 24, 25). Our present data suggest that TNF is more important for the protective host immune response during pneumococcal pneumonia than IL-1, and that these two proinflammatory cytokines contribute to the local defense against pneumococci in the lung by a concerted action. These findings not only add to our understanding of the role of IL-1 and TNF in pneumococcal pneumonia, but also suggest caution in use of combined anti-IL-1 and anti-TNF treatments for inflammatory conditions such as rheumatoid arthritis.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Anita W. Rijneveld, Department of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail address: a.w.rijneveld{at}amc.uva.nl
3 Abbreviations used in this paper: IL-1Ra, IL-1R antagonist; BAL, bronchoalveolar lavage; BALF, BAL fluid; MIP, macrophage inflammatory protein; Wt, wild type.
Received for publication July 18, 2000. Accepted for publication August 27, 2001.
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Q. Chen, G. Sen, and C. M. Snapper Endogenous IL-1R1 Signaling Is Critical for Cognate CD4+ T Cell Help for Induction of In Vivo Type 1 and Type 2 Antipolysaccharide and Antiprotein Ig Isotype Responses to Intact Streptococcus pneumoniae, but Not to a Soluble Pneumococcal Conjugate Vaccine J. Immunol., November 1, 2006; 177(9): 6044 - 6051. [Abstract] [Full Text] [PDF]
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H. M. Marriott, P. G. Hellewell, S. S. Cross, P. G. Ince, M. K. B. Whyte, and D. H. Dockrell Decreased Alveolar Macrophage Apoptosis Is Associated with Increased Pulmonary Inflammation in a Murine Model of Pneumococcal Pneumonia J. Immunol., November 1, 2006; 177(9): 6480 - 6488. [Abstract] [Full Text] [PDF]
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C. Mold and T. W. Du Clos C-Reactive Protein Increases Cytokine Responses to Streptococcus pneumoniae through Interactions with Fc{gamma} Receptors. J. Immunol., June 15, 2006; 176(12): 7598 - 7604. [Abstract] [Full Text] [PDF]
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 M. Tanabe, T. Matsumoto, K. Shibuya, K. Tateda, S. Miyazaki, A. Nakane, Y. Iwakura, and K. Yamaguchi Compensatory response of IL-1 gene knockout mice after pulmonary infection with Klebsiella pneumoniae J. Med. Microbiol., January 1, 2005; 54(1): 7 - 13. [Abstract] [Full Text] [PDF]
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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]
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 J. T. Giles and J. M. Bathon Serious Infections Associated with Anticytokine Therapies in the Rheumatic Diseases J Intensive Care Med, November 1, 2004; 19(6): 320 - 334. [Abstract] [PDF]
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K. F. van der Sluijs, L. J. R. van Elden, M. Nijhuis, R. Schuurman, J. M. Pater, S. Florquin, M. Goldman, H. M. Jansen, R. Lutter, and T. van der Poll IL-10 Is an Important Mediator of the Enhanced Susceptibility to Pneumococcal Pneumonia after Influenza Infection J. Immunol., June 15, 2004; 172(12): 7603 - 7609. [Abstract] [Full Text] [PDF]
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 J. P. Mizgerd, M. M. Lupa, J. Hjoberg, J. C. Vallone, H. B. Warren, J. P. Butler, and E. S. Silverman Roles for early response cytokines during Escherichia coli pneumonia revealed by mice with combined deficiencies of all signaling receptors for TNF and IL-1 Am J Physiol Lung Cell Mol Physiol, June 1, 2004; 286(6): L1302 - L1310. [Abstract] [Full Text] [PDF]
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 J. R. Timoshanko, A. R. Kitching, Y. Iwakura, S. R. Holdsworth, and P. G. Tipping Contributions of IL-1{beta} and IL-1{alpha} to Crescentic Glomerulonephritis in Mice J. Am. Soc. Nephrol., April 1, 2004; 15(4): 910 - 918. [Abstract] [Full Text] [PDF]
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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]
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 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]
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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]
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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]
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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]
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E. Saeland, G. Vidarsson, J. H. W. Leusen, E. van Garderen, M. H. Nahm, H. Vile-Weekhout, V. Walraven, A. M. Stemerding, J. S. Verbeek, G. T. Rijkers, et al. Central Role of Complement in Passive Protection by Human IgG1 and IgG2 Anti-pneumococcal Antibodies in Mice J. Immunol., June 15, 2003; 170(12): 6158 - 6164. [Abstract] [Full Text] [PDF]
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P. J. G. Zwijnenburg, T. van der Poll, S. Florquin, J. J. Roord, and A. M. van Furth IL-1 Receptor Type 1 Gene-Deficient Mice Demonstrate an Impaired Host Defense Against Pneumococcal Meningitis J. Immunol., May 1, 2003; 170(9): 4724 - 4730. [Abstract] [Full Text] [PDF]
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M. J. Schultz, S. Knapp, S. Florquin, J. Pater, K. Takeda, S. Akira, and T. van der Poll Interleukin-18 Impairs the Pulmonary Host Response to Pseudomonas aeruginosa Infect. Immun., April 1, 2003; 71(4): 1630 - 1634. [Abstract] [Full Text]
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M. A. Matthay, G. A. Zimmerman, C. Esmon, J. Bhattacharya, B. Coller, C. M. Doerschuk, J. Floros, M. A. Gimbrone Jr, E. Hoffman, R. D. Hubmayr, et al. Future Research Directions in Acute Lung Injury: Summary of a National Heart, Lung, and Blood Institute Working Group Am. J. Respir. Crit. Care Med., April 1, 2003; 167(7): 1027 - 1035. [Abstract] [Full Text] [PDF]
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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]
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) mice.
Mortality was assessed twice daily for 10 days. n =
12–15/group for each bacterial dose.
) mice. n = 8/group.
, Wt;