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Physiology Program, Harvard School of Public Health, Boston, MA 02115
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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B and the expression of the chemokine macrophage
inflammatory protein-2 did not differ between WT and TNFR1/IL1R1 lungs.
However, the concentration of the chemokine KC was significantly
decreased in the bronchoalveolar lavage fluids of TNFR1/IL1R1 mice
compared with that in WT mice. Thus, while many of the molecular and
cellular responses to E. coli in the lungs did not
require signaling by either TNFR1 or IL1R1, early response cytokine
signaling was critical to KC expression in the pulmonary air spaces and
neutrophil emigration from the alveolar septae. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B family of transcription factors (7, 8, 9).
TNF-
signals through two different receptors, TNFR1 and TNFR2. TNFR1
induces proinflammatory signaling, as evidenced by the activities of
specific agonists of TNFR1 (10, 11) and by overexpression
of TNFR1 induced by transfection (12). TNFR2 is also
capable of generating proinflammatory signals, as evidenced by
TNFR2-specific agonists (13) and by TNF-mediated
activation of cells that do not express TNFR1 (14), but
this receptor requires higher doses of ligand and/or nonsoluble forms
of ligand (15). The gene-targeted deletion of TNFR1
compromises cellular responses to soluble TNF-, including NF-B
translocation in fibroblasts (16) and adhesion molecule
expression on endothelial cells (17), and results in an
inability to control bacterial infections (18, 19, 20). In
contrast, deficiency of TNFR2 has only modest effects on TNF-induced
NF-B translocation in cultured fibroblasts (16), and
TNFR2-deficient mice do not demonstrate compromised antibacterial
defenses (21). Thus, although TNFR2 is capable of
eliciting proinflammatory signaling, TNFR1 appears to function as the
primary signaling receptor for TNF-.
IL-1 cytokines (IL-1 and IL-1
) bind to two distinct receptors,
IL1R1 and IL1R2, but IL1R2 contains a minimal cytoplasmic tail and is
incapable of conveying intracellular signals from extracellular IL-1
molecules (for review, see Ref. 22). IL1R1 interacts with
a different set of adapter molecules from TNFR1, but the downstream
pathways (including NF-B) and effects (transcription of chemokines
and adhesion molecules) of IL1R1 activation are largely overlapping
with those of TNFR1 (discussed in Refs. 1, 2, 3, 23, 24).
The similar biologic effects of TNF and IL-1 suggest that these
cytokines share important functions. In the present studies signaling
by both TNF and IL-1 was interrupted by combined genetic deficiencies
of TNFR1, the primary signaling receptor for TNF-, and IL1R1, the
only signaling receptor for IL-1 and IL-1. To determine whether
early response cytokine functions were essential to orchestrating
innate immune responses to pulmonary infection, multiple parameters of
acute inflammation were compared in wild-type (WT) and combined
TNFR1/IL1R1-deficient mice (TNFR1/IL1R1 mice) after the intratracheal
(i.t.) instillation of E. coli.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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TNFR1/IL1R1 mice (21), WT mice of similar random
hybrid genetic background (C57BL/6 x 129/Sv), and IL1R1-deficient
mice (25) that were backcrossed five generations onto a
C57BL/6 background were maintained under specific pathogen-free
conditions in a full-barrier facility. C57BL/6 mice were purchased from
Taconic Farms (Germantown, NY). All experiments used mice at 6–10 wk
of age. Lungs from additional sets of mice at 
52 wk of age were
histologically examined for evidence of spontaneous inflammatory
processes in the absence of experimental infection, but these older
mice were not included in the no instillation control groups. Mice were
anesthetized by i.m. injection of ketamine hydrochloride (100 mg/kg)
and acepromazine maleate (5 mg/kg), and
125I-labeled human albumin (Mallinckrodt,
Hazelwood, MO) was injected i.v. as a marker for plasma content. The
trachea was surgically exposed, and an angiocatheter was inserted via
the trachea into the left bronchus. Fifteen minutes after the injection
of 125I-labeled albumin, a suspension of E.
coli (108 CFU/ml) and colloidal carbon
(5%), to mark the site of deposition, was instilled into the left lung
lobe at a dose of 2.3 µl/g body weight. After 5 h and 58 min
mice received i.v. injections of 51Cr-labeled
murine RBC as a marker for blood content. Mice were killed 6 h
after bacterial instillation by inhalation of a lethal overdose of
halothane. The hearts were tied off to maintain pulmonary blood, and
peripheral blood samples were collected from the inferior vena cava.
Lungs were excised and fixed by i.t. instillation of 6% glutaraldehyde
at a pressure of 23 cm H2O. Emigrated and
sequestered neutrophils were quantified by morphometry in histologic
lung sections, as previously described (26, 27).
Pulmonary edema, as measured by the vascular leakage of 125I-labeled albumin, was quantified before dissection of the lungs for morphometry, as previously described (26, 27). The specific activities of 125I-labeled albumin and 51Cr-labeled RBC were measured for blood and plasma samples and for excised, fixed lungs from each mouse. The hematocrit of each mouse was calculated from the 125I-labeled albumin activities in the blood and plasma samples. The pulmonary blood volume was derived from the 51Cr-labeled RBC activity in the lungs and blood sample. The total volume of plasma equivalents in the lungs was calculated from the 125I-labeled albumin activities in the lungs and the plasma sample. The volume of intravascular plasma in the lungs was derived from the hematocrit and the pulmonary blood volume. The volume of extravascular plasma equivalents in the lungs was calculated as the difference between the total volume of plasma equivalents and the volume of intravascular plasma. Edema fluid accumulation was expressed as microliters of extravascular plasma equivalents per lung.
Circulating neutrophils were quantified in peripheral blood samples. After RBC lysis, leukocytes were counted using a hemacytometer, and differential distributions were assessed in blood smears stained with LeukoStat (Fisher Scientific, Pittsburgh, PA).
NF-B translocation
WT and TNFR1/IL1R1 mice were anesthetized and instilled with
bacteria as described above. After 6 h mice were killed by
halothane overdose. Colloidal carbon-containing lung lobes from mice
instilled with E. coli, left lung lobes of mice that did not
receive bacterial instillation, and liver lobes from the same mice,
were excised, snap-frozen in liquid nitrogen, and stored at -80°C
until protein extraction. Nuclear proteins were collected from frozen
tissue samples, and protein concentrations were measured using a
bicinchonic acid assay with BSA as the standard. Nuclear proteins were
incubated at 0.5 mg/ml with 3.5 nM
[
-32P]ATP-labeled NF-B consensus
oligonucleotide (Promega, Madison, WI). Protein-oligonucleotide
complexes were separated from protein-free oligonucleotides by PAGE,
detected by autoradiography, and quantitated by densitometry using
Scion ImagePC software (Scion, Frederick, MD).
Chemokine expression
WT and TNFR1/IL1R1 mice were anesthetized and instilled with bacteria as described above. After 6 h mice were killed by halothane overdose. The chest cavity was opened, a catheter was tied into the trachea, and the airways to the right lung lobes were clamped closed. The left lung lobe was lavaged nine times with 0.5 ml of PBS. After centrifugation to rid the bronchoalveolar lavage fluids (BALF) of cells and debris, the BALF was snap-frozen in liquid nitrogen and stored at -80°C until KC and MIP-2 concentrations were measured by ELISA (R&D Systems, Minneapolis, MN).
Statistics
Data were presented as the mean ± SE for four to six mice per group. Comparisons among multiple groups used one-way ANOVA and post hoc Scheffé tests. Comparisons between two groups used Student’s t test. Differences were considered significant when p < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A characteristic pattern of patchy pulmonary inflammation
spontaneously developed in TNFR1/IL1R1 mutant mice. Although most of
the lung tissue from each of the TNFR1/IL1R1 mice appeared to be
normal, focal inflammatory infiltrates were observed in histologic
sections from three of four TNFR1/IL1R1 mice examined at 10 wk of age
and six of nine mice examined at 52 wk of age (Fig. 1
). Infiltrates contained mixed
populations of emigrated leukocytes. They typically localized to the
pleura, subpleural alveoli, and perivascular tissue, but in the most
severe example, an entire cross-section from one of the lung lobes of a
52-wk-old mouse was involved. Eosinophilic crystalline deposits were
observed in the alveolar air spaces of affected regions. Apart from
these regions that suggested chronic inflammatory processes, which were
sparse and focal, the lung tissue from TNFR1/IL1R1 mice did not appear
histologically distinct from that in age-matched WT mice. No leukocytic
infiltrates, crystalline deposits, or other evidence of infection and
inflammation were evident in four WT mice examined at 9 wk of age or
six WT mice examined at >52 wk of age.
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Apart from the patchy and localized infiltrates described above,
which were readily differentiated from acute pneumonia (Fig. 1
) and
were excluded from morphometric analyses, the alveolar air spaces of WT
and TNFR1/IL1R1 mice that did not receive bacterial instillations were
devoid of emigrated neutrophils (Fig. 2A). The i.t. instillation of
E. coli induced neutrophil emigration in the lungs of both
WT and TNFR1/IL1R1 mice (Figs. 1 and 2A). Significantly less
emigration was induced in the mutant mice compared with WT mice (Fig. 2A).
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B),
suggesting no differences in vascular permeability between noninfected
WT and TNFR1/IL1R1 mice over the 6-h period in which they were
examined. The instillation of E. coli resulted in an
increased accumulation of extravascular plasma, consistent with
pulmonary edema, in both WT and TNFR1/IL1R1 mutant mice (Fig. 2B). Similar to neutrophil emigration, the E.
coli-induced plasma extravasation was reduced, but not eliminated,
by the deficiency of TNFR1 and IL1R1 (Fig. 2B). Intravascular neutrophils in the absence of TNFR1 and IL1R1
To determine whether the decreased neutrophil emigration and edema
accumulation resulted from a paucity of circulating neutrophils in
TNFR1/IL1R1 mice, circulating neutrophil counts were compared in WT and
mutant mice. There were no significant differences in the numbers of
neutrophils per milliliter of peripheral blood between WT and
TNFR1/IL1R1 mice, with or without E. coli pneumonia (Fig. 3A). Thus, decreased
inflammatory responses in the lungs of TNFR1/IL1R1 mice did not result
from peripheral blood neutropenia.
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B). E.
coli instillation resulted in increased numbers of septal
neutrophils in both WT and TNFR1/IL1R1 mice, consistent with neutrophil
sequestration (Fig. 3B). The numbers of neutrophils in
alveolar septae of E. coli-instilled TNFR1/IL1R1 mice did
not significantly differ from those in WT mice (Fig. 3B),
suggesting that neutrophil sequestration was not impaired by the
deficiency of TNFR1 and IL1R1.
NF-B translocation in the absence of TNFR1 and IL1R1
Both TNFR1 and IL1R1 induce the nuclear translocation of NF-B
transcription factors (23), and NF-B mediates the
transcription of many genes that regulate inflammatory responses
(28). To determine whether NF-B was differentially
activated in the presence or the absence of TNFR1 and IL1R1, the
nuclear translocation of NF-B was examined in the lungs of WT and
TNFR1/IL1R1 mice. Levels of NF-B proteins in the nuclear fractions
from noninfected lungs did not significantly differ between genotypes
(Fig. 4A). The instillation of
E. coli resulted in the accumulation of NF-B proteins in
the nuclear fractions, consistent with nuclear translocation of these
transcription factors (Fig. 4A). There were no significant
differences in the net nuclear accumulation of NF-B proteins in the
lungs of WT and TNFR1/IL1R1 mice (Fig. 4B).
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B (31, 32, 33). To determine whether systemic responses
to intrapulmonary E. coli were affected by deficiency of
early response cytokine receptors, the nuclear translocation of NF-B
in the liver was compared in WT and TNFR1/IL1R1 mice. Similar levels of
NF-B proteins were present within the nuclei of livers from
noninfected WT and TNFR1/IL1R1 mice (Fig. 4, C and
D). The instillation of E. coli resulted in the
nuclear accumulation of NF-B proteins in the livers of WT mice (Fig. 4, C and D). In contrast, no accumulation of
NF-B proteins was detected in the livers of TNFR1/IL1R1 mice
instilled with E. coli (Fig. 4, C and
D), suggesting that these early response cytokine receptors
are essential for activation of NF-B in the liver in response to
pulmonary E. coli infection. Chemokine expression in the absence of TNFR1 and IL1R1
Chemokines direct the migration of neutrophils, and the rodent
chemokines KC and MIP-2 are essential for maximal neutrophil emigration
in response to i.t. instillation of E. coli LPS (4, 6). To determine whether KC and/or MIP-2 expression required the
early response cytokine receptors TNFR1 and IL1R1, KC and MIP-2
concentrations were compared in BALF collected 6 h after E.
coli instillation to WT and TNFR1/IL1R1 mice. KC expression was
detected in all mice examined, but KC concentrations in BALF of
E. coli-instilled TNFR1/IL1R1 mice were significantly less
than those in WT mice (Fig. 5). MIP-2
expression was detected in all mice examined, but, unlike KC, there
were no significant differences between MIP-2 concentrations in BALF
from WT and TNFR1/IL1R1 mice (Fig. 5).
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To determine whether the deficiency of IL1R1 alone was sufficient
to compromise these inflammatory processes, C57BL/6 mice and
IL1R1-deficient mice on C57BL/6 backgrounds received i.t. instillations
of E. coli. After 6 h there were no statistically
significant differences in the numbers of emigrated, sequestered, or
circulating neutrophils in C57BL/6 and IL1R1-deficient mice (Table I). There were no significant differences
in E. coli-induced plasma extravasation in C57BL/6 and
IL1R1-deficient mice (Table I). Thus, in mice with uninterrupted
expression of TNFR1, the deficiency of IL1R1 did not compromise
neutrophil emigration or edema accumulation 6 h after the
instillation of E. coli.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The combined deficiencies of TNFR1 and IL1R1 compromised neutrophil emigration and edema accumulation in response to E. coli in the alveolar air spaces, indicating an essential role for early response cytokine signaling in coordinating these innate immune responses. In contrast, neither the combined deficiency of both TNFR1 and TNFR2 (27) nor the deficiency of IL1R1 alone compromised neutrophil emigration or edema accumulation 6 h after the i.t. instillation of E. coli. Altogether these data suggest that TNFR1 and IL1R1 serve essential signaling functions in eliciting acute inflammatory responses to E. coli in the lungs, but the essential functions mediated by these receptors are shared and can be elicited by either receptor in the other’s absence.
The mechanisms by which the deficiency of TNFR1 and IL1R1 compromises neutrophil emigration are not entirely clear. Neutrophil numbers were significantly decreased in the alveolar air spaces, but not in the alveolar septae, suggesting that signaling from these receptors is not required for neutrophil sequestration, but is essential to coordinating neutrophil migration across the endothelial or epithelial barriers or through the interstitium.
Deficiency of TNFR1 and IL1R1 significantly decreased KC expression,
but not MIP-2 expression, elicited by E. coli in the lungs.
Differential regulation of these two chemokines is surprising and has
not been previously reported to our knowledge. Expression of each of
these chemokines is regulated transcriptionally, but the dominant
factor mediating LPS- or TNF-induced expression from the promoters of
each of these genes is common to both, NF-B (8, 38). It
is possible that other transcription factors, not yet identified,
amplify the transcription of KC but not MIP-2, and these other factors
may require TNFR1 and IL1R1 signaling for their activation in the lungs
during E. coli pneumonia. Furthermore, transcriptional
regulation of the genes encoding KC and MIP-2 could require distinct
coactivators, differentially dependent on TNFR1 and IL1R1 for their
activation during E. coli pneumonia, to link NF-B and/or
other transcription factors with the transcriptional machinery.
Finally, the divergent effects of TNFR1/IL1R1 deficiency on the
concentrations of these chemokines in the BALF of mice with E.
coli pneumonia could result from differential posttranscriptional
regulation of KC and MIP-2.
Decreased KC expression could be the means by which the deficiency of TNFR1 and IL1R1 compromised neutrophil emigration in the present studies, since KC function is essential to neutrophil emigration in response to E. coli LPS in the alveolar air spaces (4). Although only two chemokines were measured in these studies, many pro- and anti-inflammatory factors are regulated by the early response cytokines and may be affected by TNFR1/IL1R1 deficiency. The combined deficiency of these two receptors almost certainly resulted in complex disturbances in the balance of inflammatory mediators in the lungs of mice infected with E. coli, and the resulting shift in this balance is most likely responsible for the observed decreases in neutrophil emigration and edema accumulation.
Both TNFR1 and IL1R1 induce NF-B translocation, and NF-B is
essential to neutrophil emigration in response to E. coli
LPS in the lungs.7 However, in
the present studies NF-B translocation in the lungs was not
decreased by TNFR1/IL1R1 deficiency when examined using EMSAs and
nuclear protein extracts from whole lung lobes. Thus, receptors other
than TNFR1 and IL1R1 are sufficient for propagating NF-B signaling
in the lungs. TNFR2 (13, 14, 15) and Toll-like receptors 2 and
4 (39, 40, 41, 42) are capable of inducing NF-B translocation,
are probably activated in the lungs during E. coli
pneumonia, and may be mediating this signaling. Despite this evidence
of NF-B activation, neutrophil emigration and edema accumulation
were significantly decreased by deficiency of TNFR1 and IL1R1.
Therefore, the signaling by TNFR1 and IL1R1 which is essential to
neutrophil emigration and edema accumulation may be mediated by factors
other than NF-B. Alternatively, TNFR1/IL1R1 deficiency may decrease
essential NF-B translocation in specific subsets of lung cells,
which may be indiscernible with the methods used in these studies.
NF-B translocation was inhibited by TNFR1/IL1R1 deficiency in the
livers of pneumonic mice, suggesting that at least some extrapulmonary
transmission of proinflammatory signaling requires these receptors.
Whether hepatic activation of NF-B and the acute phase response
contribute to neutrophil emigration in the lungs is unknown. The
transcription of the acute phase proteins serum amyloid A
(32) and complement C3 (33) is NF-B
dependent, and these proteins can influence neutrophil activation and
recruitment (43, 44, 45, 46). If the acute phase response
contributes to innate immune responses in pneumonic lungs, then the
decreased pulmonary inflammation in TNFR1/IL1R1 mutant mice may be due
in part to a lack of activation of NF-B in the liver.
Although neutrophil emigration and edema accumulation were compromised
in TNFR1/IL1R1 mice compared with WT mice, these processes were not
completely inhibited. Approximately half of the neutrophil emigration
and a third of the edema accumulation occurred despite the complete
absence of TNFR1 and IL1R1. Other mediators and receptors are clearly
capable of propagating and coordinating signals required to elicit
acute inflammatory responses to bacteria in the lungs. Some of these
signaling events might be transmitted by TNF-, particularly
membrane-bound TNF- (15), through TNFR2, which remains
functional in the TNFR1/IL1R1 mice. Additional studies will be required
to determine whether acute inflammatory responses that occur in the
absence of TNFR1 and IL1R1 are mediated by TNFR2 or are entirely
independent of the early response cytokines TNF and IL-1.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Joseph P. Mizgerd, Physiology Program, Harvard School of Public Health, Building I, Room 301, 665 Huntington Avenue, Boston, MA 02115.
3 Current address: Division of Integrative Biology, Rainbow Babies Children’s Hospital, Cleveland, OH 44106.
4 Current address: Division of Integrative Biology, Rainbow Babies Children’s Hospital, Cleveland, OH 44106.
5 Abbreviations used in this paper: MIP, macrophage inflammatory protein; BALF, bronchoalveolar lavage fluid; IL1R1, type I IL-1 receptor; TNFR1, TNF receptor 1 (p55, CD120a); TNFR2, TNF receptor 2 (p75, CD120b); WT, wild type; i.t., intratracheal.
6 E. A. Alcamo, J. P. Mizgerd, B. H. Horwitz, R. Bronson, A. A. Beg, M. Scott, C. M. Doerschuk, R. O. Hynes, and D. Baltimore. Targeted mutation of tumor necrosis factor receptor 1 rescues the RelA-deficient mouse and reveals a critical role for NF-B in leukocyte recruitment. Submitted for publication.
7 E.A. Alcamo, J.P. Mizgerd, B.H. Horwitz, R. Bronson, A.A. Beg, M. Scott, C.M. Doerschuk, R.O. Hynes, and D. Baltimore. Targeted mutation of tuor necrosis factor receptor 1 rescues the RelA-deficient mouse and reveals a critical role for NF-B in leukocyte recruitment. Submitted for publication.
Received for publication July 27, 2000. Accepted for publication January 2, 2001.
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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. 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. P. Mizgerd Competing Benefits of Tumor Necrosis Factor-{alpha} for Bacteria and for Host Defense Am. J. Respir. Crit. Care Med., December 15, 2003; 168(12): 1410 - 1411. [Full Text] [PDF]
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J.-H. Lee, L. Del Sorbo, A. A. Khine, J. de Azavedo, D. E. Low, D. Bell, S. Uhlig, A. S. Slutsky, and H. Zhang Modulation of Bacterial Growth by Tumor Necrosis Factor-{alpha} In Vitro and In Vivo Am. J. Respir. Crit. Care Med., December 15, 2003; 168(12): 1462 - 1470. [Abstract] [Full Text] [PDF]
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J. P. Mizgerd, M. M. Lupa, M. S. Kogan, H. B. Warren, L. Kobzik, and G. P. Topulos Nuclear Factor-{kappa}B p50 Limits Inflammation and Prevents Lung Injury during Escherichia coli Pneumonia Am. J. Respir. Crit. Care Med., October 1, 2003; 168(7): 810 - 817. [Abstract] [Full Text] [PDF]
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S. C. Higgins, E. C. Lavelle, C. McCann, B. Keogh, E. McNeela, P. Byrne, B. O'Gorman, A. Jarnicki, P. McGuirk, and K. H. G. Mills Toll-Like Receptor 4-Mediated Innate IL-10 Activates Antigen-Specific Regulatory T Cells and Confers Resistance to Bordetella pertussis by Inhibiting Inflammatory Pathology J. Immunol., September 15, 2003; 171(6): 3119 - 3127. [Abstract] [Full Text] [PDF]
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S. Tasaka, L. Qin, A. Saijo, S. M. Albelda, H. M. DeLisser, and C. M. Doerschuk Platelet Endothelial Cell Adhesion Molecule-1 in Neutrophil Emigration during Acute Bacterial Pneumonia in Mice and Rats Am. J. Respir. Crit. Care Med., January 15, 2003; 167(2): 164 - 170. [Abstract] [Full Text] [PDF]
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M. A. Koay, J. W. Christman, L. J. Wudel, T. Allos, D.-S. Cheng, W. C. Chapman, and T. S. Blackwell Modulation of endotoxin-induced NF-kappa B activation in lung and liver through TNF type 1 and IL-1 receptors Am J Physiol Lung Cell Mol Physiol, December 1, 2002; 283(6): L1247 - L1254. [Abstract] [Full Text] [PDF]
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J. P. Mizgerd, M. L. Scott, M. R. Spieker, and C. M. Doerschuk Functions of I{kappa}B Proteins in Inflammatory Responses to Escherichia coli LPS in Mouse Lungs Am. J. Respir. Cell Mol. Biol., November 1, 2002; 27(5): 575 - 582. [Abstract] [Full Text] [PDF]
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D. Jarrar, J. F. Kuebler, L. W. Rue III, S. Matalon, P. Wang, K. I. Bland, and I. H. Chaudry Alveolar macrophage activation after trauma-hemorrhage and sepsis is dependent on NF-kappa B and MAPK/ERK mechanisms Am J Physiol Lung Cell Mol Physiol, October 1, 2002; 283(4): L799 - L805. [Abstract] [Full Text] [PDF]
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B. D. Brown and D. Lillicrap Dangerous liaisons: the role of "danger" signals in the immune response to gene therapy Blood, July 30, 2002; 100(4): 1133 - 1140. [Abstract] [Full Text] [PDF]
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J. C. Leemans, M. J. B. M. Vervoordeldonk, S. Florquin, K. P. van Kessel, and T. van der Poll Differential Role of Interleukin-6 in Lung Inflammation Induced by Lipoteichoic Acid and Peptidoglycan from Staphylococcus aureus Am. J. Respir. Crit. Care Med., May 15, 2002; 165(10): 1445 - 1450. [Abstract] [Full Text] [PDF]
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, Significant
differences compared with WT after same instillation.
