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*
Physiology Program, Harvard School of Public Health, Boston, MA 02115; and
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In contrast, pneumonic lungs from CD18-deficient human or veterinary
patients display abundant emigrated neutrophils (6, 7, 14), demonstrating that CD18-independent pathways can be
used for neutrophil emigration from the pulmonary circulation.
Blocking Ab studies suggest that neutrophils use CD18-dependent or
CD18-independent pathways in the lungs, depending on the stimulus
inducing pneumonia. Blocking Abs against CD11/CD18 prevent neutrophil
emigration by 
70% during 4–6 h of pneumonia induced by
Escherichia coli LPS, E. coli, Pseudomonas
aeruginosa, IgG immune complexes, IL-1
, and phorbol esters
(12, 15, 16, 17, 18), but blocking Abs against CD11/CD18 do not
affect neutrophil emigration during 4–6 h of pneumonia induced by
S. pneumoniae, group B Streptococcus,
Staphylococcus aureus, complement fragment C5a, hyperoxia,
or hydrochloric acid (12, 16, 18, 19, 20).
Consistent with clinical observations of neutrophils in the lungs of CD18-deficient patients, but contrasting with predictions based on blocking Ab studies, mice rendered CD18-deficient by gene targeting show no defect in neutrophil emigration compared with wild-type (WT)5 mice during experimental pneumonias induced by either E. coli or S. pneumoniae (21). Furthermore, experimental pneumonias induced by Pasteurella haemolytica in cows with spontaneous deficiencies of CD18 show no defect in neutrophil emigration compared with normal (CD18-expressing) cows (22). Thus, the results from all studies to date suggest that CD18 deficiency does not compromise the emigration of neutrophils from the pulmonary circulation. However, the genetic deficiency of CD18 results in systemic phenotypic alterations (1, 7, 23), including soft tissue infections, neutrophilia, splenomegaly, and lymphadenopathy, which may affect neutrophil emigration and confound comparisons of CD18-deficient and control animals. To directly examine the roles of CD11/CD18 in neutrophil emigration in the lungs, we endeavored to compare the emigration of WT and CD18-deficient neutrophils within the same physiological environment. To accomplish this, mice with both types of neutrophils in their blood were generated after reconstitution of the hemopoietic systems of lethally irradiated mice with mixtures of fetal liver cells from WT and CD18-deficient mice.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The hemopoietic systems of lethally irradiated C57BL/6 host mice
were reconstituted after injection of fetal liver cells as described
(24). In short, CD18-deficient mice (23),
provided by Dr. Arthur L. Beaudet, and WT mice of similar randomly
mixed C57BL/6 x 129/Sv background were mated with the like
genotype, and fetuses were collected after 14 days of gestation.
Single-cell suspensions were prepared from WT and CD18-deficient fetal
livers, and mixtures of 1–2 x 106 total
cells were injected i.v. into host mice that had received radiation
doses of 800 and 400 rad, separated by 3 h, from a
137Cs source. To minimize possible systemic
physiological effects caused by CD18 deficiency, these studies were
performed using mice reconstituted with mixtures of fetal liver cells
in which a minority of the inoculum was from CD18-deficient animals
(
10% in the E. coli LPS and S. pneumoniae
experiments and 25% in the P. aeruginosa experiments).
After transplantation, mice received trimethoprim-sulfamethoxazole in
their drinking water and were maintained under barrier conditions.
Animals were analyzed a minimum of 4 wk after irradiation to allow for
reconstitution. Several mice reconstituted with mixed WT and
CD18-deficient fetal liver cells had their lungs lavaged (see below)
and then fixed by instillation of 10% formalin at 22 cm
H2O. Lavage fluids were analyzed for neutrophil
content, and histological sections from the fixed lungs were examined
to determine whether irradiation and reconstitution resulted in
pulmonary inflammation.
Pneumonia
Pneumonias were induced by intratracheal (i.t.) instillations
(21). Mice were anesthetized by i.m. injection of ketamine
hydrochloride (100 mg/kg) and acepromazine maleate (5 mg/kg). The
tracheas were surgically exposed, and 50 µl of E. coli LPS
serotype O55:B5 (Sigma, St. Louis, MO) at 2 mg/ml, of P.
aeruginosa at 1 x 108 CFU/ml, or of
S. pneumoniae at 5 x 109 CFU/ml
were instilled i.t. At the indicated times, mice were killed by
inhalation of a lethal overdose of halothane. Blood was collected from
the inferior vena cava, and erythrocytes were hypotonically lysed.
Bronchoalveolar lavage (BAL) was performed after cannulating the
trachea. A syringe containing 1 ml of ice-cold PBS containing 0.6 mM
EDTA was inserted into the cannula, 0.5 ml were injected while the
chest was massaged, and then as much volume as possible was recovered.
The lavage steps were twice repeated without changing the syringe,
after which the syringe was removed from the cannula and the contents
were evacuated into a test tube and kept on ice. The entire procedure
was repeated twice more, so that the lungs received a total of 9
lavages of 0.5 ml pooled in 3 ml final volume. Blood and BAL
leukocytes were washed with fresh PBS/EDTA, and WT and CD18-deficient
cells were differentiated using mAb against CD11a and CD11b.
For flow cytometric analyses, blood and BAL cells were stained with saturating concentrations of a FITC-conjugated mAb against murine CD11a (M17/4, PharMingen, San Diego, CA) and a PE-conjugated mAb against the murine granulocyte marker Gr-1 (RB6-8C5, PharMingen). Overlapping spectra of FITC and PE were accounted for by adjusting compensation using cells stained with single Abs. Gr-1 bright cells had forward and right angle scatter characteristics consistent with granulocytes. The percentage of neutrophils that were CD18 deficient was assessed for each sample by scoring 5000 Gr-1 bright cells as either positive or negative for CD11a/CD18.
For immunohistochemical analyses, blood and BAL cells were cytocentrifuged onto glass slides, allowed to air dry, and then fixed with acetone-methanol (1:1). Slides were treated with a rat mAb against murine CD11b (M1/70, PharMingen), and M1/70 was visualized using biotinylated goat anti-rat IgG and a streptavidin-alkaline phosphatase detection system (Kirkegaard and Perry, Gaithersburg, MD). Control slides demonstrated no staining of WT or CD18-deficient cells when nonspecific rat IgG replaced M1/70 and no staining of cells from CD18-deficient mice by M1/70. Slides were counterstained with hematoxylin, and the percentage of neutrophils which were CD18-deficient was assessed for each sample by scoring 300 polymorphonuclear cells as either positive or negative for CD11b/CD18.
Statistics
In each group, the percentages of CD18-deficient neutrophils in the blood and in the BAL fluid were compared by paired t tests, and differences were considered significant when p < 0.05. Results were expressed as mean and SEM. Each group consisted of five to eight mice.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Whereas peripheral blood neutrophils from WT mice are uniformly
positive for CD11a, CD11b, and CD18, neutrophils from CD18-deficient
mice are uniformly negative for CD11a and CD11b as well as CD18
(21, 23), similar to patients with spontaneous
deficiencies of CD18 (1, 2). Abs against CD11a and CD11b
were used to differentiate WT and CD18-deficient neutrophils in the
present studies. When lethally irradiated C57BL/6 mice were
reconstituted with WT fetal liver cells, their peripheral blood
neutrophils expressed CD11a/CD18 (Fig. 1
A). When lethally irradiated
C57BL/6 mice were reconstituted with CD18-deficient fetal liver cells,
their peripheral blood neutrophils did not express CD11a/CD18 (Fig. 1B). When lethally irradiated C57BL/6 mice were
reconstituted with mixtures of WT and CD18-deficient fetal liver cells,
anti-CD11a/CD18 staining revealed both WT and CD18-deficient
neutrophils in the circulating blood (Fig. 1C). Similar
results were observed when WT and CD18-deficient neutrophils were
differentiated using immunohistochemistry for CD11b/CD18 (data not
shown).
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E. coli LPS pneumonia
The intratracheal instillation of E. coli LPS to mice
with hemopoietic systems reconstituted with mixed WT and CD18-deficient
fetal liver cells resulted in neutrophil emigration by 6 h, as
measured by the recovery of neutrophils by BAL (1.8 ± 0.6 x
105 neutrophils/ml). To determine whether the WT
and CD18-deficient neutrophils were equally capable of emigrating
6 h after E. coli LPS instillation, the percentage of
CD18-deficient neutrophils in the circulating pool (peripheral blood)
and in the emigrated pool (BAL fluid) were compared. In these animals,
9.3% of the circulating neutrophils were CD18-deficient, but only
2.8% of the emigrated neutrophils were CD18-deficient (Fig. 2A), indicating that
CD18-deficient neutrophils had a defect in emigration compared with
neutrophils expressing CD11/CD18. The BAL fluid contained a smaller
fraction of CD18-deficient neutrophils than the circulating blood in
every mouse, whether the cells were differentiated by anti-CD11b
staining of polymorphonuclear cells examined by immunohistochemistry
(Fig. 2A) or by anti-CD11a staining of Gr-1-positive
cells examined by flow cytometry (data not shown).
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B). Similar results were observed when WT and
CD18-deficient cells were differentiated by anti-CD11a staining of
Gr-1-positive cells examined by flow cytometry (data not shown). P. aeruginosa pneumonia
To determine whether CD18-deficient neutrophils were compromised
in emigration during pneumonia induced by living Gram-negative
organisms, P. aeruginosa were instilled i.t. into mice with
CD18-negative and -positive neutrophils in their blood. After 6 h,
3.4 ± 0.6 x 105 neutrophils/ml were
recovered in the BAL fluid. Immunohistochemical staining for CD11b/CD18
revealed that 46% of the neutrophils were CD18-deficient in the
peripheral blood, whereas only 11% of the neutrophils were
CD18-deficient in the BAL fluid (Fig. 3).
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To determine whether CD18-deficient neutrophils were compromised
in emigration during streptococcal pneumonia, S. pneumoniae
were instilled i.t. into mice with hemopoietic systems reconstituted
from mixtures of WT and CD18-deficient stem cells. After 6 h,
1.4 ± 0.6 x 106 neutrophils/ml were
recovered in the BAL fluid. At this time, 12.7% of the circulating
neutrophils were CD18-deficient and 12.8% of the emigrated neutrophils
were CD18-deficient (Fig. 4A), indicating
that CD18-deficient neutrophils did not have a defect in emigration
compared with CD18-positive neutrophils.
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B),
suggesting that neutrophil emigration over this time frame remained
free of requirements for CD11/CD18 adhesion complexes. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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70% during 4–6 h of pneumonia induced by E. coli LPS,
E. coli, or P. aeruginosa (12, 17, 18). However, no defect in emigration is observed in neutrophil
emigration in CD18-deficient mice during 6 h of E. coli
pneumonia (21). The reason for these discrepant results is
unclear but may reflect confounding effects of either Ab treatments or
targeted gene deletions. Blocking Abs against CD11/CD18 may have
effects other than simply the prevention of ligand binding. For
example, they may cross-link CD11/CD18 molecules or interact with Fc
receptors. The targeted deletion of CD18 induces systemic phenotypic
changes (23), including peripheral blood neutrophilia and
chronic inflammatory lesions, which also may confound comparisons of
neutrophil emigration in CD18-deficient and WT mice.
The present results compared the emigration of WT and CD18-deficient
neutrophils within the same animal and are free from these confounding
factors. Pneumonias were induced in hemopoietically reconstituted mice
with both WT and CD18-deficient neutrophils circulating in their
peripheral blood, to directly compare the emigrating abilities of these
neutrophils. The percentage of neutrophils that were CD18-deficient was
significantly smaller in the BAL fluid than in the blood 6 h after
i.t. instillation of E. coli LPS to mice with 10% of
their circulating cells CD18-deficient. Similar results were observed
6 h after the i.t. instillation of living P. aeruginosa
to mice with 50% of their circulating cells CD18-deficient. These
data suggest that CD18 deficiency compromises neutrophil emigration
during acute pneumonia elicited by either of these two Gram-negative
stimuli.
Blocking Ab studies and comparisons of WT and CD18-deficient animals investigate the effects of inhibiting CD11/CD18 function on all hemopoietic cells. Accordingly, any observed differences might be the result of CD11/CD18 expressed by either neutrophils or other cells. For example, macrophages express CD11/CD18 molecules. Because CD11/CD18 can mediate uptake or signaling in response to complement-opsonized particles, LPS, and other stimuli (23, 25, 26, 27, 28, 29, 30), the expression of inflammatory mediators produced by macrophages could be affected by blocking CD11/CD18 function, leading to decreased emigration through mechanisms other than blockade of neutrophil CD18. In the present studies, CD11/CD18-positive and CD11/CD18-negative neutrophils were directly compared within the same environment, while exposed to the same chemoattractants, cytokines, and lipid mediators. Thus, the compromised emigration of CD18-deficient neutrophils under these conditions demonstrates a critical role for the CD11/CD18 molecules expressed by neutrophils per se.
Although the present studies were free from several limitations discussed above inherent to comparisons of Ab-treated or gene-targeted mice with controls, limitations inherent to the present techniques also bear consideration. First, neutrophil emigration was studied by analysis of lavaged cells. It is conceivable that CD18 deficiency affects the adhesion of emigrated neutrophils to the alveolar epithelium, and such differential adhesion could affect the relative recovery by lavage of WT and mutant cells. Second, the mice in these studies were lethally irradiated and then hemopoietically reconstituted before the studies of pneumonia. These experimental manipulations could potentially affect the regulation of acute inflammatory responses in the lungs in as yet unrecognized ways. Blocking Ab studies (12, 17) and the studies reported in this article are subject to different experimental limitations, but the results collected with either approach suggest that CD11/CD18 is critical to neutrophil emigration during 4–6 h of pneumonia elicited by LPS or P. aeruginosa.
To determine whether the requirements for CD11/CD18 changed as the pneumonia progressed, the percentages of CD18-deficient neutrophils were compared in the blood and BAL fluid 24 h after the i.t. instillation of E. coli LPS. Similar to observations at the earlier time points, a significantly smaller percentage of neutrophils were CD18-deficient in the BAL fluid compared with the blood 24 h after instillation of E. coli LPS. In previous studies of peritonitis induced in rabbits by the injection of E. coli or protease peptone, blocking Abs against CD18 compromised neutrophil emigration during the first several hours, but emigration during 24 h of peritonitis was no longer affected by blocking Abs (31). These results indicate that CD18-independent pathways become available over this time frame of peritonitis. The present data suggest that neutrophil emigration during E. coli LPS pneumonia remains dependent on CD18 for at least 24 h. Although these studies used different animal species and inflammatory stimuli, the present results suggest that the temporal regulation of CD18 dependence in mediating neutrophil emigration may differ in the vascular beds of the lungs and of the peritoneum.
In contrast to the results with E. coli LPS or P. aeruginosa pneumonias, similar percentages of CD18-deficient neutrophils were present in the blood and BAL fluid 6 h after the instillation of S. pneumoniae. Previous studies demonstrate that blocking Abs against CD11/CD18 do not affect neutrophil emigration during 4–6 h of pulmonary inflammation induced by S. pneumoniae, group B Streptococcus, Staphylococcus aureus, complement fragment C5a, hyperoxia, or hydrochloric acid (12, 16, 18, 19, 20). Several factors have been suggested as responsible for the inability of blocking Abs to inhibit neutrophil emigration during such pneumonias, including: 1) failure to obtain sufficient Ab concentrations to the required anatomic or cellular locations to completely prevent ligand binding; 2) alternative epitopes on CD11/CD18 that mediate neutrophil emigration and are not blocked by the Abs; or 3) a distinct pathway for neutrophil emigration that does not require CD11/CD18. The present data, indicating that the emigration of CD18-deficient neutrophils is not compromised compared with WT during streptococcal pneumonia, suggest that S. pneumoniae elicits a distinct pathway for neutrophil emigration in the lungs that is truly CD18 independent, not utilizing any region of CD11/CD18 complexes for either adhesion or signaling events essential for emigration. Furthermore, the present results demonstrate that neutrophil emigration remains CD18 independent throughout 24 h of pneumonia induced by S. pneumoniae.
These roles for CD11/CD18 in mediating neutrophil emigration during pneumonias could not be appreciated when comparing neutrophil emigration in CD18-deficient and WT mice (21), likely due to the diverse physiological effects resulting from the genetic deficiency of CD18 by all leukocytes. However, these roles for CD11/CD18 became clear in mice with reconstituted hemopoietic systems in which the behaviors of cells of different genotypes were studied within the same physiological environment. To our knowledge, these data are the first to demonstrate that the deficiency of an adhesion molecule compromises neutrophil emigration during pneumonia. Furthermore, these studies identified CD11/CD18 expressed by neutrophils per se as critical to mediating emigration during E. coli LPS and P. aeruginosa pneumonias. These requirements for CD11/CD18 persisted for at least 24 h of E. coli LPS pneumonia. Finally, the data conclusively demonstrate that in contrast to E. coli LPS or to P. aeruginosa, S. pneumoniae induces neutrophil emigration in the lungs that does not require CD11/CD18.
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Acknowledgments |
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Footnotes |
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2 Current address: Division of Immunology Research, Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115.
3 Current address: Biogen, Inc., Cambridge, MA 02142.
4 Address correspondence and reprint requests to Dr. Claire M. Doerschuk, Physiology Program, Harvard School of Public Health, Building I, Room 305, 665 Huntington Avenue, Boston, MA 02115. E-mail address:
5 Abbreviations used in this paper: WT, wild type; BAL, bronchoalveolar lavage; i.t., intratracheal.
Received for publication December 18, 1998. Accepted for publication May 10, 1999.
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B-deficient fetal liver cells. Immunity 6:765.[Medline]
B activation and TNF production induced by lipopolysaccharide and group B streptococcal cell walls. J. Immunol. 160:4535.This article has been cited by other articles:
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E. 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 TNF Receptor I Rescues the RelA-Deficient Mouse and Reveals a Critical Role for NF-{kappa}B in Leukocyte Recruitment J. Immunol., August 1, 2001; 167(3): 1592 - 1600. [Abstract] [Full Text] [PDF]
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B. H. Horwitz, J. P. Mizgerd, M. L. Scott, and C. M. Doerschuk Mechanisms of granulocytosis in the absence of CD18 Blood, March 15, 2001; 97(6): 1578 - 1583. [Abstract] [Full Text] [PDF]
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V. C. Ridger, B. E. Wagner, W. A. H. Wallace, and P. G. Hellewell Differential Effects of CD18, CD29, and CD49 Integrin Subunit Inhibition on Neutrophil Migration in Pulmonary Inflammation J. Immunol., March 1, 2001; 166(5): 3484 - 3490. [Abstract] [Full Text] [PDF]
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 C. M. Doerschuk, S. Tasaka, and Q. Wang CD11/CD18-Dependent and -Independent Neutrophil Emigration in the Lungs . How Do Neutrophils Know Which Route to Take? Am. J. Respir. Cell Mol. Biol., August 1, 2000; 23(2): 133 - 136. [Full Text]
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M. R. Gyetko, S. Sud, T. Kendall, J. A. Fuller, M. W. Newstead, and T. J. Standiford Urokinase Receptor-Deficient Mice Have Impaired Neutrophil Recruitment in Response to Pulmonary Pseudomonas aeruginosa Infection J. Immunol., August 1, 2000; 165(3): 1513 - 1519. [Abstract] [Full Text] [PDF]
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D. A. Mark, C. E. Donovan, G. T. De Sanctis, H. Z. He, M. Cernadas, L. Kobzik, D. L. Perkins, A. Sharpe, and P. W. Finn B7-1 (CD80) and B7-2 (CD86) Have Complementary Roles in Mediating Allergic Pulmonary Inflammation and Airway Hyperresponsiveness Am. J. Respir. Cell Mol. Biol., March 1, 2000; 22(3): 265 - 271. [Abstract] [Full Text]
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J. P. Mizgerd, J. J. Peschon, and C. M. Doerschuk Roles of Tumor Necrosis Factor Receptor Signaling during Murine Escherichia coli Pneumonia Am. J. Respir. Cell Mol. Biol., January 1, 2000; 22(1): 85 - 91. [Abstract] [Full Text]
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 C. Huang, G. T. De Sanctis, P. J. O'Brien, J. P. Mizgerd, D. S. Friend, J. M. Drazen, L. F. Brass, and R. L. Stevens Evaluation of the Substrate Specificity of Human Mast Cell Tryptase beta I and Demonstration of Its Importance in Bacterial Infections of the Lung J. Biol. Chem., July 6, 2001; 276(28): 26276 - 26284. [Abstract] [Full Text] [PDF]
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