Departments of 1 Anesthesiology, 3 Physiology and Biophysics, and 4 Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama 35233; and 2 Division of Pulmonary, Critical Care, and Occupational Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202
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ABSTRACT |
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We investigated whether nitration of
surfactant apoprotein (SP) A alters its ability to bind to
mannose-containing saccharides on Pneumocystis
carinii and its potential role in the mediation of
P. carinii adherence to alveolar
macrophages. Human SP-A was nitrated by incubation with
tetranitromethane at pH 8.0 or synthetic peroxynitrite
(ONOO) at pH 7.4, which
resulted in significant nitration of tyrosines in its carbohydrate
recognition domain [0.63 ± 0.001 (SE) and 1.25 ± 0.02 mol
nitrotyrosine/mol monomeric SP-A, respectively; n = 3 samples]. Binding of SP-A
to P. carinii was calcium dependent and competitively inhibited by
-methyl-D-mannopyranoside.
Nitration of SP-A by ONOO
or tetranitromethane decreases its binding to P. carinii by increasing its dissociation constant from
7.8 × 10
9 to 1.6 × 10
8 or 2.4 × 10
8 M, respectively,
without significantly affecting the number of binding sites (7.1 × 106/P.
carinii organisms, assuming that the native molecular
mass of oligomeric SP-A is 650 kDa). Furthermore,
ONOO
-nitrated SP-A failed
to mediate the adherence and phagocytosis of P. carinii to rat alveolar macrophages as observed with
normal SP-A. Binding of SP-A to rat alveolar macrophages was not
altered by nitration. These results indicate that nitration of SP-A
interferes with its ability to serve as a ligand for
P. carinii adherence to alveolar
macrophages at the site of the SP-A moleculeP.
carinii interaction.
surfactant protein A; collectin; tyrosine nitration; parasite adherence; nitric oxide; lung host defense
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INTRODUCTION |
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pneumocystis carinii PNEUMONIA remains a common and life-threatening pulmonary infection in immunocompromised patients, especially those with acquired immunodeficiency syndrome. The interaction between P. carinii and alveolar macrophages within the alveolar lining fluid of the lung represents the initial contact of the pathogen with the host immune system.
Alveolar macrophages express many different types of surface receptors that aid in their ability to bind to microorganisms. Among these are receptors for mannose (50), fibronectin (4), the Fc portion of IgG (38), the complement component C3b (66), and surfactant protein (SP) A (5). Alveolar macrophages have been shown to play a significant role in host defense by binding, phagocytosing, and degrading P. carinii (30, 58, 63).
The predominant surface membrane protein on P. carinii is a glycoprotein with an estimated molecular mass of 110-120 kDa known as major surface glycoprotein (MSG) (46). A recent study (42) suggested that MSG may serve to mediate adherence of P. carinii to the alveolar epithelium. P. carinii MSG is heavily glycosylated with mannose-containing oligosaccharide chains (46) that could function as a ligand for SP-A (69).
SP-A, the most abundant apoprotein of the pulmonary surfactants, is a member of the C-type lectin superfamily (7, 63) and along with SP-D (40), serum mannose-binding protein (MBP) A, MBP-C, conglutinin, and the recently described collectin-43 (22) forms the collectin (group III) subgroup (7, 31). The human SP-A molecule is organized into four discrete structural domains: a short amino-terminal globular domain containing a single cysteine involved in interchain disulfide bond formation, a collagen-like domain, a hydrophobic neck region, and a carboxy-terminal carbohydrate recognition domain (CRD). Thus SP-A is a lectin protein with a collagen-like domain that shares extensive structural homology with MBPs (8), conglutinin (6), and complement component C1q (56). It has multiple functions including tubular myelin formation, binding to high-affinity receptors on alveolar type II cells, regulating the recycling of surfactant lipids, and acting synergistically with other surfactant apoproteins to lower surface tension (15, 20, 28, 64). Recent studies have shown that SP-A is implicated in lung host defense by interacting with a variety of pathogens (34, 35, 54, 63, 69) and stimulating chemotaxis, phagocytosis, and production of reactive oxygen species by alveolar macrophages (32, 34, 52, 53, 59, 63, 65).
Exposure of alveolar macrophages and airway and alveolar cells to
diverse stimuli of inflammation such as cytokines (interleukin-1, tumor
necrosis factor-, and interferon-
) and lipopolysaccharide (LPS)
results in a marked upregulation of nitric oxide (· NO) and
superoxide (O
2·) production (1, 14, 45, 48, 57, 63). The product of the reaction of · NO with
O
2·, which proceeds at a near diffusion-limited rate (6.7 × 109 M/s) (39), is peroxynitrite
(ONOO
), a potent
oxidizing and nitrating agent that damages a wide spectrum of
biological molecules such as DNA (23), lipids (47), and proteins (12,
36). Recent studies (16, 17, 37, 67) have indicated that exposure of
SP-A to nitrating reagents such as
ONOO
, tetranitromethane
(TNM), or nitrogen dioxide
(· NO2) results in a
marked decrease in its ability to aggregate lipids and bind mannose.
Thus we hypothesized that nitration of SP-A would impair its ability to
bind to P. carinii, a step necessary
for the clearance of these organisms by alveolar macrophages.
In the present study we have 1) characterized the binding of normal and nitrated SP-A to both P. carinii and alveolar macrophages, 2) determined the effect of SP-A on the interaction of P. carinii with alveolar macrophages, and 3) assessed which structural domain of SP-A is involved in these processes. We found that human SP-A can bind to P. carinii through its CRD and that nitration of tyrosine residues in the CRD decreases its affinity for mannose-rich structures on the surface of P. carinii. Furthermore, normal SP-A enhances the adherence and phagocytosis of P. carinii to alveolar macrophages, whereas nitrated SP-A fails to mediate this process. Because the binding of nitrated SP-A to alveolar macrophages is not significantly affected, it is likely that nitration of SP-A interferes with its ability to serve as a ligand for P. carinii adherence to alveolar macrophages at the site of the SP-A molecule-P. carinii interaction.
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METHODS |
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Materials. BSA, HEPES,
EDTA, EGTA, DMEM, bisbenzimide (Hoechst 33258),
-methyl-D-mannopyranoside,
o-phenylenediamine, and LPS
(serotype 055:B5 from Escherichia
coli) were from Sigma (St. Louis, MO). Sodium nitrite
and hydrogen peroxide were obtained from Fisher Scientific (Fair Lawn,
NJ). TNM and 3-nitro-L-tyrosine were from Aldrich (Milwaukee, WI). Nitro blue tetrazolium and 5-bromo-4-chloro-3-indolyl-1-phosphate kit came from Promega (Madison, WI). Hanks' balanced salt solution (HBSS) without calcium or magnesium was from GIBCO BRL (Grand Island, NY). Bicinchoninic acid protein assay
kit was from Pierce Chemical (Rockford, IL).
51Cr-labeled sodium chromate was
from NEN (Boston, MA). Goat anti-rabbit IgG and Tween 20 were from
Bio-Rad (Richmond, CA). Immulon 2 ELISA plates were from Dynatech
(Chantilly, VA). Rabbit anti-human SP-A and anti-nitrotyrosine were
kind gifts of Drs. D. S. Phelps (Pennsylvania State University,
Hershey, PA) and J. S. Beckman (University of Alabama at Birmingham,
Birmingham, AL), respectively.
Isolation of P. carinii. P. carinii pneumonia was induced in Lewis rats (Harlan Sprague Dawley, Indianapolis, IN) by immunosuppression with dexamethasone and transtracheal inoculation of P. carinii. P. carinii were isolated, purified as previously described (60), and washed extensively with HBSS containing 5 mM EGTA to remove endogenously bound rat SP-A (33). Purification of the P. carinii suspension results in >98% of the cellular material representing trophozoites (43, 44). P. carinii were quantified by the method of Bartlett et al. (2). A typical yield was 2 × 107 P. carinii organisms/rat. Any preparations found to contain bacterial, fungal, or inflammatory cell contamination were discarded.
Purification of human SP-A. SP-A was
purified from bronchoalveolar lavage fluid of patients with alveolar
proteinosis by n-butanol extraction as
previously described (17). SP-A was dissolved in 10 mM HEPES buffer, pH
7.4, the protein concentration was determined by the bicinchoninic acid
method, and the samples were stored in small aliquots at
20°C until used. The purity of SP-A was demonstrated by
SDS-PAGE and Western blotting, and the function was checked by its
lipid aggregation and mannose-binding abilities (16, 19, 67). the
endotoxin level tested negative (<0.01 endotoxin unit/ml) with the
amebocyte lysate assay performed by the University of Alabama at
Birmingham Media Preparation Shared Facility.
Synthesis of ONOO.
ONOO
was synthesized from
sodium nitrite and hydrogen peroxide with a quenched-flow reactor as
previously described (3) and treated with manganese dioxide to remove
contaminated hydrogen peroxide. The
ONOO
concentration was
determined spectrophotometrically at 302 nm (molar extinction
coefficient = 1,670 M/cm) before each experiment.
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RESULTS |
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EGTA removal of endogenously bound rat SP-A from P. carinii and alveolar macrophages. SDS-PAGE and Western blotting studies shown in Fig. 1 indicated that washing P. carinii and alveolar macrophages with HBSS containing EGTA removed all surface-associated SP-A. This is in agreement with previous results (60).
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SP-A nitration. Unexposed SP-A or SP-A
treated with inactive ONOO
contained background levels of nitrotyrosine (<0.001 mol
nitrotyrosine/mol monomeric SP-A). In contrast, SP-A exposed
to two boluses of 0.5 mM
ONOO
or a single dose of
0.5 mM TNM contained significant levels of nitrotyrosine as measured by
ELISA (0.63 ± 0.001 and 1.25 ± 0.02 mol nitrotyrosine/mol
monomeric SP-A, respectively; n = 3 samples; Fig.
2A).
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SP-A binding to P. carinii. Figure
2A also shows the calcium dependence
of SP-A binding to P. carinii. The
total binding in the presence of 5 mM
CaCl2 was corrected for
sedimentation of SP-A due to its self-association. Binding of control
SP-A to P. carinii was decreased by
84% in the presence of 5 mM of EGTA
(P < 0.01), indicating a
calcium-dependent process and the surface nature of the binding (69).
Nitration of SP-A by ONOO
or TNM significantly decreased its total binding in the presence of 5 mM CaCl2 but not its
calcium-independent binding in the presence of 5 mM EGTA. Furthermore,
the extent of decrease in the SP-A-specific (i.e., calcium-dependent)
binding to P. carinii was
correlated with SP-A nitrotyrosine levels (Fig.
2B).
To clarify a potential mechanism for the decreased binding of nitrated
SP-A to P. carinii, Scatchard analysis
was performed. As shown in Fig.
3A, both
normal and nitrated SP-A bound to P. carinii in a specific and saturable fashion. Scatchard
plots of specific-binding data (i.e., calcium-dependent binding) are
linear, suggesting a homogeneous population of binding sites for both normal and nitrated SP-A on P. carinii
(Fig. 3B). Normal SP-A bound
P. carinii with a binding dissociation
constant (Kd)
of 7.8 × 109 M. The
estimated number of SP-A binding sites was 7.1 × 106/P.
carinii organisms, assuming that the native molecular
mass of oligomeric SP-A is 650 kDa (25). Nitration of SP-A by
ONOO
or TNM decreased its
binding to P. carinii by increasing
the Kd value to
1.6 × 10
8 and 2.4 × 10
8 M,
respectively, without significantly affecting the number of binding
sites. The magnitude of the
Kd increase
correlated with nitrotyrosine levels in SP-A. These results indicate
that modification of tyrosine residues by nitrating agents in the CRD
of SP-A decreased its affinity for SP-A binding sites on
P. carinii.
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Because P. carinii express a great
abundance of surface mannose-type oligosaccharides (42, 43) and the
specific affinity of SP-A for mannose has been well documented (15),
-methyl-D-mannopyranoside was
used to determine whether SP-A binds to P. carinii surface carbohydrate through its CRD. SP-A
binding was inhibited by 72% in the presence of 750 mM
-methyl-D-mannopyranoside
(Fig. 4), which suggests that SP-A binds to
P. carinii surface carbohydrate through its CRD.
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Role of normal and ONOO-nitrated
SP-A in P. carinii adherence and phagocytosis to alveolar
macrophages.
Consistent with the findings of Williams et al. (60), the
SP-A used in these adherence and phagocytosis studies was shown to
enhance P. carinii adherence to
alveolar macrophages in a concentration-dependent manner (Fig.
5A).
However, for the first time, the results in Fig.
5A indicate that SP-A nitrated by
ONOO
significantly loses
its ability to promote adherence of P. carinii to alveolar macrophages at 4°C
(P < 0.01). Similarly, this
difference was also demonstrated at 37°C where normal SP-A (10 µg/ml) enhanced adherence and phagocytosis of P. carinii by alveolar macrophages from 21.5 ± 2.0 to 36.7 ± 2.4% (P < 0.05). Adherence and phagocytosis were not significantly altered
(18.3 ± 2.0%) by the presence of the same concentration of
ONOO
-nitrated SP-A (Fig.
5B).
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DISCUSSION |
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The data reported herein indicate that nitration of human SP-A
decreases its binding affinity (i.e., increases the
Kd) for P. carinii in a
concentration-dependent fashion. Human SP-A contains eight tyrosine
residues per monomer, which are located in its CRD (11). Nitration of
one or more of these tyrosines decreases the acidic dissociation
constant of tyrosine from 10 to 7.5 (49), rendering
nitrotyrosine more hydrophilic, thus potentially inducing conformational change in the tertiary structure of the globular CRD
region of SP-A secondary to alterations in its ionic charge. Previous
studies by our laboratory (13, 19, 67) have shown that
nitration of SP-A decreases its ability to aggregate lipids in the
presence of calcium and to bind to mannose. Amino acid analysis of
ONOO- or TNM-treated SP-A
failed to identify any oxidized amino acids to account for these
changes (13, 19). These results, along with the finding that the
adherence of SP-A to P. carinii was competitively inhibited by
-methyl-D-mannopyranoside,
suggest that an intact CRD is necessary for the adherence of SP-A to
P. carinii, in agreement with previous
findings (69) showing that rat SP-A binds to P. carinii MSG through its CRD.
Levels of nitrotyrosine in control SP-A samples (0.001 mol nitrotyrosine/mol monomeric SP-A, which corresponds to 30 pmol nitrotyrosine/mg SP-A, assuming that the molecular mass of monomeric SP-A is 30 kDa) are similar to what has been measured by ELISA in normal rat lung tissue [~30 pmol nitrotyrosine/mg protein (51)], normal human serum albumin [~30 pmol nitrotyrosine/mg human serum albumin (24)], and normal human plasma low-density lipoprotein [~85 pmol nitrotyrosine/mg protein (24)]. Significantly higher nitrotyrosine levels have been measured in the lungs of pediatric patients who died with acute respiratory distress syndrome (18) and in the lungs of rats exposed to endotoxin (62) or hyperoxia.
SP-A may bind to alveolar macrophages by a number of different
mechanisms. Because SP-A is a lectin as well as a glycoprotein with
N-glycosidic glycans, it can bind to surface
-D-mannosyl residues, C1q
receptors, or SP-A receptors (5, 28, 41, 63, 64). Pison et al. (41)
reported that the binding of SP-A to macrophages is blocked by
collagen-like protein C1q and type V collagen in a dose-dependent
fashion, also suggesting a collagen-like domain-mediated mechanism.
However, another study (61) suggested that SP-A binds to alveolar
macrophages through a mannose-dependent process that may involve the
CRD of SP-A. Our results indicate that nitration of SP-A decreases its
affinity for P. carinii but does not
alter its binding to alveolar macrophages. Because nitration of SP-A
decreases its ability to bind to mannose (19, 67), our findings suggest
that, under our experimental conditions, binding of SP-A to macrophages
is primarily mediated by its collagen-like domain, although the
involvement of its CRD is not excluded (61).
Previous reports (10, 27, 53, 55, 63) suggested that SP-A and SP-D enhance the phagocytosis of bacteria and viruses. Indeed, in a recent report, Hickman-Davis et al. (21) demonstrated that the killing of Mycoplasma pulmonis by alveolar macrophages required the presence of SP-A. Williams et al. (60) reported that human SP-A enhanced adherence of P. carinii to alveolar macrophages. Our results clearly demonstrated that nitration of SP-A results in decreased binding to P. carinii and an abrogation of its ability to mediate P. carinii adherence to macrophages, whereas its binding to alveolar macrophages was not significantly affected. Because our present data and those of others (69) indicate that the CRD of the SP-A molecule interacts with the MSG on the P. carinii surface, whereas the collagen-like domain of the molecule interacts with alveolar macrophages, it is likely that nitration of SP-A interferes with its ability to serve as a ligand for P. carinii adherence to alveolar macrophages at the site of the SP-A molecule-P. carinii interaction rather than at the interaction between SP-A and macrophages. This conclusion is consistent with the speculation by Koziel et al. (26). However, they also found that human SP-A reduced rat P. carinii adherence to human alveolar macrophages by ~20%. Possible explanations for the discrepancy between the results of Koziel et al. (26) and ours include the use of rat versus human macrophages and the extent of control SP-A nitration.
This is the first report to show that the modification of a single
amino acid in SP-A under pathological conditions modulates an important
in vivo function, and thus our results are of much important biological
significance. During lung inflammation, there is a marked upregulation
of both · NO and O2· production by alveolar macrophages (1, 14, 45, 48, 57, 63) in close
proximity to SP-A. The reaction product of · NO and
O
2· is
ONOO
, a potent oxidation
and nitrating agent. A recent report (9) indicated that myeloperoxidase
from infiltrated neutrophils in the lung also can catalyze chlorination
and nitration reactions with nitrite
(NO
2), the end product of
· NO, and hydrogen peroxide, the dismutated product of
O
2·, as substrates, suggesting a
novel mechanism for protein nitration. A study by Zhu et al. (68) also
showed that horseradish peroxidase catalyzes SP-A nitration with
hydrogen peroxide and NO
2 as
substrates and inhibits both its lipid aggregation and mannose-binding functions. Furthermore, our most recent studies
(unpublished observations) show that reactive oxygen-nitrogen
intermediates generated by rat alveolar macrophages stimulated by LPS
nitrated human SP-A. This also suggests that, under inflammatory
conditions, SP-A nitration may have a pivotal role in host defense of
the lungs against P. carinii infection.
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ACKNOWLEDGEMENTS |
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We acknowledge the valuable comments and suggestions of Drs. John P. Crow and Imad Y. Haddad and the excellent technical assistance of Dr. Rajamouli Pasula and Carpantanto Myles.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute Grants HL-31197 and HL-51173 (to S. Matalon) and HL-43524 and HL-51962 (to W. J. Martin II) and Office of Naval Research Grant N00014-97-1-0309 (to S. Matalon).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests: S. Matalon, Dept. of Anesthesiology, Univ. of Alabama at Birmingham, 619 South 19th St., Birmingham, AL 35233-6810.
Received 12 May 1998; accepted in final form 28 August 1998.
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