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Division of Pulmonary Biology, Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHOD
RESULTS
DISCUSSION
REFERENCES
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Mice
carrying a null mutation of the surfactant-associated protein A (SP-A)
gene have normal respiratory function, but their surfactant lacks
tubular myelin, is sensitive to protein inactivation in vitro, and
contains decreased pool sizes of the biophysically active
large-aggregate surfactant. We hypothesized that SP-A-deficient mice
would be more susceptible to exercise-induced stress and O2-induced lung injury. SP-A-(
/) and SP-A-(+/+) mice
tolerated 1 h of swimming or 45 min of running on a treadmill at
15 m/min equivalently, without alterations of the amount of alveolar
saturated phosphatidylcholine. After 3 days of hyperoxia, SP-A-(/)
mice had increased alveolar protein, but pressure-volume curves were not different between groups. Alveolar protein concentration was similarly increased in SP-A-(/) and SP-A-(+/+) mice after 4 days of
exposure to hyperoxia. Survival rates were similar after 4 days of
hyperoxia. SP-A-(/) mice were equally tolerant to exercise and 4 days of hyperoxia, indicating that the SP-A-dependent alterations in
surfactant did not result in functional deficits.
saturated phosphatidylcholine; protein permeability; lung injury; pressure-volume curve; surfactant metabolism
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHOD
RESULTS
DISCUSSION
REFERENCES
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SURFACTANT-ASSOCIATED PROTEIN (SP) A (SP-A), a member of the collectin family of proteins, is expressed by respiratory epithelial cells and secreted into the air space, where it is primarily associated with surfactant phospholipids as an oligomer of ~650 kDa. Primarily on the basis of in vitro studies, SP-A modulates the surface properties of mixtures of surfactant lipids and the other surfactant proteins (3, 17), decreases the secretion and increases the uptake of surfactant lipids in vitro (4, 10), and enhances host defense against microbes by increasing phagocytosis and free radical production and modulating cytokine levels (21). In vivo clearance of group B Streptococcus, Pseudomonas aeruginosa, and respiratory viruses is decreased in SP-A-deficient mice (11-13). In contrast, mice lacking SP-A have no major abnormalities in surfactant pool sizes, surfactant lipid, or surfactant protein metabolism, indicating that SP-A is not a critical regulator of surfactant metabolism under normal physiological conditions (7). The biophysical properties, including absorption and minimum surface tension, of surfactant from SP-A-deficient mice are normal at physiological concentrations, but the SP-A-deficient surfactant is less surface active at very low concentrations (8, 9). Surfactant from SP-A-deficient mice lacks tubular myelin, and the ratio of large-aggregate to small vesicular forms of pulmonary surfactant is decreased (7, 8). Furthermore, adsorption and surface tension-lowering properties of SP-A-deficient surfactant are more sensitive to inhibition by plasma proteins than surfactant from normal mice (8). Because stress or hyperoxic lung injury can induce alveolar-capillary leak, which might influence lung function in mice with SP-A deficiency, we compared the tolerances of SP-A-deficient and -sufficient mice to swimming, running on a treadmill, and exposure to 95% O2.
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METHOD |
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TOP
ABSTRACT
INTRODUCTION
METHOD
RESULTS
DISCUSSION
REFERENCES
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Mice.
Homozygous SP-A-(/) mice were maintained as a breeding colony in
the Black Swiss background in the vivarium at Children's Hospital
(Cincinnati, OH) (9). SP-A-(+/+) mice were NIH-Black Swiss
from Taconic (Germantown, NY). All mice were studied at 7-9 wk of
age. All protocols were approved by the Institutional Animal Care and
Use Committee.
Swimming.
The swimming exercise was performed according to the protocol used by
Nicholas et al. (18) for rats. Mice failed the swimming test if their heads bobbed and they needed to be rescued. After swimming for 1 h in water at 34°C, 25 SP-A-(/) mice and 22 SP-A-(+/+) mice were deeply anesthetized with intraperitoneal
pentobarbital sodium, and the distal aorta was cut to exsanguinate each
animal. The chest of the animal was opened, a 20-gauge blunt needle was tied into the trachea, and 1 ml of 0.9% NaCl was flushed into the
airways to fully expand the lungs and was withdrawn and reinfused by
syringe three times for each lavage. Five lavages for each animal were
pooled, and the volume was measured. The lavaged lung tissue was
homogenized in 0.9% NaCl. Aliquots of alveolar lavages and the lung
homogenates were extracted with chloroform-methanol (2:1), and
saturated phosphatidylcholine (Sat PC) was recovered after exposure of
the lipid extracts to OsO4 (16). The Sat PC was quantified by phosphorus assay (1). Sat PC pool sizes
for the exercised mice were compared with pool sizes of 8 SP-A-(/) mice and 11 SP-A-(+/+) mice that were not exercised.
Running.
Twenty two SP-A-(/) mice and 23 SP-A-(+/+) mice were run on a
treadmill for mice (Columbus Instrument, Columbus, OH) at a speed of 15 m/min for 45 min. The Sat PC pool sizes in alveolar washes and lung
homogenates of five mice from each group were measured immediately
after the run. Pool size was measured in five SP-A-(/) and five
SP-A-(+/+) mice 1 h after completion of the running exercise.
Hyperoxia.
SP-A-(/) mice and SP-A-(+/+) mice were exposed to 95%
O2, and survival was evaluated. Pressure-volume curves were
measured after 3 days of exposure to 95% O2. Mice were
sedated with pentobarbital sodium (100 mg/kg ip) and placed in a box
containing 100% O2 to ensure complete collapse of the
alveoli by O2 absorption after spontaneous breathing
stopped. The mice were killed by exsanguination, and the trachea was
cannulated and connected by a syringe to a pressure sensor (Mouse
Pulmonary Testing System, TSS, Cincinnati, OH) via a three-way
connector. After the diaphragm was opened, the lungs were inflated in
75-µl increments every 10 s to a maximum pressure of 33 cmH2O and similarly deflated. Maximum lung volume per
kilogram was determined as the volume of the lung at 33 cmH2O divided by body weight. The volumes of the lungs at
10, 5, and 0 cmH2O during inflation and deflation also were
recorded (19). Sat PC pool sizes in alveolar lavage and in
lung homogenate were measured after 3 and 4 days of hyperoxia and
compared with values for mice not exposed to O2. Total
protein was determined in an aliquot of alveolar lavage
(14).
Statistics.
Values are means ± SD. Two-group comparisons were carried out by
unpaired two-tailed t-tests. The distributions of surviving animals in hyperoxia were evaluated by 
2 analysis.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHOD
RESULTS
DISCUSSION
REFERENCES
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Swimming.
Two of 27 SP-A-(/) mice and 3 of 25 SP-A-(+/+) mice failed to
complete the 1 h of swimming as indicated by head bobbing. There
were no differences between SP-A-(/) and SP-A-(+/+) mice in the Sat
PC pool sizes in alveolar lavages and total lungs without exercise
(Fig. 1). Sat PC pool sizes after 1 h of swimming were not changed, and values for SP-A-(/) and
SP-A-(+/+) mice were similar.
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Running.
All SP-A-(/) mice and SP-A-(+/+) mice successfully ran on the
treadmill for 45 min. At completion of running, the surfactant pool
sizes were similar in the two groups of mice (Fig.
2). There also were no changes or
differences in surfactant pool sizes between SP-A-(+/+) and
SP-A-(/) mice 1 h after running. Surfactant Sat PC pool sizes
after running were unchanged from those in animals that were not
exercised (Fig. 2).
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Hyperoxia.
There were no deaths of SP-A-(+/+) or SP-A-(/) mice on days
1 and 2. On day 3, 8% of SP-A-(+/+) and
2.4% of SP-A-(/) mice died, and by day 4, 20% of
SP-A-(+/+) mice and 2.4% of SP-A-(/) mice had died. There were no
differences in surfactant Sat PC pool sizes in surviving SP-A-(+/+) and
SP-A-(/) mice (Fig. 3). Total
alveolar protein increased with time of O2 exposure in both groups of mice. On day 3, lavage protein was significantly
higher in SP-A-(/) than in SP-A-(+/+) mice (P < 0.05). Total alveolar protein increased approximately eightfold in the
SP-A-(/) and SP-A-(+/+) mice that survived to day 4. To
test whether hyperoxia differentially altered lung function in
SP-A-(/) mice compared with SP-A-(+/+) mice, pressure-volume curves
were performed after 3 days of hyperoxia, a time at which alveolar
protein increased in SP-A-(/) mice (Fig.
4). Pressure-volume curves were similar in SP-A-(+/+) and SP-A-(/) mice after 3 days in 95%
O2.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHOD
RESULTS
DISCUSSION
REFERENCES
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Exercise-induced stress and hyperoxia were used to assess
surfactant function in SP-A-(/) and SP-A-(+/+) mice. No differences in tolerances and surfactant Sat PC pool sizes were detected after swimming or running. There also were no differences in death between the two genotype groups after 4 days of 95% O2 exposure.
Although the amount of protein in alveolar washes increased after 3 days of hyperoxia in SP-A-(/) mice relative to SP-A-(+/+) mice, no differences in pressure-volume curves were detected. Mice lacking SP-A
tolerated exercise-induced stress as well as did normal mice. During
hyperoxia, small alterations in protein leak occurred on day
3 in the absence of SP-A, although survival and protein leak on
day 4 were similar in SP-A-(+/+) and SP-A-(/) mice.
The rationale for testing exercise and O2-induced tolerance
of lung injury in SP-A-(/) mice is based on the striking
alterations in surfactant structure and function in SP-A-deficient mice
(8). Tubular myelin has been considered to be the
reservoir of surfactant material from which the surface film is
replenished (23). SP-A-deficient mice lack tubular myelin,
but the surfactant contains lipid arrays that are larger and more dense
in electron micrographs than the surfactant from SP-A-(+/+) mice.
Surfactant can be fractionated by differential or sucrose density
gradient centrifugation into large-aggregate forms that have good
surface tension-lowering properties (22, 24)
and smaller less dense vesicles that have poor surface tension-lowering
properties. Because the alveolar surfactant pool from SP-A-(/) mice
is similar in size but contains less large-aggregate forms than
surfactant from SP-A-(+/+) mice, the SP-A-(/) mice have a smaller
pool of functional surfactant. The large-aggregate surfactant from
SP-A-(/) mice has good biophysical function and is effective in
treatment of surfactant-deficient preterm rabbits in vivo. However,
surfactant from SP-A-(/) mice converts to the inactive forms more
rapidly with surface area cycling in vitro and is more sensitive to
inactivation of its surface tension-lowering properties by plasma
proteins (8). These differences between surfactants that
contain SP-A and lack SP-A have been demonstrated repeatedly in
experiments evaluating surfactant component function in vitro and in
preterm animals treated with surfactant that contains SP-A
(5, 25, 26).
Nicholas et al. (18) used a rat model of swimming exercise
to demonstrate a maximal effect on surfactant secretion that increased
the alveolar surfactant pool size by 35% after 30 min of swimming. The
surfactant pool returned to baseline after a period of rest. If
exercise increased the need for surfactant to replenish the surface
film, we hypothesize that mice lacking SP-A would respond adversely to
exercise. However, no differences in pool sizes were detected in
exercised SP-A-(+/+) and SP-A-(/) mice, although the group numbers
were too small for us to detect small changes in pool sizes. The
tolerance of these mice to exercise could have resulted from inadequate
respiratory stimuli induced by swimming. However, it is likely that >1
h of swimming would have resulted in a high failure rate for SP-A-(+/+)
and SP-A-(/) mice, since SP-A-(+/+) and SP-A-(/) mice were
clearly tiring, as evidenced by head bobbing, by 1 h. We found the
same lack of effect on exercise tolerance and surfactant pools after a
substantial running exercise. Mice have a very rapid baseline
respiratory rate of ~170 breaths/min (6), and the
respiratory responses of mice to exercise have not been measured to our
knowledge. The tolerance to swimming exercise for SP-A-(+/+) mice was
equivalent to that for mice overexpressing SP-A (5).
To assess tolerance to a different form of lung injury, we
modeled the 95% O2 exposure after recent studies in mice
that are heterozygous for SP-B deficiency [SP-B-(+/)]
(20). SP-B-(/) mice die at birth, but SP-B-(+/) mice
survive with no apparent abnormalities in surfactant (2).
However, strikingly decreased survival and altered pressure-volume
curves were observed in SP-B-(+/) mice on the 3rd day of
O2 exposure. These abnormalities were reversed by
pretreatment with a surfactant containing SP-B (19). In
contrast, no differences in survival between SP-A-(/) and
SP-A-(+/+) mice were observed and no differences in pressure-volume
curves were seen after 3 days of O2 exposure. There were
also no changes in surfactant pool sizes with O2 exposure,
although these measurements were of low resolution because groups of
only five or six animals were used for the measurements. We previously
reported that lung injury and edema induced by
N-nitroso-N-methylurethane were similar in
SP-A-(/) and SP-A-(+/+) mice (8). Therefore, in these two models of lung injury, both of which increase alveolar protein levels, lung function was similar in SP-A-(/) and SP-A-(+/+) mice.
Although the lack of SP-A alters surfactant structure and
sensitivity to inhibition by plasma, SP-A deficiency does not result in
changes in exercise tolerance or responses to hyperoxia. Possible adaptive responses of the mice, such as increased rates of secretion and recycling to maintain large aggregate pools, were not evaluated. However, steady-state surfactant metabolism is remarkably normal in
SP-A-(/) mice when it is evaluated by measurements of surfactant secretion and clearance (7). The previously described
effects on isolated type II cells of increased surfactant uptake and
decreased secretion caused by SP-A do not seem to occur in vivo
(4, 10). Although SP-A binds to surfactant
lipids and alters structure and function, these effects are very
important to the in vivo performance of surfactant. SP-A has important
roles in host defense to facilitate clearance and killing of organisms
(11-13, 15). It also modulates the
inflammatory response caused by viral and bacterial agents. Thus it may
help maintain the biophysical function of surfactant during infectious
challenges. SP-A does not appear to play a primary role in surfactant homeostasis.
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ACKNOWLEDGEMENTS |
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This work was supported in part by National Institutes of Health Grants HL-58795, HL-56387, HD-12714, and HL-61646.
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FOOTNOTES |
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Address for reprint requests and other correspondence: M. Ikegami, Children's Hospital Medical Center, Div. of Pulmonary Biology, 3333 Burnet Ave., Cincinnati, OH 45229-3039 (E-mail: machiko.ikegami{at}chmcc.org).
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.
Received 5 January 2000; accepted in final form 25 March 2000.
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INTRODUCTION
METHOD
RESULTS
DISCUSSION
REFERENCES
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