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Departments of 1 Physiology and 2 Pharmacology, University of South Alabama, Mobile, Alabama 36688
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Although many recently produced transgenic mice
possess gene alterations affecting pulmonary vascular function, there
are few baseline measurements of vascular resistance and permeability. Therefore, we excised the lungs of C57/BL6 mice and perfused them with
5% bovine serum albumin in RPMI-1640 culture medium at a nominal flow
of 0.5 ml/min and ventilated them with 20%
O2-5% CO2-75%
N2. The capillary filtration
coefficient, a sensitive measurement of hydraulic conductivity, was
unchanged over 2 h (0.33 ± 0.03 ml · min
1 · cmH2O1 · 100 g1) in a control group
ventilated with low peak inflation pressures (PIP) but increased
4.3-fold after high PIP injury. Baseline pulmonary vascular resistance
was 6.1 ± 0.4 cmH2O · ml1 · min · 100 g1 and was distributed 34%
in large arteries, 18% in small arteries, 14% in small veins, and
34% in large veins on the basis of vascular occlusion pressures.
Baseline vascular compliance was 5.4 ± 0.3 ml · cmH2O1 · 100 g1 and decreased
significantly with increased vascular pressures. Baseline pulmonary
vascular resistance was inversely related to both perfusate flow and
microvascular pressure and increased to 202% of baseline after
infusion of 104 M
phenylephrine due to constriction of large arterial and venous segments. Thus isolated mouse lung vascular permeability, vascular resistance, and the longitudinal distribution of vascular resistance are similar to those in other species and respond in a predictable manner to microvascular injury and a vasoconstrictor agent.
vasoconstriction; pulmonary edema; mechanical stress failure; capillary filtration coefficient; transgenic mice
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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RECENT DEVELOPMENTS in genetic engineering have resulted in a proliferation of transgenic mice, many of which include gene alterations that affect pulmonary vascular permeability or tone (13). Many studies of the effects of these gene manipulations concentrate on the observed histological features with few detailed studies of the functional physiological effects of gene expression on pulmonary microvascular permeability and vascular hemodynamic function in mouse lungs. This can be attributable to the small size of mice, which renders surgical procedures more difficult than in larger species. However, an additional advantage of mouse lungs used for isolated lung experiments is the small perfusion volume, which permits the use of small amounts of reagents that may have high cost or low availability.
The isolated perfused lung preparation has been widely used for studies of vascular function in sheep (2), dogs (11), ferrets (1), rabbits (4), rats (3), and, recently, mice (16). The capillary filtration coefficient (Kfc), a sensitive measurement of microvascular hydraulic conductivity, can be measured by gravimetric, indicator hemoconcentration, or tracer methods (9, 10) but has not previously been reported for mouse lungs. Although measurements of total pulmonary vascular resistance in isolated and in situ mouse lungs have recently been published (13, 16), the longitudinal distribution of segmental vascular resistances and pulmonary vascular compliance (Cvas) have not been determined for mouse lungs.
The purpose of the present study was to extend our isolated perfused lung preparation to mouse lungs to measure baseline vascular resistances and filtration coefficients and determine the responsiveness of the preparation to perturbations that increase vascular permeability and vascular tone.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Isolated Lung Preparation
C57/BL6 male mice, weighing 29.3-38.9 g (34.2 ± 1.0 g), were anesthetized with an intraperitoneal injection of ketamine and xylazine. The trachea was cannulated, and the lungs were ventilated with a gas mixture of 20% O2-5% CO2-75% N2 by using a piston-type respirator (model 683 rodent ventilator; Harvard, South Natick, MA). The tidal volume was adjusted to obtain a peak inflation pressure (PIP) of ~10 cmH2O at a respiratory rate of 65 breaths/min, with 3 cmH2O positive end-expiratory pressure (PEEP). The chest was opened, heparin (100 IU) was injected into the right ventricle, and a suture was placed around the pulmonary artery and aorta. Cannulas were placed in the pulmonary artery and left atrium, and lungs and heart were removed en bloc and suspended from a balance beam attached to a force transducer (FT03D; Grass, Quincy, MA). The force transducer was positioned on the opposite side of the beam fulcrum from the lung. To improve weight sensitivity, the force transducer was one-third the distance from the fulcrum as the lung. Plastic drapes surrounded the preparation to eliminate weight artifacts caused by air currents. The initial 1-2 ml of perfusate, which contained residual blood cells and plasma, were discarded and not recirculated. Lungs were then perfused in a recirculating system with 5% bovine albumin in RPMI-1640 cell culture medium by using a roller pump (Minipuls 2; Gilson, Middleton, WI) at a flow rate of 0.5 ml/min. To minimize the system volume, the heat exchanger was removed and the lungs were perfused at 29°C. The venous outflow was collected in a reservoir, the height of which could be adjusted to increase venous pressure.Arterial, venous, and airway pressures were continuously monitored by pressure transducers (Cobe, Lakewood, CO) that were zeroed at the midlung level, and pressures and lung weight were recorded on a Grass model 7D polygraph.
Pulmonary Vascular Resistances
Total (RT) and segmental pulmonary vascular resistances were calculated from the perfusate flow and the differences between pulmonary artery (Ppa) and vein (Ppv), double-occlusion capillary [Pdo or Ppc], and arterial (Pao) and venous (Pvo) occlusion pressures as previously described (11, 12, 17) as follows
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(1) |
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(2) |
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(3) |
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(4) |
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(5) |
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(6) |
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(7) |
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(8) |
is perfusate flow.
Pdo has been shown to accurately predict the average capillary
filtration pressure (11, 14), whereas the selective arterial and venous
occlusions allow separation of segmental vascular resistances across
large and small arterial and venous vessel segments. All resistances
were normalized to predicted lung weight as
cmH2O · l · 1 · min · 100 g1.
Kfc
Kfc (in ml · min1 · cmH2O1 · 100 g1) is a sensitive
measurement of endothelial hydraulic conductivity when capillary
surface area is maintained constant (14). After an isogravimetric state is attained, Ppv is increased by ~6
cmH2O for 20 min, and the change
in capillary pressure (dPpc) is determined by double occlusion before
and after the Ppv increase. The rate of lung weight gain (dWt/dt) between 18 and 20 min is
used to calculate
Kfc by using
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(9) |
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(10) |
Cvas
Cvas was measured according to Rippe et al. (11) by using perfusate flow and the rate of increase in Ppv (dPpv/dt; in cmH2O/min) after a venous occlusion
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(11) |
1 · 100 g1.
Experimental Protocol
The general protocol consisted of an isogravimetric state for 20-30 min, followed by vascular occlusion pressure measurements and a Kfc measurement. At 1 and 2 h after the initial Kfc measurement, the occlusion pressure and Kfc measurements were repeated for a total of three Kfc measurements. Occlusion pressures were also measured during the increased venous pressure states during the Kfc measurements and after the last Kfc measurement.Low-PIP control group. In five lungs, PIP was maintained at 10 cmH2O and PEEP at 3 cmH2O throughout the Kfc and occlusion pressure measurements. Occlusion pressures were repeated after the last (2 h) Kfc measurement to serve as a time control for the phenylephrine-infusion group.
High-PIP injury group.
In five lungs, PIP was increased to 30-31
cmH2O and PEEP to 6-7
cmH2O for 20 min after the second
Kfc measurement.
After the third
Kfc measurement,
Ppv was returned to baseline and phenylephrine (104 M) was infused into
the venous reservoir. The vascular occlusion pressures were then
repeated to determine RT and
segmental vascular resistances.
Hemodynamic group. In five lungs, PIP was maintained at 10 cmH2O and PEEP at 3 cmH2O for two Kfc measurements 1 h apart. These baseline Kfc and occlusion pressure measurements were similar to baseline values in the other two groups and are not presented. Between Kfc measurements, stepwise increases in either flow or venous pressure were used to construct the vascular pressure-flow, pressure-resistance, flow-resistance, and pressure-compliance curves for the pulmonary circulation. The vascular pressure-compliance relationships were measured by using venous occlusions after step increases in venous pressure with constant flow. Experiments were then terminated, and the lungs were weighed.
Statistics
All values are expressed as means ± SE unless otherwise stated. The Kfc values, pressures, and resistances were compared by using an ANOVA with repeated measures and a Newman-Keuls posttest with the use of CRUNCH4 statistical software on a Gateway 2000 digital computer. A significant difference was determined where P < 0.05.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Kfc
Figure 1 compares the Kfc measurements in the high-PIP injury group (
) and the low-PIP control group (
).
Kfc was unchanged in either group at 0 and 1 h of low-PIP ventilation but increased significantly by 4.3-fold in the high-PIP injury group compared with
paired baseline
Kfc and the
low-PIP control group after 20 min of ventilation with a PIP of 32 cmH2O. Terminal lung weights were
0.171 ± 0.011 g for uninjured lungs in the low-PIP control group
and were significantly higher at 0.243 ± 0.012 g for the high-PIP
injury group.
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Pulmonary Vascular Pressures
Table 1 summarizes the vascular pressures and perfusate flow at high- and low-pressure states in the high-PIP injury group, after phenylephrine infusion, and the 2-h baseline pressures in the low-PIP time control group. Vascular pressures in the low-PIP control group did not change significantly with time and were not significantly different from those in the high-PIP injury group. Isogravimetric capillary pressures averaged 5.5-5.9 cmH2O in uninjured lungs at a perfusate flow of 0.51 ml/min. Baseline Ppa was significantly increased from baseline after PE infusion and from the low-PIP control group at the same time period.
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Figure 2 indicates the vascular
pressure-perfusate flow relationship for Ppa and Ppv as perfusate flow
was increased from 0.3 to 1.0 ml/min.
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Vascular Resistance and Cvas
Table 2 summarizes RT, Ra, and Rv, Ra/Rv, and Cvas at low and high venous pressures. There were trends toward a decrease in RT when venous pressure was increased during Kfc measurement, but these did not reach significance. However, Cvas decreased significantly after every venous pressure increase. After phenylephrine infusion RT, Ra, and Ra/Rv were significantly increased compared with values in the preceding low-venous-pressure state and the comparable time in the low-PIP control group.
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RT decreased in response to
increased perfusate flow (Fig. 3) and
increased capillary pressure at constant perfusate flow (Fig.
4). Cvas also decreased in a curvilinear
fashion as capillary pressure increased at a constant perfusate flow
(Fig. 5).
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Segmental Vascular Resistances
The segmental vascular resistance at high and low venous pressures in the high-PIP injury group, after phenylephrine infusion, and at 2 h in the low-PIP control group are summarized in Table 3. Rla and Rlv were significantly increased by phenylephrine infusion.
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Figure 6 shows the changes in mean
segmental vascular resistances between high-and low-pressure states and
between phenylephrine infusion and control groups. Increased venous
pressures decreased segmental pressures in small artery and venous
segments, whereas phenylephrine infusion increased segmental Rla and
Rlv.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The isolated perfused lung preparation has become an accepted standard for physiological and pharmacological analysis of pulmonary vascular function (14). In the present study, we have adapted the same isolated lung preparation previously used in studies in dogs (11), rabbits (4), and rats (3) to the mouse lung. Although the small size of the mouse renders surgical isolation of the lung more difficult, isolated mouse lungs can be used to investigate the altered vascular function of targeted genes in relevant transgenic mouse models (13). In addition, the large array of immunological reagents available for mice and the small circulating perfusate volume in this preparation permit the use of reagents that are not available in other species, or the cost or availability of which may prohibit use in larger animal models. Although nominal perfusate volumes were 5 ml in these studies, a system volume of 2.5 ml was practical for perfusion at baseline vascular pressures. Therefore, these reservoir volumes approach the fluid volumes used in a cell culture plate. Modifications of our previous preparations that were used to prepare mouse lungs include the use of magnifying dissecting glasses, a cantilever-beam system to enhance the sensitivity of the force transducer, and drapes to block air currents. RPMI cell culture medium was used rather than Krebs or other physiological buffers to compare resistance values with those observed in the mouse lung preparation of von Bethmann et al. (16).
Kfc is a
sensitive measurement of transcapillary fluid conductance and has not
previously been reported for mouse lungs (14). The normalized baseline
Kfc value for
mouse lung of 0.33 ml · min1 · cmH2O1 · 100 g1 is similar to
Kfc values
previously reported for isolated rat lungs (0.33 ± 0.03 ml · min1 · cmH2O1 · 100 g1) by Seibert et al.
(12) and isolated rabbit lungs (0.33 ± 0.03 ml · min1 · cmH2O1 · 100 g1) by Hernandez et al.
(4). However, exact quantitative comparisons of gravimetric
Kfc values are
highly dependent on the portion of the weight gain curve used to
represent transcapillary filtration (14). One of the advantages of
using the rate of weight gain at 20 min after a venous pressure
increase is that the slow component of vascular stress relaxation is
minimized (9). However, the method used here for estimating
Kfc has been used
in several previous isolated lung studies and produces stable and
consistent values (7, 8).
We observed a 4.5-fold increase in
Kfc in mouse
lungs after 20 min of ventilation with a PIP of 30.4 cmH2O (PEEP = 6.8 cmH2O; mean airway pressure = 14.8 cmH2O) (Table
4). This compares with a 3.7-fold increase
in Kfc in
isolated rat lungs after 30 min at a PIP of 35 cmH2O and a 9.7-fold increase
after 60 min at a PIP of 30 cmH2O
in isolated rabbit lungs (4, 7). Only minimal increases occurred in dog
lungs at these PIP levels (10). Exact comparisons of injury are
difficult because the degree of airway pressure-induced injury varies
with peak pressure, duration and rate of ventilation, and mean airway
pressure (6). However, mouse lungs are approximately as susceptible to
ventilation-induced mechanical injury as are rabbit and rat lungs but
have a greater susceptibility to injury than dog lungs.
Mathieu-Costello et al. (5) also observed a higher threshold of dog
lungs to mechanical stress injury due to vascular pressure compared
with rabbit lungs, as evaluated by the number of epithelial breaks.
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The high baseline Cvas of the mouse lung (5.37 ± 0.34 ml · cmH2O1 · 100 g1) is similar to the
5.62 ± 0.26 ml · cmH2O1 · 100 g1 observed in rat lung
(17) and higher than the 4.04 ± 0.32 ml · cmH2O1 · 100 g1 in rabbit lungs (4) and
the 2.18 ± 0.29 ml · cmH2O1 · 100 g1 in dog lungs (11). The
high Cvas in mice and rats could lead to a greater potential vascular
stress relaxation artifact for Kfc measurement
in their lungs compared with that in dogs (9).
Pulmonary vascular resistance has recently been reported for partially
isolated, perfused mouse lungs (16) and intact, open-chest mice (13).
Normalized to
cmH2O · l1 · min · 100 g1, the
RT values of von Bethmann et al.
(16) in perfused mouse lungs ranged from 7.4 to 10.2 cmH2O · l1 · min · 100 g1 at a flow of 1.0 ml/min.
Although the nominal perfusion rate was 0.5 ml/min in the present
study, a comparable RT of 11.3 cmH2O · l1 · min · 100 g1 was obtained at a
perfusion rate 1.0 ml/min. Correcting
RT for a 16% increase in
viscosity due to perfusion at 29 rather than 37°C would result in
an RT of 9.5 cmH2O · l1 · min · 100 g1, a value similar to that
obtained by von Bethmann et al. In intact, open-chest mice, Steudel et
al. (13) reported aortic flows of 6.2 to 9.3 ml/min and an average
pulmonary artery pressure of 22.3 cmH2O. An
RT of 3.2 cmH2O · l1 · min · 100 g1, or about one-third of
that measured in isolated perfused lungs, can be calculated for these
intact mice. A comparable difference in the slopes of the flow-pressure
curves was obtained between their intact mouse lungs and the isolated
mouse lungs of the present study (3.3 vs. 0.92 cmH2O · l1 · min · 100 g1).
Pulmonary vascular resistance was inversely related to vascular pressure and flow in the present study (Figs. 3 and 4). Rippe et al. (11) reported a decreasing RT as Ppc increased as well as significant decreases in both Rmc and Cvas at higher vascular pressures. However, the decrease in Rmc/RT for dog lungs attained statistical significance only at higher venous pressures than those used in the present study (11). In the present study there was a trend for both RT and Rmc/RT to decrease at increased venous pressures, and Cvas decreased significantly with every increase in venous pressure. These decreases in vascular resistance and Cvas as vascular flow and pressure increase indicate the well-known effects of recruitment and distention of microvessels on vascular resistance and Cvas as perfusate flow and pressure increase (15).
Although segmental vascular resistances have not been previously reported for mouse lungs, we observed a longitudinal distribution of vascular resistance that was similar to that previously reported for the lungs of other species (Table 4). That is, vascular resistance was approximately equally distributed among large arteries, the middle compartment (small arteries and veins), and large veins. The absence of muscular arterioles such as are present in the systemic circulation results in a significant portion of the resistive pressure drop occurring across the microvessels in the lung (15). An increased percentage of RT after phenylephrine infusion was attributable mainly to the significant increase in Rla and Rlv (Table 3). In a previous study in dog lungs, Rippe et al. (11) also observed increases in the large artery and vein components of RT at constant flow with decreases in fractional Rmc in response to norepinephrine and serotonin in dog lungs. Histamine produced resistance increases primarily in the large veins in the above-mentioned study.
In conclusion, consistent baseline vascular resistance, Cvas, and microvascular permeability measurements could be obtained in the isolated mouse perfused lung preparation. These remained stable over 2 h and responded in a predictable manner to increases in vascular pressure and flow. The responses to injurious levels of high airway pressure and a vasoconstrictor agent were similar to those observed in other species. Thus this preparation can be readily used to assess pulmonary vascular effects of genetic alterations in mice or the vascular application of immunologic agents that require a small perfusate volume.
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ACKNOWLEDGEMENTS |
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This work was supported by American Heart Association Grant 9810180SE.
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FOOTNOTES |
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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 and other correspondence: J. C. Parker, Dept. of Physiology, MSB 3024, College of Medicine, Univ. of South Alabama, Mobile, AL 36688 (E-mail: jparker{at}usamail.usouthal.edu).
Received 31 July 1998; accepted in final form 15 June 1999.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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P < 0.05 vs. low-PIP control group at same
time period.
