(Circulation. 2000;102:2011.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Pulmonary Capillary Endothelium-Bound Angiotensin-Converting Enzyme Activity in Acute Lung Injury
From the Critical Care Department, Evangelismos Hospital, University of Athens Medical School (S.E.O., A.A., C.G., E.P., P.K., P.S., C.R.), and Department of Nursing, University of Athens (U.G.D.), Greece; the Vascular Biology Center, Medical College of Georgia, Augusta (J.D.C.); and the Division of Cardiology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada (D.L.).
Correspondence to Dr Stylianos Orfanos, Critical Care Department, Evangelismos Hospital, 45-47, Ipsilandou St, 10675, Athens, Greece. E-mail stelmar{at}ath.forthnet.gr
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Abstract |
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Background—Pulmonary capillary endothelium-bound (PCEB) angiotensin-converting ectoenzyme (ACE) activity alteration is an early, sensitive, and quantifiable lung injury index in animal models. We hypothesized that (1) PCEB-ACE alterations can be found in patients with acute lung injury (ALI) and (2) PCEB-ACE activity correlates with the severity of lung injury and may be used as a quantifiable marker of the underlying pulmonary capillary endothelial dysfunction.
Methods and Results—Applying indicator-dilution techniques, we measured single-pass transpulmonary hydrolysis of the synthetic ACE substrate 3H-benzoyl-Phe-Ala-Pro (BPAP) in 33 mechanically ventilated, critically ill patients with a lung injury score (LIS) ranging from 0 (no lung injury) to 3.7 (severe lung injury) and calculated the kinetic parameter Amax/Km. Both parameters decreased early during the ALI continuum and were inversely related to APACHE II score and LIS. Hydrolysis decreased with increasing cardiac output (CO), whereas 2 different patterns were observed between CO and Amax/Km.
Conclusions—PCEB-ACE activity decreases early during ALI, correlates with the clinical severity of both the lung injury and the underlying disease, and may be used as a quantifiable marker of underlying pulmonary capillary endothelial dysfunction.
Key Words: lung • endothelium • angiotensin • enzymes • acute lung injury
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Introduction |
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Acute lung injury (ALI) is an acute, diffuse, and severe alteration of lung structure and function that occurs after exposure to noxious external or endogenous agents. ALI represents a pathological continuum, with various degrees of arterial blood gas and chest radiograph abnormalities.1 The most severe extreme of this continuum is the acute respiratory distress syndrome (ARDS), an overt noncardiogenic pulmonary edema.2 ALI/ARDS pathogenesis is only partly understood; however, pulmonary endothelium plays a major role by (1) altering its metabolic activity, thus affecting pulmonary and systemic homeostasis; (2) mediating cell-cell adhesion, especially with neutrophils; and (3) changing its barrier permeability, thus promoting pulmonary edema formation.3
Pulmonary endothelium participates in numerous important physiological and pharmacokinetic processes.4 5 Ectoenzymes located on the endothelial luminal surface are directly accessible to blood-borne substrates, and their activities may be measured in vivo by means of indicator-dilution techniques.5 6 7 Among them, angiotensin-converting enzyme (ACE; kininase II; EC 3.4.15.1), a major regulator of vascular tone, hydrolyzes angiotensin I and deactivates bradykinin.8 ACE molecules are uniformly distributed along the luminal pulmonary endothelial surface, including the membrane caveolae.9
Pulmonary capillary endothelium-bound (PCEB)-ACE activity has been extensively studied by means of indicator-dilution techniques in animals: Under physiological conditions, PCEB-ACE activity allows estimations of dynamically perfused capillary surface area (DPCSA)7 10 11 ; under toxic conditions, PCEB-ACE dysfunction is an early and sensitive index of lung vascular injury.6 12 13 14 15 The PCEB-ACE indicator-dilution technique has recently been validated in humans, providing evidence that it can be performed safely at the bedside and establishing the range of PCEB-ACE activity values for humans without lung disease.16
We therefore tested the hypothesis that PCEB-ACE activity (1) is altered in critically ill patients with ALI, (2) correlates with the severity of lung injury and the underlying disease, and (3) may be used as a quantifiable marker of the underlying pulmonary capillary endothelial dysfunction.
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Methods |
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Subjects
Thirty-three critically ill patients, 22 men and 11 women, 14 to 87 years old, suffering from illnesses that can cause ARDS2 (Table
)
participated in a protocol approved by our Hospital Ethics Committee.
Informed written consents were obtained. All patients were hospitalized
in a general Intensive Care Unit (ICU), were mechanically ventilated,
had no history of chronic lung or heart disease, and were not on ACE
inhibitors. Patients were recruited at the first ICU visit
of the assigned investigator. An initial PCEB-ACE activity estimation
was performed for each patient. Eleven patients had 2 additional
estimations (total=3) 48 hours apart.
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Patients were grouped according to their lung injury score (LIS), introduced by Murray et al,17 as having no lung injury (nLI; LIS=0), mild-to-moderate lung injury (mLI; LIS=0.1 to 2.5), and severe lung injury (sLI; LIS>2.5). To allow comparisons with other studies, patients were also grouped according to the American-European Consensus criteria1 as not having acute lung injury (NoALI) and having ALI/ARDS.
To validate the technique reproducibility, 7 other mechanically ventilated, head-trauma patients with LIS=0 were studied. Two PCEB-ACE activity estimations were performed per patient, 30 minutes apart.
All patients had catheters placed in either the subclavian or the internal jugular vein and in the radial artery as part of their routine treatment. On the day of PCEB-ACE activity measurements, the following were performed or recorded: full hematological-biochemical profile, chest radiographs, vital signs, nutrient/drug administration, and central nervous system status assessment (Glasgow Coma Scale). Immediately before measurement, heart rate, mean systemic arterial pressure (MAP), ventilator mode/settings, positive end-expiratory pressure (PEEP), and the inspiratory oxygen fraction (FIO2) were recorded; arterial blood was withdrawn for arterial blood gas and hematocrit determinations. Disease and lung injury severity were estimated by assessing the acute physiology, age, and chronic health evaluation (APACHE II),18 and LIS (chest-roentgenogram score, PaO2/FIO2, and PEEP), respectively.17 Survival was subsequently recorded at ICU discharge.
Using indicator-dilution techniques, we estimated under first-order
reaction conditions the single-pass transpulmonary hydrolysis
of the synthetic ACE substrate
3H-benzoyl-Phe-Ala-Pro
(3H-BPAP) by PCEB-ACE. The methodology used is
described in detail elsewhere.16 Briefly, for each
determination, a 1.5-mL normal saline solution was prepared containing
20 µCi of 3H-BPAP (22.2 Ci/mmol). From it,
1.3 mL (
17 Ci) was injected as a bolus into the pulmonary
circulation through either the distal port of a central vein catheter
or the proximal port of a Swan-Ganz catheter.
Simultaneously, arterial blood was withdrawn
with a peristaltic pump through the radial artery catheter into a
fraction collector (1.2 mL blood per tube, 16 tubes). Blood was
collected into 1.75 mL of normal saline containing 5 mmol/L EDTA
and 6.8 mmol/L 8-hydroxyquinoline-5-sulfonic acid to prevent
further activity of blood ACE, and heparin 1000 IU/L ("stop"
solution). Four additional tubes containing 1.75 mL stop solution, 1.2
mL blood withdrawn before isotope administration, and 0.02 mL of the
isotope mixture were used to calculate the exact amount of
radioactivity administered.
Blood samples were collected and centrifuged (3000 rpm, 10
minutes). From the supernatant, a 0.5-mL aliquot of a given sample was
transferred into a scintillation vial, and total
3H radioactivity was measured in the presence of
5 mL Ecoscint (National Diagnostics). For the determination
of metabolite-associated radioactivity, another 0.5 mL of the
supernatant was transferred into a separate vial containing 2.5 mL HCl
(0.12N); 3 mL of Toluene-Scintillator (Packard) was added, samples were
mixed, and radioactivity was measured 48 hours later. In this way,
70% of the 3H-BPAP metabolite
3H-benzoyl-Phe (3H-BPhe)
and <10% of the parent 3H-BPAP were extracted
in the organic phase of the mixture (ie, toluene). The precise values
were calculated by identical processing of separate tubes containing
substrate or previously synthesized product.
Enzyme Activity Indices
PCEB-ACE activity was estimated as v
(3H-BPAP transpulmonary hydrolysis) and
Amax/Km.16
Hydrolysis (v)=capillary enzyme concentrationxreaction time (capillary-transit time, tc)xkcat/Km (catalytic rate constant/Michaelis-Menten constant).12 16 19
Amax/Km=total enzyme massxkcat/Km.16 20
Pulmonary plasma flow and cardiac output (CO) were calculated as previously described.20
Under normal lung conditions, Amax/Km is an index of PCEB-ACE mass and, for ACE that is evenly distributed along the luminal endothelial surface area,9 an index of DPCSA in animals7 10 11 and humans.16 Under toxic conditions (alterations of enzyme expression and/or kinetic constants), Amax/Km should be considered an index of functional capillary surface area (FCSA),16 related to enzyme quantity available for reaction (the product of DPCSA and the enzyme mass expressed on the endothelial surface) and to enzyme kinetic constants. In this case, Amax/Km may not be used as a DPCSA index.
Statistical Analysis
Data are presented as mean±SEM and individual values.
Paired and Student’s t test, ANOVA followed by the
Newman-Keuls’ test, ANCOVA for repeated measures, regression
analysis, and Fisher’s exact test were used as appropriate.
Pearson’s correlation coefficient (r) and Spearman’s
coefficient (rs) are reported where
appropriate. Differences were considered significant at a value of
P<0.05.
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Results |
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Single/First PCEB-ACE Activity Estimation
Patients’ characteristics, diagnosis, hematocrit, hemodynamics, arterial blood gases, and days of ventilatory failure at PCEB-ACE activity determination are presented in the Table
. Ventilatory failure duration was
not related to v (r=-0.080, P=0.657),
Amax/Km
(r=-0.119, P=0.509), or any other
disease-related parameter (LIS, LIS components, APACHE II,
or CO; data not shown). Consequently, ventilatory failure duration did
not affect the obtained data.
Arterial outflow concentration curves of total
3H and the surviving
3H-BPAP through a single transpulmonary
pass and the corresponding hydrolysis (v) of
3H-BPAP by PCEB-ACE of 2
representative patients are shown in Figure 1. The patient with mLI (LIS=1.7)
exhibits higher cumulative v (0.63) than the sLI patient (LIS=2.7;
v=0.2).
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PCEB-ACE activity parameters of the 33 patients, grouped
according to the American-European Consensus Criteria,1
are presented in Figure 2 (top).
The only patient who met the criteria for ALI was added to the ARDS
group. Both v and Amax/Km
were decreased in ALI/ARDS (n=20) compared with NoALI (n=13) (0.4±0.05
versus 1.15±0.06, P<0.01, and 2184±497 versus 6128±693
mL/min, P<0.01, respectively, by Student’s t
test). Similar decreases were present in the 19 ARDS patients
(0.39±0.05 and 2226±522 mL/min, P<0.01 versus the NoALI
group).
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PCEB-ACE activity values of the 33 patients grouped according to
LIS17 are presented in Figure 2 (bottom).
As LIS increased from 0 (nLI; n=7) to >2.5 (sLI; n=8), v and
Amax/Km decreased from
1.11±0.09 to 0.3±0.06, P<0.001, and 6596±768 to
1332±266 mL/min, P<0.005, respectively, by ANOVA.
Significant v differences were observed among all 3 groups, whereas
there were no differences in
Amax/Km between mLI (n=18;
LIS=0.1 to 2.5) and sLI (Newman-Keuls’ test).
The negative correlations of individual v and
Amax/Km values versus the
corresponding LIS are shown in Figure 3:
As LIS increased from 0 to 3.7, v decreased linearly from 1.56 to 0.08
(r=-0.827, P<0.001), and
Amax/Km decreased linearly
from 10 149 to 385 mL/min (r=-0.684, P<0.001).
The relations of v and
Amax/Km with the 3 LIS
components17 are presented in Figure 4: Both v and
Amax/Km correlated
inversely with chest roentgenogram score
(rs=-0.775, P<0.001 and
rs=-0.687, P<0.005,
respectively) and PEEP (rs=-0.646,
P<0.001 and rs=-0.566,
P<0.001, respectively), whereas they increased linearly
with increasing
PaO2/FIO2
(r=0.712, P<0.001 and r=0.703,
P<0.001, respectively). An inverse correlation was noted
between v, Amax/Km, and
APACHE II score18 (Figure 5; n=29; r=-0.672,
P<0.001 and r=-0.704, P<0.001,
respectively).
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Individual v and Amax/Km
values plotted against CO are shown in Figure 6 (left). Hydrolysis (v) appeared to be
independent of CO (r=0.228), whereas a positive linear
relationship was observed between
Amax/Km and CO
(r=0.731, P<0.001). However, a multiple linear
regression analysis including both enzyme activity
parameters revealed that v was associated positively with
Amax/Km
(P<0.001) and negatively with CO (P<0.001).
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When Amax/Km values are
divided above and below the observed mean (3738 mL/min), they form a
high group (13 patients;
Amax/Km range, 4378 to
10 149 mL/min) and a low group (20 patients;
Amax/Km range, 385 to 3144
mL/min). The relationship of v versus CO, when divided into these
groups, is presented in the top right of Figure 6:
Regression analysis, adjusting for groups and the group-CO
interaction, showed a negative relationship between v and CO
(P<0.01). The low-group slope
(ßlow=-0.093) was steeper but not
significantly different from the high-group slope
(ßhigh=-0.048). A similar analysis
revealed a significantly steeper positive slope for the high group in
Amax/Km (Figure 6, bottom right; P<0.05). When each group was examined
separately, v correlated inversely with CO in the low
(r=-0.484, P<0.05) and approached significance
in the high group (r=-0.552, P=0.051);
Amax/Km was independent of
CO in the low (r=-0.154) and positively related to CO
(r=0.589, P<0.05) in the high group.
PCEB-ACE activity parameters versus
PaO2/FIO2
and chest roentgenogram score in the low and high groups are
presented in Figure 7. Both v and
Amax/Km were positively
related to
PaO2/FIO2
in the low group (r=0.573, P<0.01 and
r=0.449, P<0.05, respectively) and independent
of
PaO2/FIO2
in the high group (r=0.361 and r=0.101,
respectively). Hydrolysis (v) and
Amax/Km correlated
inversely with chest roentgenogram score in the low group
(rs=-0.477, P<0.05 and
rs=-0.449, P<0.05,
respectively) and were unrelated to it in the high group
(rs=-0.430 and
rs=0.311, respectively).
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Fourteen patients survived and 19 did not. Twelve survivors belonged in
the high group (12/13) and 2 in the low group (2/20), denoting a higher
survival rate in the former (Figures 6 and 7;
P<0.001 with Fisher’s exact test).
Multiple (n=3) PCEB-ACE Activity Estimations
In 11 subjects, as LIS increased significantly from 0.85±0.24 to
1.27±0.29 (P<0.05), v decreased from 0.86±0.11 to
0.66±0.10 and Amax/Km
decreased from 5077±970 to 3715±581 mL/min. Hydrolysis (v) correlated
inversely to LIS (P<0.01); there was no correlation between
LIS and Amax/Km (ANCOVA
repeated measures).
Technique Reproducibility
In 7 patients with LIS=0, v and
Amax/Km values were similar
in the first and second PCEB-ACE activity estimation (1.14±0.18 versus
1.08±0.15 and 4450±788 versus 4104±639 mL/min, respectively, by
paired t test), with tight repeatability in each patient
(6% and 8%, respectively).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Pulmonary endothelium possesses important metabolic activities, which may be altered early in ALI and may contribute to its progression.3 4 5 Numerous investigations of endothelium-related mediators of ALI in animals and humans have provided insights into the pathogenesis of the syndrome and have examined potential predictors of either ARDS development in high-risk patients or outcome.3 In this respect, pulmonary endothelium-mediated extraction of serotonin correlated with ARDS severity, whereas pulmonary propranolol extraction was decreased in patients at risk.21 More recently, the net balance between pulmonary clearance and release of endothelin-1, which is produced by endothelial cells and extracted by pulmonary endothelium, was decreased early in ALI, whereas it reversed in patients who recovered.22 Other markers of endothelial dysfunction in ALI/ARDS include plasma levels of von Willebrand factor,23 soluble endothelium-derived adhesion molecules (E- and P-selectins, intracellular adhesion molecule-1),3 and plasma soluble-ACE activity.24 The endothelial markers thus far identified, however, have not been useful to predict ARDS development in multiple at-risk patients.3 Consequently, the need for new methods of directly assessing pulmonary endothelial function in humans still exists.
In this study, using indicator-dilution techniques, we have estimated PCEB-ACE activity in vivo in critically ill patients. Animal studies have shown that PCEB-ACE dysfunction is an early and sensitive index of ALI induced by insults such as bleomycin, oxygen toxicity, phorbol esters, and chest irradiation.6 13 14 15 In humans without lung disease, there is evidence for homogeneous PCEB-ACE concentrations and tc in both lungs.16 In that study, BPAP hydrolysis appeared to be independent of CI, within the normal CI range, indicative of similar tc among subjects. PCEB-ACE parameters showed a relatively broad range of values among subjects, with tight reproducibility in each individual.16 A similar pattern was obtained in our 7 patients with LIS=0, further confirming the repeatability of the technique.
Two typical determinations of the single-pass
transpulmonary BPAP hydrolysis in 1 mLI patient and 1 sLI
patient are given in Figure 1. The former exhibited a moderate
decrease of v; the latter, a profound depression of PCEB-ACE activity.
Sample-to-sample hydrolysis (instantaneous v) appears to fluctuate in
both patients. Instantaneous v should reflect ACE activity within
individual groups of capillaries and may be influenced by substrate
transit time, enzyme concentration, and kinetic constants. The pattern
in both patients may reflect the presence of a mild
tc heterogeneity, possibly
related to pathway alterations, including flow alterations, in
remodeled microvessels.25 Alternatively, different
capillary groups in the same patient might exhibit various degrees of
kinetic constant or enzyme concentration alterations. The latter would
be consistent with the nonhomogeneous lung
pathology in ALI/ARDS.
Patients were grouped according to the American-European Consensus
criteria1 to allow comparisons with other studies:
PCEB-ACE activity parameters were decreased in patients
with ALI/ARDS compared with NoALI patients (Figure 2),
suggesting pulmonary endothelial dysfunction.
BPAP v and Amax/Km values
in NoALI patients were similar to values reported in humans with no
lung disease (1.29±0.14 and 4564±425 mL/min),16
possibly suggesting unaltered pulmonary
endothelial function in these high-risk, mechanically
ventilated patients.
The use of LIS introduced by Murray et al17 allows
quantification of the clinical severity of lung injury. PCEB-ACE
activity was already altered at the stage of mLI (Figures 2 and 3), suggesting that pulmonary
endothelial dysfunction might occur early during the
ALI continuum. The negative correlation of v and
Amax/Km with increasing LIS
denotes that the clinical severity of the syndrome is related to the
degree of PCEB-ACE activity depression and consequently to the
underlying pulmonary endothelial dysfunction.
This is further supported by the sustained negative correlation of v
with LIS over time in the subjects who underwent sequential studies.
The lack of correlation between LIS and
Amax/Km should be related
to variations of FCSA during the course of the disease.
The relationships between PCEB-ACE activity and the individual
LIS parameters studied may be indicative of the
pulmonary endothelial contribution to the
pathogenetic process (Figure 4): The negative correlation of
PCEB-ACE activity with the chest roentgenogram score suggests that
greater endothelial dysfunction might be related to
increased vascular permeability and the subsequent pulmonary
edema revealed on chest radiographs.2 3 The positive
correlation of PCEB-ACE activity with
PaO2/FIO2
may be related to endothelium-mediated edema formation,
altered flow in remodeled microvessels,25 gas diffusion
abnormalities, and metabolic alterations of vasoactive
peptide synthesis or clearance, all of which promote
intrapulmonary shunting.2 Hydrolysis (v) increases
linearly with increasing
PaO2/FIO2
and reaches a plateau after 300 mm Hg, which appears to
represent the optimal substrate hydrolysis, in the absence of
ALI/ARDS. The negative correlation of PCEB-ACE activity with PEEP
might reflect the underlying clinical severity that necessitates high
PEEP application. It might also reflect decreased capillary recruitment
secondary to the increased thoracic pressure and the subsequent fall of
right ventricular preload. However, this should have
induced a fall in CO; the fact that CO was not related to PEEP
(rs=-0.244) makes this explanation less
likely.
The APACHE II classification system validates disease severity and
allows estimations of patient prognosis in a general ICU
population.18 The negative correlation between v,
Amax/Km, and the APACHE II
score (Figure 5) indicates the relationship between
pulmonary endothelial dysfunction and the
underlying pulmonary and extrapulmonary disease
severity. How might pulmonary endothelium be
related to extrapulmonary disease? Endothelial
dysfunction may be part of a cytokine-induced
panendothelial injury, which might lead to multiple
organ failure.26 ALI would thus be the
pulmonary manifestation of this generalized syndrome.
Alternatively, pulmonary endothelial
metabolic alterations may induce the presence of cytotoxic
mediators in the systemic circulation, thus promoting
extrapulmonary injury.
Under normal conditions, transpulmonary hydrolysis was
independent of CO in animals5 10 11 and
humans.16 Repeated PCEB-ACE activity determinations
performed in brain-dead subjects with LIS=0, at different cardiac
outputs in each subject, showed unchanged v over a wide range of CO
(3.3 to 14.1 L/min), whereas
Amax/Km increased linearly
with flow.27 This implies that higher
pulmonary blood volumes are accommodated mainly through
parallel recruitment of capillaries with similar enzyme concentrations
and tc.5 7 27 In our ALI/ARDS
patients, the apparent independence of v from CO occurs because
Amax/Km acts as a
confounding factor (Figure 6). When both enzyme
parameters were included in the analysis or when
patients were divided into high and low groups, v correlated inversely
with CO, suggesting decreasing tc at higher CO.
This probably reflects vascular loss occurring from occluded or
obliterated vessels25 or metabolic
alterations affecting vascular tone.2 When all accessible
capillaries are recruited, increases in blood flow result in lower
tc and consequently lower v.
The division into high and low groups, above and below the observed
Amax/Km mean, reveals 2
different profiles in the
Amax/Km versus CO
relationship (Figure 6): In the high group, higher CO is related
to higher Amax/Km. This
might suggest that reserves of healthy or mildly injured vascular bed
are present and blood volume increases are accommodated, at least
in part, through capillary recruitment. In the low group, the absence
of an Amax/Km increase with
higher CO suggests that higher blood volumes should be accommodated
mainly through dysfunctional capillaries, whereas no FCSA reserves are
available to be recruited. The fact that v has a slope that is steeper
than, although not significantly different from, the high group does
not contradict the above hypothesis and should reflect the expected
greater dependence of v on tc.
The division into subgroups makes apparent significantly
different profiles in v and
Amax/Km versus indices of
clinical severity such as
PaO2/FIO2
and the chest roentgenogram score (Figure 7): In the low group,
higher enzyme parameters are related to better values of
both indices, confirming the relation of PCEB-ACE activity to the
clinical severity; in the high group, the lack of a relationship might
suggest that enzyme activity is close to optimal, revealing the
healthier status of these patients.
In our population, 12 of 14 survivors belong in the high
Amax/Km group; 9 among the
former have no ALI (Figures 6 and 7). These healthier
survivors have fewer failing organs, a more mildly injured
pulmonary vascular bed, and consequently more adequate
pulmonary endothelial function, indicated by
high Amax/Km values.
In summary, our study demonstrates that assessing pulmonary endothelial ACE activity in ICU patients, at the bedside, by means of indicator-dilution type techniques provides a safe, direct, and quantifiable index of pulmonary endothelial dysfunction in ALI. PCEB-ACE activity, ie, pulmonary endothelial function, is altered at an early stage of ALI and correlates with the severity of both lung injury and the underlying disease. This study provides new insights into ALI/ARDS pathophysiology.
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Acknowledgments |
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This study was supported by the European Union, the Greek General Secretariat of Research and Technology-PENED 1997, the Thorax Foundation, NIH grant HL-31422, the Fonds de la Recherche en Santé du Québec, and the Bank of Montreal Center for the Study of Cardiovascular Disease in Women.
Received April 7, 2000; revision received May 24, 2000; accepted May 24, 2000.
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