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antibody attenuates ventilator-induced lung injury in rabbits
1 Pathophysiology Research
Laboratory, To evaluate the
role of tumor necrosis factor (TNF)-
conventional mechanical ventilation; intratracheal
instillation
MECHANICAL POSITIVE-PRESSURE ventilation can lead to
the production or worsening of lung injury (18). Ventilator-induced lung injury has been implicated as a major cause of deterioration in
acute respiratory distress syndrome (ARDS) that leads to death or to
chronic lung disease in survivors (15, 20, 21). The morbidity and
mortality of acute respiratory failure remain high (9), and adverse
effects from ventilator-induced lung injury remain a significant
problem in the care of critically ill patients (20, 21). Research has
focused primarily on the mechanical forces [i.e., high peak
airway pressure (Paw) and large tidal volumes] that produce
ventilator-induced lung injury (17). Several recent studies have noted
an association between lung inflammatory response and the development
of ventilator-induced lung injury. We found that conventional
mechanical ventilation (CMV), as opposed to high-frequency oscillatory
ventilation (HFOV), led to increased neutrophil infiltration and
activation (13) and to increased lung lavage levels of
platelet-activating factor (PAF) and
thromboxane-A2 in a saline-lavaged
rabbit lung model of ventilator-induced lung injury (10). In a recent
study (24), CMV produced large increases in the intra-alveolar gene
expression of tumor necrosis factor- The goal of the present study was to better understand the inflammatory
aspects of the pathogenesis of ventilator-induced lung injury and to
evaluate the role of proinflammatory cytokines, especially TNF- The study protocol was reviewed and approved by the Institutional
Animal Research Committee.
Animal Preparation
ABSTRACT
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
in the pathogenesis of
ventilator-induced lung injury, we
1) measured TNF- production in
the lung caused by conventional mechanical ventilation (CMV) and
2) evaluated the protective effect
of anti-TNF- antibody (Ab) in saline-lavaged rabbit lungs. After
they received saline lung lavage, rabbits were intratracheally
instilled with 1 mg/kg of polyclonal anti-TNF- Ab in the
high-dose group (n = 6), 0.2 mg/kg of anti-TNF-
Ab in the low-dose group (n = 6), serum IgG fraction in the Ab control group
(n = 6), and saline in the saline
control group (n = 7). Animals then
underwent CMV for 4 h. Levels of TNF- in lung lavage fluid were
significantly higher after CMV than before in both control groups.
Pretreatment with intratracheal instillation of high and low doses of
anti-TNF- Ab improved oxygenation and respiratory compliance,
reduced the infiltration of leukocytes, and ameliorated pathological
findings. CMV led to TNF- production in the lungs, and intratracheal
instillation of anti-TNF- Ab attenuated CMV-induced lung injury in
this model.
INTRODUCTION
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
(TNF-) when compared with
HFOV in the same model. Injurious ventilatory strategies increased
TNF- mRNA expression and actual lung lavage levels of TNF-
protein in an isolated rat lung model (25).
. The
first objective of this study was to determine whether CMV would lead
to the production of TNF- protein in the lungs in a saline-lavaged
rabbit lung model. Because the results of this study demonstrated
significantly increased levels of TNF- protein in the air spaces
after CMV, the second objective was to determine whether pretreatment
with intratracheal administration of anti-TNF- antibody (Ab) would
reduce the magnitude of the CMV-induced lung injury in the same model.
The latter study was designed to measure the pathophysiological indexes
of acute lung injury, gas exchange, lung compliance, and the number of
polymorphonuclear leukocytes (PMN) in the lung lavage fluid and to
compare the pathological findings in the lung at the end of the experiment.
METHODS
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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1 · h1
of 5% dextrose in Ringer lactate solution during the following experiments. A tracheostomy was performed, and a 4.0-mm-ID endotracheal tube was inserted and fixed in place while the animal was manually ventilated at a fraction of inspired
O2
(FIO2) of 1.0 for 3-4
min. Immediately after the tracheostomy was performed, the animal was
placed on a piston-pump HFOV ventilator (Humming II; Senko Medical
Instrument Manufacturers, Tokyo, Japan). We used HFOV for preparation
and stabilization, as described later, because we and others have
previously demonstrated that HFOV leads to a smaller magnitude of lung
injury than CMV in this saline-lavaged rabbit lung model (6, 8, 11,
22). Sinusoidal volume changes were delivered at an
FIO2 of 1.0, an oscillatory frequency of 15 Hz, and a mean Paw of 5 cmH2O. The stroke volume was
adjusted to keep arterial CO2
partial pressure (PaCO2) levels between
35 and 45 Torr. Blood pressure and blood-gas analysis were measured
through a fluid-filled catheter in the femoral artery. Arterial blood
gases were intermittently measured by a pH/blood-gas analyzer (model
178; Corning, Medfield, MA). Systemic arterial blood pressure was
continuously monitored by a pressure transducer (CDX-3; Cobe
Laboratory, Lakewood, CO) and blood temperature was maintained between 37 and 39°C with a servo-controlled radiant heater and a heating pad. After the animal was stabilized, the rabbit
lungs were lavaged with 30 ml/kg of warmed normal saline to remove lung
surfactant. The solution was flushed in and out of the lungs five
times, and the saline was gently sucked out at the end of each lavage.
The above procedure was repeated three times, following the same
protocol as Hamilton et al. (8). Mean Paw was raised by 5 cmH2O, and sustained inflation
(SI) of 30 cmH2O for 15 s was
performed to minimize hypoxemia before the next lung lavage. After this
procedure was completed, mean Paw was set on 15 cmH2O and stabilized,
PaCO2 levels were maintained between 30 and 50 Torr by adjustment of stroke volume, and the frequency was fixed
at 15 Hz during HFOV. The arterial
PO2 (PaO2 ) of the animal soon returned
to the prelavage level, i.e., >350 Torr, after several SI maneuvers.
The drained lavage fluid was collected as in the sample before CMV. The
percentage of volume of lavage fluid recovered was 72 ± 8%.
Protocols
General procedures.
The rabbits were randomly divided into four groups: an anti-TNF- Ab
high-dose group (n = 6), an
anti-TNF- Ab low-dose group (n = 6), an Ab control group (n = 6), and a
saline control group (n = 7). Rabbits
were instilled with 1 mg/kg of polyclonal anti-TNF- Ab in the
anti-TNF- Ab high-dose group, 0.2 mg/kg of polyclonal anti-TNF-
Ab in the anti-TNF- Ab low-dose group, 1 mg/kg of serum IgG fraction
in the Ab control group for control of the irrelevant elements of
polyclonal anti-TNF- Ab, and saline (placebo) in the saline control
group, through a 6-Fr feeding catheter that was gently passed through
the tracheal tube until just beyond the tip of the endotracheal tube.
Anti-TNF- Abs in the high-dose, low-dose, and Ab control groups were
dissolved in 10 ml of saline. The dissolved saline solution with Ab or
10 ml of saline by itself (placebo) were instilled into the lungs over
3 min. SI of 30 cmH2O for 15 s was
performed two times after instillation to enhance the uniform delivery
of the instilled dose to all lung fields. The animal was mechanically
ventilated by HFOV at a mean Paw of 15 cmH2O and a
FIO2 of 1.0 for 1 h for stabilization. After it was confirmed that the
PaO2 of the animal was
>350 Torr, the animals received CMV for 4 h at a
FIO2 of 1.0. This procedure
in rabbits, when the animals subsequently receive CMV for several
hours, produces a progressive ventilator-induced lung injury
characterized by diffuse microatelectasis, pulmonary edema, infiltration of neutrophils, and hyaline membrane formation (8, 10, 13,
25). CMV was performed with the CMV mode of Humming II (time-cycled in
the pressure-limited ventilation mode). Peak inspiration pressure was
25 cmH2O, positive end-expiratory
pressure was 5 cmH2O, mean Paw was
15 cmH2O, and
FIO2 was 1.0. On the basis of our preliminary experiments, the tidal volume was
estimated to be 12-15 ml/kg. Respiratory frequency was changed to
maintain PaCO2 levels between 30 and 50 Torr. Peak inspiratory pressure, positive end-expiratory pressure, and
mean Paw were monitored at the proximal end of the endotracheal tube
with a pressure transducer. Arterial blood gases were measured every hour with a blood-gas analyzer. Total respiratory system compliance (Crs) was measured before lung lavage and after ventilation for 4 h. On
termination of ventilation, total lung lavage was performed, as
described above, and the lung lavage fluid was collected in the same
way as the postventilation sample. The percentage of volume of lavage
fluid recovered was 64 ± 12%. The animals were killed by KCl
injection at the termination of the experiment.
Series 1 study: levels of rabbit TNF- in the lung
lavage fluid before and after ventilation in the control group.
We measured the concentration of rabbit TNF- before and after CMV
for 4 h in the Ab control group (n = 6) and saline control group (n = 7).
Series 2 study: the effect of intratracheal instillation of
anti-TNF- Ab on lung injury with CMV.
We compared arterial blood gas, Crs before lung lavage and after 4 h of
CMV, numbers of PMN and macrophages in the lung lavage fluid sample
after 4 h of CMV, and pathological findings in the lung at the end of
the experiment in all four groups [anti-TNF- Ab high-dose
group (n = 6), anti-TNF- Ab
low-dose group (n = 6), Ab control
group (n = 6), and saline control
group (n = 7)] as measures of pathophysiology.
Measurement of TNF- Ab Concentrations in Lung
Lavage Fluid
concentrations in lung lavage fluid were measured by using
sandwich ELISA that was based on the cytokine ELISA protocol of
PharMingen (San Diego, CA). These assays were performed by using a
combination of purified polyclonal goat anti-rabbit TNF- Ab as a
capture Ab and biotinylated polyclonal goat anti-rabbit TNF- Ab for
detection. Standard material, which was used in the rabbit TNF-
conditioned medium (PharMingen), and obtained samples were run in
duplicate. The limit of detection in this assay was 75 pg/ml, and
linear standard curves were obtained that ranged from 75 to 15,000 pg/ml.
Generation of the Polyclonal Ab to TNF- and Serum
IgG Fractions for the Ab Control Group
Ab was produced by immunization of the rabbits
with carrier-free human recombinant TNF- (Tonen, Tokyo, Japan) that
was affinity purified by using protein A Sepharose. As measured by the
L-cell assay, 45 mg of the anti-TNF- Ab preparation used in this
study neutralized 2 mg of human TNF- activity in vitro. Rabbit
globulin fraction as a control Ab was prepared by using protein A Sepharose.
Measurement of Crs
We measured Crs with the passive expiratory flow-volume technique after 4 h of ventilation and before the lung lavage. Airway occlusion pressure was measured from an endotracheal tube by using a simple slide valve. Expiratory flow was measured with a Fleisch no. 0 pneumotachometer. There was a linear relationship between expiratory flow and its integral volume in all subjects. Crs was calculated by extrapolation of the linear function to zero flow and zero volume (12).Counts of Cells, PMNs, and Macrophages in Lung Lavage Fluid
The number of total lavage cells was counted by a standard hemocytometer. Cells were differentiated by use of Wright-Giemsa-stained preparations, and the percentages of PMN and macrophages were shown.Histopathologic Examination
Immediately after the rabbits were killed, the lungs were fixed with an instillation of 10% buffered Formalin at a transpulmonary pressure of 15 cmH2O. Midsagittal cross sections were stained with hematoxylin and eosin for postmortem microscopic examination. Lung injury was scored by a blinded observer on a five-point scale, according to combined assessments of alveolar congestion, hemorrhage, infiltration, aggregation of neutrophils in the air space or vessel walls, and thickness of the alveolar wall or hyaline membrane formation. The points on the scale were as follows: 0, minimal (little) damage; 1+, mild damage; 2+, moderate damage; 3+, severe damage; and 4+, maximal damage.Data Analysis
Results are presented as means ± SD. We used a two-way ANOVA to determine the statistical significance of group differences in levels of TNF- before and after ventilation, as well as the intergroup
differences in blood-gas data at different time points, Crs, numbers of
PMNs in final lavage fluid, and lung-injury score. A
P value <0.05 was considered significant.
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Series 1: Levels of Rabbit TNF- in the Lung Lavage
Fluid Before and After Ventilation in the Control Groups
in the lung lavage fluid before and after 4-h
CMV in the controls were 113 ± 16 and 6,641 ± 2,069 (SD) pg/ml
in the saline control group (n = 7) and 108 ± 20 and 6,745 ± 4,933 pg/ml in the Ab control group
(n = 6), respectively. These values
were significantly higher after ventilation than before ventilation in
both controls (P < 0.01). No
significant differences were seen between the saline and Ab control groups.
Series 2: The Effect of Intratracheal Instillation of
Anti-TNF- Ab on Lung Injury with CMV
Gas exchange.
Arterial blood-gas data are summarized in Fig.
1. After CMV was started, all
PaO2 values for the
anti-TNF- Ab high-dose group and the anti-TNF- Ab low-dose group
were significantly higher than were the corresponding values of the Ab
control group or saline control groups
(P < 0.01).
PaO2 values for the anti-TNF- Ab
high-dose group were higher than were the corresponding values for the
low-dose group (P < 0.05).
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Compliance.
Changes in Crs after 4 h of ventilation were significantly greater in
the anti-TNF- Ab high- and low-dose groups than in the Ab control
and saline control groups (P < 0.05). Change in Crs in the anti-TNF- Ab high-dose group was
significantly higher than in the anti-TNF- Ab low-dose group
(P < 0.05; Fig.
2).
|
Cell and PMN count.
At termination of ventilation, cells recovered in the lung lavage fluid
included macrophages and PMN. Values of PMN count in the saline
control, Ab control, anti-TNF- Ab low-dose, and anti-TNF- Ab
high-dose groups were (mean ± SD) 10.4 ± 3.4, 11.9 ± 3.5, 7.8 ± 1.9, and 4.3 ± 1.5 × 107/total lung lavage,
respectively. The values of the anti-TNF- Ab high-dose
group were significantly less than in the Ab control and saline control
groups (P < 0.01; Fig.
3).
|
Histopathology.
Microscopic examination of the lungs of animals in the Ab control and
saline control group showed extensive hyaline membrane formation and
infiltration of PMN in the terminal airways and alveoli (Fig.
4, C and
D). The pathological findings from
the lungs of animals in the anti-TNF- Ab high- and low-dose groups showed less hyaline membrane formation and PMN infiltration than did
those in the Ab control group and saline control group. Expanded lung
parenchyma with well-preserved alveoli were also seen in the
anti-TNF- Ab high- and low-dose groups (Fig. 4,
A-C). Lung injury scores were lower
in the anti-TNF- Ab high- and low-dose groups than in the Ab control
and saline controls (P < 0.01; Table 1).
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DISCUSSION |
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The first objective of this study was to determine whether CMV would
induce the production of TNF- protein in the lung in a
saline-lavaged rabbit lung model. We previously confirmed that only 1 h
of CMV produces large increases in TNF- mRNA in intra-alveolar cells
in the same model (24). We hypothesized that enhanced TNF- gene
expression at the transcriptional level, which occurred very shortly
after the initiation of CMV, would lead to actual production of TNF-
protein in the lung. The results of the present study demonstrated that
there was a great amount of TNF- protein in the air spaces after 4 h
of CMV. Actual production of TNF- protein in the lung, caused by
CMV, was confirmed in this saline-lavaged rabbit lung model. Increased
TNF- protein then initiates an inflammatory cascade in the lung.
This results in production of lipid mediators, such as PAF or
thromboxane A2, and neutrophil
infiltration and activation in the alveolar space, as observed in our
previous studies (10, 11, 13) and those of others (1, 23). TNF- is
known to be particularly important in lung injury because of the large
reservoir of TNF--producing cells that are susceptible to extrinsic
insults. Intra-alveolar macrophages are prime candidates for TNF- production (19), as they have been shown to be
capable of production a number of cytokines. There is some evidence
from the literature that alveolar-type II cells also may
play a pivotal role in cytokine networking within the lung, especially
in production of TNF- (17). Further studies are necessary to
determine which cells generate TNF- in the lung.
No significant differences were seen between the saline control and Ab
control groups in regard to the levels of TNF- and the
pathophysiological indexes after 4 h of CMV. Serum IgG fraction, used
as a globulin control, was seen to have no effect on TNF- production
in the lung and to have no effect on producing lung injury in this
model. Therefore we could evaluate the effect of anti-TNF- Ab, by
itself, in the series 2 pretreatment study.
In the present study, pretreatment with intratracheal instillation of
anti-TNF- Ab improved both oxygenation and Crs and also attenuated
the infiltration of PMNs in a dose-dependent fashion. This was
expected, because neutralization of intra-alveolar TNF- from the
beginning of ventilation should attenuate TNF--related inflammatory
processes in the lung. These, in turn, propagate a process that
eventually leads to ventilator-induced lung injury. Neutralization of
TNF- reduced neutrophil influx into the air spaces of the lung.
Several mechanisms may be operative in TNF--mediated neutrophil
recruitment. A recent study (22) indicates that alveolar macrophages
activated by TNF- produce interleukin-8, which is a very potent and
specific neutrophil chemotactic factor and is known to be associated
with the development of acute lung injury by recruiting neutrophils
(5). TNF- reportedly triggers the production of PAF by several types
of cells indigenous to the lung (4, 26). PAF exhibits potent neutrophil
chemotactic activity (2). TNF- also results in the expression of
adhesion molecules, such as intracellular adhesion molecule-1, on
endothelial cells, followed by transmigration of the neutrophils into
the interstitial and intra-alveolar compartment (16). More
significantly, it was the neutrophils recruited to the lung by TNF-
that were associated with ventilator-induced lung injury in this model
(11, 13, 23).
TNF- is a major proximal cytokine in the early phase of various
inflammatory processes, with substantial effects and stimulation on
many inflammatory cells and cytokines (27). The results of the present
study, along with previous reports that clarify the role
of neutrophils and chemical mediators, suggest that the inflammatory response is involved in ventilator-induced lung injury and that TNF-
plays a pivotal role in ventilator-induced lung injury in rabbits.
Because TNF- mRNA was generated in the air spaces in our previous
study (24) and TNF- concentration was high in that compartment in
the present study, the route of intratracheal administration of
anti-TNF- Ab seems to be beneficial to reduce the magnitude of lung
injury in this model. Intrapulmonary administration of the agents that
inhibit inflammatory cytokines may thus provide a useful way to
attenuate ventilator-induced lung injury.
However, as would be expected, given the complexity and redundancy of
the stress and/or injury response, lung injury in this model was not completely abrogated. There was very little difference in
the final compliances measured between the anti-TNF- Ab low-dose group and saline or Ab controls, supporting the involvement of other
factors (e.g., other cytokines, arachidonic acid derivatives, complement, reactive oxygen species, and other proteolytic enzymes or
inflammatory cells) in the pathogenesis of ventilator-induced lung
injury. TNF- is recognized clinically as the key cytokine that
initiates and amplifies the process of sepsis and ARDS (3, 15, 27), and
there have been some clinical trials of intravenous anti-TNF- Ab in
patients with septic shock (4, 6). This treatment does not seem to be
clinically beneficial. Clinical studies in humans with septic shock
showed that intravenous administration of anti-TNF- Ab did not
improve clinical outcomes or attenuate cytokine
activation. This suggests additional involvement of other factors in the process of septic shock in critically ill patients.
Recently, the possibility has been proposed that mechanical ventilation
used in ARDS serves to initiate and/or potentiate an inflammatory
response in the lung, and this in turn propagates a vicious cycle of
inflammation leading to tissue injury locally and possibly systemically
(9, 15, 25). The compartmentalization of alveolar TNF-
was lost in the injured lung, and systemic release of TNF- occurred
in an isolated perfused rat model (26). Intrapulmonary administration
of the agents that inhibit inflammatory cytokines may thus provide a
useful way to attenuate ventilator-induced lung injury and may
attenuate the development of a vicious cycle of systemic inflammation
in ARDS patients.
In summary, CMV led to the production of TNF- protein in the lung.
Pretreatment with intratracheal administration of anti-TNF- Ab
attenuated ventilator (CMV)-induced lung injury in a saline-lavaged rabbit lung model.
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ACKNOWLEDGEMENTS |
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We thank Drs. Toshiharu Nakajima and Hirohisa Saito of the Department of Allergy Research, National Children's Medical Research Center, for their kind assistance.
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FOOTNOTES |
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This research was supported in part by The Ministry of Health and Welfare, Japan (H3-P-K-5).
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: K. Miyasaka, National Children's Medical Research Center, 3-35-31 Taishido, Setagaya-ku, Tokyo, 154-8509 Japan.
Received 1 July 1998; accepted in final form 10 March 1999.
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INTRODUCTION
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RESULTS
DISCUSSION
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