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ABSTRACT |
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ABSTRACT
INTRODUCTION
METHODS
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The novel effects of FK506 on shock induced by lipopolysaccharide and phorbol myristate acetate (LPS/PMA) were studied using beagles. Five groups were studied: endotoxin shock control group (both 0.5 mg/kg of LPS and 30 µg/kg of PMA, n = 6); methylprednisolone-treated endotoxin shock group (n = 5); FK506-treated endotoxin shock groups in which intravenous infusions of FK506 at 2.5 µg/kg/h (low dose, n = 5), 8 µg/kg/h (medium dose, n = 5), and 25 µg/kg/h (high dose, n = 5) were administered. In the control group, the survival rate was 33%. Also, arterial hypoxemia, systemic hypotension, and marked increases in pulmonary vascular resistance (PVR) and wet-to-dry weight ratio (W/D) were observed. FK506 treatment at both medium and high doses significantly attenuated these LPS/PMA-induced physiological changes, and the survival rates were 80 and 100%, respectively. On the other hand, in the methylprednisolone group, no obvious effects were observed. The present study suggests that FK506 could have prophylactic potential against acute lung injury in endotoxin shock.
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
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Endotoxin is thought to be a potent inducer of septic shock associated with high mortality. Shock inducement and other biologic activities of endotoxin have been found to be mediated by many factors. Among these, cytokines with or without the synergistic effect of other cytokines, are one of the most important mediators to induce shock.
Interleukin-2 (IL-2), which is released from activated T-lymphocytes, is known to be an effective cancer chemotherapeutic agent in humans as well as in animal models (1, 2). However, it has also been shown that IL-2 therapy produces various side effects, including systemic edema, possibly caused by microvascular injury (3). In animal models, systemic administration of recombinant IL-2 has resulted in fluid retention and an increase in pulmonary microvascular permeability to albumin (4, 5).
Furthermore, various kinds of cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-
), working together with IL-2 synergistically, have also been reported
to induce shock or shock-like symptoms in animals and in humans (6, 7). Clinically, it has been reported that high levels of
TNF- together with increased IL-2 blood levels have been
observed in patients with septic shock with a high mortality rate
(8). These reports may suggest that the cooperative activation
between lymphocytes and monocytes is involved prior to the
development of septic shock or multiple organ dysfunction syndrome (MODS).
Tacrolimus (FK506), a macrolide immunosuppressant is
known as a potent and effective inhibitor of lymphocytes (9),
and it inhibits the production of IL-2 from the T-lymphocyte.
Furthermore, it has been reported that FK506 could reverse
the production of IL-1 and TNF- observed in the rat liver model
of ischemia/reperfusion injury (10). These reports seem to imply that FK506 has the potential not only to inhibit the production of IL-2 but also that of IL-1 and TNF-, and to suppress the progression of septic shock or MODS, by inhibiting
orchestrations between monocyte/macrophage and lymphocytes. Therefore, in this study, we examined the protective effects of FK506 on the canine model of acute lung injury.
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METHODS |
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INTRODUCTION
METHODS
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DISCUSSION
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Materials
Lipopolysaccharide (LPS): Escherichia coli serotype 0111:B4 (Sigma Chemical Co., St. Louis, MO), 0.5 mg/kg, was suspended in isotonic saline, and administered intravenously. Phorbol myristate acetate (PMA): P-8139 (Sigma Chemical) was dissolved in dimethylsulfoxide (DMSO), and then further diluted in 9.7 ml of saline for use. Methylprednisolone (MP) (LK948; Pharmacia Upjohn Co., Tokyo, Japan): 1 g was dissolved in 16 ml of distilled water and administered intravenously for 30 min at a dose of 30 mg/kg. FK506 (Fujisawa Pharmaceutical Co. Ltd., Osaka, Japan): 0.5 ml, for intravenous injection (10 mg/ ml) was diluted in 49.5 ml of saline. This adjusted solution (10 ml) was further diluted in saline for use.
Animal Preparation
Twenty-six beagles weighing 9 to 16 kg were anesthetized intravenously with 50 mg/kg of sodium pentobarbital (Dainabot Co., Osaka,
Japan). The use of beagles in the experiment was approved by the Ethics Review Committee in Fujisawa Medicinal Biology Research Laboratories. Supplemental doses of sodium pentobarbital were administered as required. Also, we found that there were no differences in
dosage administration between the groups. After the introduction of
the anesthesia, the trachea was exposed and incised, followed by cannulation for artificial ventilation and the measurement of airway pressure. The animals were ventilated with a mixture of 30% O2 and 70%
N2 (tidal volume, 18 ml/kg; respiration rate, 10 to 20 breaths/min; inspiration-expiration ratio, 1:1.5) using a Model B2 ventilator (Igarashi
Ika Kogyo Co. Ltd., Tokyo, Japan). Polyethylene catheters were used
for bilateral cannulation of the femoral arteries to measure mean arterial pressure (
) and to obtain blood samples, and also for bilateral
cannulation of the femoral veins to measure right atrial pressure (PRA)
and to administer drugs and saline. A flow-directed, balloon-tipped, 5F
thermodilution Swan-Ganz catheter (Model TS113H-5F; Baxter Healthcare Co., Irvine, CA) was inserted into the right jugular vein and advanced into the main pulmonary artery. Measurements of mean pulmonary arterial pressure (
) and blood samples were taken through
this catheter. , PRA, and were monitored and recorded continuously throughout the study. Cardiac output (CO) was measured using
the thermodilution technique (Edwards cardiac output computer; Baxter
Healthcare Co.). Pulmonary vascular resistence (PVR) was calculated
using the following formula: PVR (dynes · s/cm5) = 80 · (mm
Hg)/CO (L/min).
After surgical preparation was completed, the animal was left to stabilize (i.e., to achieve a PaCO2 of 35 to 45 mm Hg and an arterial pH of 7.35 to 7.45) before the start of the study. A heating pad (Model SMS-1000J; Seabrook, Tokyo, Japan) was placed under the animal to prevent hypothermia. At the end of consecutive experiments, the animal was killed with an excess amount of sodium pentobarbital, and the lower lobe of the left lung was removed to estimate the lung wet-to-dry weight (W/D) ratio.
Experimental Protocols
All 26 animals received intravenous administrations of both 0.5 mg/kg of LPS and 30 µg/kg of PMA, and then were divided into five groups. In the first group (n = 6) receiving both LPS and PMA, saline as a vehicle was infused intravenously from 30 min before LPS/PMA challenge (baseline) to 6.5 h thereafter (endotoxin shock control group). In the second group (n = 5), MP was infused intravenously (30 mg/kg) for 30 min before the LPS/PMA injection (MP group). In the third group (n = 5), FK506 was infused intravenously (25 µg/kg/h) starting 30 min prior to LPS/PMA injection and continuing for the duration of the experiment (high FK506 group). In the fourth (n = 5) and fifth (n = 5) groups, FK506 was given intravenously under the same conditions as those of the third group, except for the infusion rates of FK506 (8 and 2.5 µg/kg/h in the medium- and low-dose FK506 groups, respectively). Measurement of each hemodynamic parameter and blood gas analysis was performed 30 min before and just prior to LPS/PMA challenge, and hourly thereafter.
Measurement of Hemodynamics
and PRA were measured by catheters placed in the left femoral artery and the left femoral vein, which were connected to pressure
transducers (Model AP-630G and Model AP-601G; Nihon Kohden, Tokyo, Japan), respectively. In addition, was measured through a
Swan-Ganz catheter connected to a pressure transducer (Model AP-641G; Nihon Kohden).
Arterial Blood Gas Analysis
Both arterial and mixed venous blood samples (about 0.2 ml) for blood gas analysis were taken 30 min before and just prior to LPS/PMA challenge, and hourly thereafter, through the individual catheters in the right femoral artery and the main pulmonary artery, respectively. A blood gas analyzer (Model ABL 520; Radiometer, Copenhagen, Denmark) was used to measure PaO2 and pulmonary shunt. Pulmonary shunt was calculated using a blood gas analyzer and the following formula.
Pulmonary shunt (%) = 100/{1 + [tO2 
tO2(V)]/[tO2(A) tO2]}
where tO2 = total content of oxygen in arterial blood; tO2(V) = total content of oxygen in mixed venous blood; tO2(A) = total content of oxygen in alveoli.
Lung W/D Weight Ratio Measurement
The chest was opened, either at the time of death or 6 h after LPS/ PMA challenge. Before the incision of the left lower lobe, exanguination was first performed under anesthesia with an excess amount of 50 mg/ml sodium pentobarbital given intravenously. Just after the exanguination was completed, ligation of the bronchus with surgical ligature was conducted before allowing the blood to drain through the main pulmonary artery, and the lobe was then cut and removed.
Afterwards, the lower lobe of the left lung was removed, placed in a container, weighed immediately for the measurement of wet weight, and then dried in an oven (Sanyo, Osaka, Japan) at 105° C for 24 h. The dry tissue weight was then measured, and the W/D ratio was calculated to evaluate the degree of lung edema.
Plasma Albumin Concentration
Pulmonary arterial blood (about 2 ml) was sampled using a heparinized syringe just before and at 2, 4, 5, and 6 h after LPS/PMA challenge and was centrifuged to obtain plasma samples. These samples
were stored at 30° C until the albumin concentration was measured.
Measurement of Whole Blood FK506 Concentrations
Heparinized blood samples (about 1.5 ml) were obtained just before and at 1, 3, and 6 h after LPS/PMA challenge. The whole-blood FK506 concentrations were measured by the ELISA method. The detectable range for concentrations using this method was 0.5 to 200 ng/ml.
Lymphocyte Culture
Splenic tissues, derived from female BALB/C mice 6 wk of age (SLC
of Japan, Hamamatsu, Japan), were removed aseptically and homogenized. The homogenized solution was filtered through mesh and centrifuged at 1,200 rpm for 5 min. Filtered cells were washed three times,
and then finally resuspended in RPMI-1640 containing 10% FCS, 5 × 10
2 M melcaptoethanol and penicillin-streptomycin. The number of spleen cells was adjusted, and 3 × 106 cells (final volume, 0.5 ml) were
added to the wells of 24-well microtiter plates. Concanavalin A (Con
A) (Wako Pure Chemical Industries, Ltd., Osaka, Japan) was used at
4 µg/ml (final volume, 0.5 ml) and FK506 in ethanol solution (2 µg/
ml) was used at final dilutions of 106 (final volume, 1 ml). Cells were
cultured for 24 h (5% CO2, 95% air at 37° C). After a 24-h incubation,
cultures were centrifuged (2,000 rpm for 5 min), and supernatants
were collected and stored at 20° C until assay.
Assay for IL-2 by ELISA
A murine IL-2 ELISA kit (Endogen, MA) was used to measure IL-2 levels in the culture supernatants. Briefly, IL-2 in diluted supernatants was captured by specific antibodies precoated on the wells of the ELISA plates. After incubation and washing, captured IL-2 was labeled with peroxidase-conjugated antimurine IL-2 antibody and these complexes were then detected after the addition of the substrate tetramethylbenzidine (TMB). The reaction was stopped by adding the appropriate stop solution, and the absorbance of the plate was then measured on a plate reader (Spectra Max 250; Wako Pure Chemical Industries, Ltd., Osaka, Japan) set at a wavelength of 490 nm. Finally, the amount of IL-2 was calculated from standard curves obtained with IL-2 standard reagent on the same ELISA plates.
Statistical Analysis
All data are presented as mean ± standard deviation (SD). One-way analysis of variance (ANOVA), Dunnett's multiple comparison test, Student's t test, and the Peto test were applied to assess the statistical significance between groups. A value of p < 0.05 was considered as a significant difference between groups.
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RESULTS |
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Survival
Four of six in the endotoxin shock control group and two of five in the MP group died between 3 and 6 h after injection of LPS/PMA. The cumulative survival rates at the final point in the endotoxin shock control and MP groups were 33 and 60%, respectively (Table 1). All animals from the high-dose FK506 (25 µg/kg/h) group survived for 6 h after intravenous injection of both LPS (0.5 mg/kg) and PMA (30 µg/kg) (survival rate, 100%), whereas four of five from the medium FK506 group (8 µg/kg/h) and three of five from the low FK506 group (2.5 µg/kg/h) survived for the same period (survival rate: 80 and 60%, respectively). Both the medium- and high-dose FK506 groups showed significantly greater survival rates than did the endotoxin shock control group (p < 0.05 in the medium group and p < 0.01, in high group, by Peto test).
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Hemodynamics
Intravenous infusions of vehicle, MP, or FK506 at any dose 30 min prior to LPS/ PMA challenge had no effect on hemodynamic parameters, and no statistical difference was found in any of the basal values between the groups. CO in all groups showed similar decreases soon after LPS/PMA challenge, but these decreases were significantly attenuated by FK506 in the medium dose group between 2 and 4 h postchallenge (p < 0.01 at 2 h, p < 0.05 at 3 h and 4 h versus the endotoxin shock control group (Figure 1).
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in the endotoxin shock control group decreased significantly soon after LPS/PMA challenge (66.2 ± 8.4 mm Hg at
1 h, p < 0.01 versus baseline) and recovered gradually (75.0 ± 5.0 mm Hg at 6 h, p < 0.01 versus baseline). These changes in
were similar between all groups, and no significant differences were observed (Figure 1).
In the endotoxin shock control group, the PVR increased drastically soon after LPS/PMA challenge and continued to increase above baseline levels throughout the experiments (Figure 2). The MP group also showed changes in PVR similar to those in the endotoxin shock control group (Figure 2). However, the LPS/PMA-induced increase in PVR tended to be inhibited by high and medium doses of FK506 infusion, especially between 1 and 3 h after LPS/PMA challenge, although no statistical significance was found (Figure 2).
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PRA in the endotoxin shock control group continued to increase after LPS/PMA challenge (Table 2). The value at baseline was 2.5 ± 0.5 mm Hg and rose time-dependently (at the final observation point, it reached 5.9 ± 2.1 mm Hg, p < 0.01 versus baseline). Similar changes in PRA were seen among all groups throughout the experiments (Table 2).
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Gas Exchanges
Intravenous infusions of MP or FK506 at any dose 30 min prior to LPS/PMA challenge had no effect on any of the parameters of gas exchange.
In the endotoxin shock control group, PaO2 decreased gradually after LPS/PMA administration (Figure 3). The value decreased from 153.9 ± 6.3 mm Hg at baseline to 63.5 ± 3.0 mm Hg at 6 h after injection (p < 0.01 versus baseline). Intravenous treatment with 30 mg/kg of MP failed to reverse the
LPS/PMA-induced decrease in PaO2. Intravenous infusion of
FK506 at the rate of 25 µg/kg/h significantly prevented the decrease in PaO2 in animals administered LPS/PMA (143.2 ± 7.0 mm Hg at baseline, 124.4 ± 9.8 mm Hg at 6 h) (Figure 3).
FK506 at the medium dose (8 µg/kg/h) also ameliorated the
LPS/PMA-induced decrease in PaO2 (139.0 ± 11.7 mm Hg at
6 h). However, FK506 at the low dose (2.5 µg/kg/h) failed to
reverse the LPS/PMA-induced deterioration in PaO2 (110.9 ± 11.2 mm Hg at 6 h). In the endotoxin shock control group,
pulmonary shunt increased drastically from 2.0 ± 4.4% at
baseline to 51.6 ± 5.7% at the end of the experiment (p < 0.01 versus baseline) (Figure 3). No differences in pulmonary shunt
were observed between the endotoxin shock control and MP
groups. In contrast, treatment with FK506 at the high and medium doses prevented the increase in pulmonary shunt that
was observed both in the endotoxin shock control and MP
groups (Figure 3).
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p < 0.05, The Lung W/D Ratio and Macroscopic Findings
Lung W/D ratio in the lower lobe of the left lung was 7.90 ± 1.13 in the endotoxin shock control group. Preliminary data had assured us that the mean normal lung W/D ratio in the same position of lobe was around 4.00 (data not shown). In the MP group, the ratio was almost the same (7.84 ± 0.75) as that in the endotoxin shock control group (Figure 4). Treatment with FK506 led to a reversal of the above ratio, dose-dependently (Figure 4). Macroscopically, the lungs of the endotoxin shock control group exhibited gross damage including edema with distinct petechial hemorrhages.
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Changes in FK506 Concentration
FK506 concentrations in whole blood samples were measured at times 0, 1, 3, and 6 h postchallenge. At time zero, FK506 concentrations were 5.2 ± 0.9 (low dose), 26.1 ± 10.6 (medium dose), and 19.1 ± 9.3 (high dose) ng/ml (Figure 5). At 1 h postchallenge, the corresponding values were 14.3 ± 2.9, 45.9 ± 15.5, and 128.2 ± 19.8 ng/ml. The concentrations in each FK506- dose group reached a plateau and remained unchanged thereafter (Figure 5).
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Changes in Plasma Albumin Concentration
In the control group, the plasma albumin concentration was decreased time-dependently (from 2.80 ± 0.16 mg/dl at baseline to 2.3 ± 0.2 mg/dl). Treatment with MP or each dose of FK506 failed to affect these decreases in plasma albumin concentration (Table 3).
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Mitogen-induced IL-2 Production In Vitro
FK506 at concentrations ranging from 0.01 to 100 ng/ml inhibited Con-A-induced IL-2 production from murine splenic cells dose-dependently, with the IC50 of 0.04 ng/ml (Figure 6).
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The insult utilized in this model was extremely strong and resulted in 6-hour survival of 33% of the control group; there are not many studies using such strong insult to assess the efficacy of agents on acute lung injury (ALI). The reason we used such a strong insult is that we wanted to study mainly the efficacy of FK506 on survival rate after the initiation of severe ALI. Therefore, as a first step, the efficacy of preadministered FK506 on the survival rate was examined in this study.
In the clinical setting, ALI usually develops in most patients more gradually with much milder insults, and some patients will go on to develop more severe ALI (ARDS), which leads to death. Thus, it could be reasoned that peak inflammatory responses, which lead to death, come after the initiation of the inflammatory cascade; there might be some period of milder ALI that would allow initiation of treatments. However, it is extremely difficult to develop a chronic acute lung injury model that simulates the clinical situation and allows examination of a survival rate after ALI. So, a large bolus injection of LPS/PMA was selected as an insult to initiate severe ALI, which would lead to animal death, instead of milder insults, which would cause moderate ALI without animal death. In this study, prophylactically administered FK506 30 min before the bolus injection of LPS/PMA was investigated.
The cumulative survival rate at the final point in the endotoxin shock control group was 33% in this study. Furthermore, progressive hypoxemia was observed in the group, which is considered to be due to an increase in pulmonary shunt with pulmonary edema. Kang and colleagues (11) demonstrated microscopic analysis that showed alveoli filled with edematous fluid, resulting from increased microvascular permeability, and a drastic decrease in PaO2 (less than 60 mm Hg) 2 h after administration in a canine LPS/PMA model. Although biochemical data related to MODS was not obtained, the decrease in plasma albumin concentration in this model might imply the presence of MODS with increased microvascular permeability.
The most impressive result was the reversal of the cumulative survival rate by administering FK506, especially at medium and high doses. Improvement of gas exchange could be
one of the most important factors affecting survival rate. Impairment of gas exchange observed in our endotoxin shock
control group suggested that it might be related to an increase
in the pulmonary shunt resulting from edema formation. Although albumin concentration in the lung tissue was not measured, our macroscopic findings exhibited gross damage, including edema with distinct petechial hemorrhage that might
demonstrate pulmonary edema caused by increased permeability. The mechanism by which FK506, both at medium and
at high doses, demonstrates a protective effect on pulmonary
edema, and aggravation of gas exchange might be that FK506
can suppress increased pulmonary microvascular permeability
that is due to lung vascular injury. There could be several possible mechanisms to explain these phenomena. First, it could
be due to the complete suppression of IL-2 production from
activated T cells by FK506. As stated in the introduction, IL-2
itself and/or working synergistically with other cytokines could
induce shock and microvascular damage. Additonally, several preclinical reports have demonstrated that IL-2 induces pulmonary edema through the production of inflammatory mediators such as IL-1, TNF-, thromboxane B2, and activation of
a complement system (12). These findings may suggest
that IL-2 is primarily involved in septic shock at an early clinical stage. In our in vitro data, FK506 at even smaller doses
than those in our in vivo experiment could almost completely
inhibit Con-A-induced IL-2 production from murine splenic
cells. Moreover, it has been reported that FK506 inhibits not
only IL-2 production in lymphocytes but also antigen-induced
TNF- production in macrophages, depending on the mode of
cell activation (16). Keicho and colleagues (17) have demonstrated that FK506 at the concentration of 10 nM partially suppresses the production of IL-1 alpha from the U937, a macrophagelike cell line that was stimulated with PMA. In our
study, whole blood concentrations, both in medium and in high
doses, reached more than 40 and 120 ng/ml at a plateau level,
which are relatively higher levels than obtained by Keicho and
colleagues. Therefore, FK506 at medium and high doses could
almost completely inhibit proinflammatory mediators released
from macrophages, as well as IL-2 from lymphocytes. However, there is no clear evidence of any suppressive effects of
FK506 on cytokine production because of the lack of commercially available specific antibodies against canine cytokines
such as TNF-, IL-1, IL-2, IL-6, and IL-8. Because the blood
concentration of FK506 in the high-dose group, which could
protect against acute lung injury in our model, might be substantially higher than that required to inhibit T-cell response, our results might suggest another novel anti-inflammatory
mechanisms of the macrolide FK506, unrelated to or in addition to the immunosuppressive effects on T cells. Therefore,
further studies to elucidate these mechanisms are recommended.
Second, it has been suggested that activated neutrophils or mononuclear phagocytes are involved in lung injury induced by endotoxin (18). A recent report has shown that the anti-inflammatory effects of FK506 in vivo may be mediated through the inhibition of inflammatory cells such as neutrophils as well as lymphocytes (22). Additionally, several reports have related some modulating effects of FK506 on neutrophil activation, infiltration, and production of superoxide radicals, as well as on lymphocytes in both in vitro and in vivo experiments (23, 24). These reports suggest that FK506 could have possible therapeutic potentials in a variety of inflammatory conditions.
Finally, FK506 may suppress transient pulmonary hypertension, one of the factors that could accerelate pulmonary edema during endotoxin shock. In our study, the marked increases in PVR induced by LPS/PMA challenge were observed for a couple of hours in the endotoxin shock control group. Both high and medium doses of FK506 tended to reverse the marked increases in PVR that were observed in the endotoxin shock control group, although no statistically significant difference was found between these groups. It has been reported that PMA increases PVR in isolated, blood-perfused canine lungs, and that this change is completely attenuated by the thromboxane synthase inhibitor OKY 046 (25, 26). Miyahara and colleagues (27) showed that an Ascaris suum antigen-induced increase in PVR in isolated canine lungs was blunted similarly by pretreatment with AA-2414, a thromboxane-receptor antagonist, suggesting that thromboxane may be a major mediator for the increase in PVR in the isolated canine lung. In considering these reports, thromboxane A2 released from aggregated platelets, may be responsible for the increase in PVR in our model. A recent report has revealed that ADP- or collagen-induced platelet aggregation is inhibited by FK506 at a concentration of 50 ng/ml (28). As shown in Figure 6, the infusion of FK506 at medium and high doses generated FK506 blood concentrations above 50 ng/ml, throughout the observation period. The possible mechanism whereby FK506 could reverse transient rises in PVR induced by LPS/ PMA in our study may be the ability of FK506 to prevent platelet aggregation and concomittant thromboxane A2 release.
We conclude that FK506 at medium or high doses attenuated LPS/PMA-induced acute lung injury, and improved survival rate and lung edema. Mechanisms responsible for this phenomena need further investigation. However, the present study suggests that FK506 could have prophylactic potential against acute lung injury in endotoxin shock.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Akitoshi Ishizaka, M.D., Department of Medicine, School of Medicine, Keio University, 9-2 Shinano-cho Shinjyuku-ku Tokyo, Japan. E-mail: ishiz{at}ibm.net
(Received in original form June 23, 1999 and in revised form February 22, 2000).
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References |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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