|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
ABSTRACT |
|---|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
We have tested the effects of combined treatment with a recombinant surfactant protein C based surfactant (rSP-C surfactant) containing a phosphodiesterase-4 (PDE-4) inhibitor, roflumilast, in a lung lavage model of acute lung injury. The following groups were tested: (1) controls receiving sham exposure; (2) PDE-4 inhibitor (6.0 mg/kg body weight, intratracheally) alone; (3, 4) rSP-C surfactant (25 and 100 mg phospholipids [PL] per kg body weight) alone; and (5, 6 ) treatment with rSP-C surfactant (25 and 100 mg PL per kg body weight) combined with the PDE-4 inhibitor at a dose of 6.0 mg/kg body weight. The different groups were compared with respect to improving oxygenation and histopathologic changes, e.g., hyaline membrane (HM) formation. Both doses of rSP-C surfactant improved oxygenation while even this high dose of the PDE-4 inhibitor alone did not influence oxygenation compared with untreated control animals. Addition of the PDE-4 inhibitor led to improved oxygenation based on both doses of rSP-C surfactant. The PDE-4 inhibitor alone prevented further HM formation and infiltration of neutrophil leukocytes. The rSP-C surfactant was able to prevent further HM formation. Based on both doses of rSP-C surfactant, addition of the PDE-4 inhibitor showed additional effects on oxygenation and inhibition of HM formation. The effects of combined treatment were superior to each treatment alone, leading to the conclusion that a rSP-C surfactant containing a PDE-4 inhibitor may act synergistically in this animal model of acute lung injury. We conclude that combined treatment with rSP-C surfactant and a PDE-4 inhibitor may be an effective treatment for patients with acute lung injury.
| |
INTRODUCTION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Recently, we have shown (1, 2) in an animal model of the acute respiratory distress syndrome (ARDS) that a recombinant surfactant protein C based surfactant (rSP-C surfactant) was at least equally effective as bovine-derived surfactants in improving oxygenation and inhibiting hyaline membrane (HM) formation. This animal model of surfactant depletion by repetitive total lung lavage led to histopathologic changes similar to those seen in ARDS (1). The pathologic changes observed were atelectasis, protein leakage leading to formation of HM, and edema (1, 3) as well as infiltration of polymorphonuclear neutrophils (1, 3). These changes lead to severe deterioration of gas exchange (1, 2, 4). In this investigation (1) all of the tested surfactants were unable to inhibit accumulation of polymorphonuclear neutrophil leukocytes (PMNL) in the lungs. One of the characteristic histologic features of human ARDS is an intense inflammatory process in the lungs which may progress to fibrosis (5). This finding leads to the conclusion that treatment with anti-inflammatory drugs such as glucocorticosteroids (GCS) may be useful. However, treatment with GCS did not show very promising results (6) despite the fact that an inflammatory response is present in ARDS. This is evident as PMNLs are involved in ARDS (7, 8). Recently Meduri and coworkers (9) showed that prolonged treatment with methylprednisolone (2 mg/kg/d for a total of 32 d) resulted in improvements of the lung injury and the multiple organ dysfunction syndrome. The different outcome of the latter study may be explained by the different protocols that were used. In the early study by Bernard and coworkers (6) the patients were treated with large doses of GCS before the diagnosis of ARDS. In contrast to the study by Meduri and coworkers (9) the patient received methylprednisolone in the later phase of ARDS to treat the fibroproliferative changes.
In a previous publication (10) we have compared the effects of phosphodiesterase (PDE) inhibition and treatment
with GCS using a more moderate lung lavage to induce the
acute lung injury. In this model a combined PDE-3/4 inhibitor
was able to improve oxygenation and to inhibit formation of
HM as well as infiltration with PMNL. In this model the effects of PDE inhibition were comparable to treatment with
GCS. This was despite different modes of action of the GCS
and the PDE inhibition. During recent years evidence has accumulated that selective inhibition of the isozyme phosphodiesterase-4 (PDE-4) may be useful for treating the inflammatory response during acute lung injury (11). The effects of
various PDE-4 inhibitors were evaluated in animal models of
septic shock. These animal models used high doses of systemically administered lipopolysaccharide (LPS) to induce a septic
shock (12, 13). The anti-inflammatory effects of PDE-4 inhibitors in these models include complete inhibition of LPS-induced
increases in serum levels of tumor necrosis factor-
(TNF-),
thereby improving lung injury and mortality (12, 14). In addition to the prevention of cytokine release, PDE-4 inhibitors may attenuate PMNL activation even after sequestration. This
was shown in a mouse model of acute lung injury induced by
LPS which was amplified by zymosan treatment performed after LPS was given (15). Zymosan (derived from Saccharomyces cerevisiae) activates neutrophil leukocytes leading to an increase in extravascular accumulation of albumin (15). Rolipram,
as classic PDE-4 inhibitor, was able to inhibit lung injury when
given either before or after LPS. The protective effect of rolipram was independent of the inhibition of TNF- release and of
PMNL sequestration in the lung and also occurred when zymosan was injected alone (15). This suggests that inhibition of
PMNL activation was the likely mechanism of action.
In the present study we analyzed the effects of a PDE-4 inhibitor in a lung lavage model of acute lung injury. In this animal model the effects of surfactant treatment are well established (1, 16). The specific aims of the present investigation were to see whether a PDE-4 inhibitor alone shows any effects in this animal model either on oxygenation or histopathology, and to test whether the combination of rSP-C surfactant and a PDE-4 inhibitor has an additional effect with respect to improving oxygenation, ameliorating HM formation, or preventing the accumulation of PMNLs in the lungs.
| |
METHODS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Surfactant
The rSP-C surfactant (Byk Gulden, Konstanz, Germany) used in the study contained 2% recombinant surfactant protein C (rSP-C). rSP-C is an analogue of human SP-C (1). rSP-C was associated in a 70:30 ratio with phospholipids (PL) consisting of dipalmitoylphosphatidylcholine and palmitoyloleoylphosphatidylglycerol plus 5% (wt/wt) palmitic acid. The rSP-C surfactant was resuspended with 0.9% NaCl solution to achieve a concentration of 25 mg PL per ml. The rSP-C surfactant was instilled intratracheally as bolus at doses of 25 and 100 mg PL per kg body weight in a volume of 1.2 ml per animal.
The PDE-4 inhibitor roflumilast was prepared together with the rSP-C surfactant. Therefore, different concentrations of roflumilast were combined together with the rSP-C surfactant and manufactured together during the pharmaceutical process. This process yielded a powder containing the rSP-C surfactant and different concentrations of roflumilast. This had to be resuspended before use. After resuspension roflumilast was administered intratracheally at a dose of 6.0 mg/kg body weight together with rSP-C surfactant at doses of 25 and 100 mg PL per kg body weight. In addition, a solution of roflumilast alone was administered intratracheally using the previously mentioned dose.
Preparation of the Rats
The study protocol was reviewed and approved by the Laboratory Animal Care Committee at the district presidency of Freiburg, Germany. The study was performed with a total of 84 male Sprague-Dawley rats (Harlan CBP, Zeist, The Netherlands), with a body weight of 230 to 270 g.
The anesthetic and surgical methods were the same as previously described (1). Briefly, after introduction of inhalational anesthesia, a catheter was placed into one carotid artery. Thereafter, the animals received an intraperitoneal injection of pentobarbitone (stock solution: 60 mg/ml; 1 ml/kg body weight). After completion of the tracheotomy, a tube was secured into the trachea of each animal. The animals received an intramuscular injection of pancuronium bromide (1 ml/kg body weight; solution concentration: 2 mg/ml) and ventilation was started using a Servo Ventilator (900C; Siemens-Elema, Solna, Sweden). The tracheal tubes of six animals were connected to a distributor. The animals were ventilated simultaneously using pressure-controlled mode at a respiratory rate of 30 breaths/min, fraction of inspired oxygen (FIO2) of 1.0, inspiration expiration ratio of 1:2, and peak inspiratory pressure (peak PI) of 15 cm H2O which included a positive end-expiratory pressure (PEEP) of 2 cm H2O until induction of ARDS. Additional pentobarbitone (intraperitioneally, 0.25 ml/kg of the stock solution) and pancuronium bromide (intramuscularly, 1 ml/ kg body weight) were given when appropriate.
Protocols for the Animal Experiments
The reported variables were arterial PaO2 and PaCO2. Blood gas analysis was performed with a blood gas analyzer (Radiometer Copenhagen ABL 500; Radiometer Deutschland GmbH, Willich, Germany). After determination of pretreatment values, only animals with PaO2 values of more than 480 mm Hg were included in the experiments. Peak PI was raised to 28 cm H2O and PEEP to 8 cm H2O, and the animals were subjected to multiple lung lavage (six to eight times) with 1 ml/30 g body weight of isotonic saline solution. Only those animals that had PaO2 values between 50 and 110 mm Hg were included in the study. Blood gases were determined at 5, 30, and 60 min after the last lavage. One hour after the last lavage either rSP-C surfactant or roflumilast was instilled as described previously. Untreated control rats received sham treatment with air. In additional groups the effect of combined treatment with rSP-C surfactant and the PDE-4 inhibitor was investigated when administered 1 h after the last lavage. Subsequently, 30, 60, 90, 120, and 150 min after treatment (equivalent to 90, 120, 150, 180, and 210 min after the last lavage) blood gases were determined. During the whole experimental period the peak PI and PEEP were kept constant at 28 cm H2O and 8 cm H2O, respectively. The experimental scheme is shown in Figure 1.
|
Preparation of the Lungs
Two control groups were used for histologic investigations. In Group 1 the animals were killed 1 h after the last lavage, and in Group 2, in which the animals received sham treatment with air, the animals were killed at 210 min after the last lavage. All treated animals were killed subsequently after the last blood gas determination (equivalent to approximately 210 min of experimental time). The histopathologic procedures used in the study were the same as previously described (1). From each rat lung, all lobes were evaluated, using an hematoxylin-eosin-stained, 5 µm-thick tissue slide. The lobes were trimmed in a longitudinal manner, using the largest area of each lung lobe. Slides were coded so that the pathologist could evaluate and diagnose all lung lobes of the same animal at once. From each lobe, five consecutive fields were analyzed. After randomization and codification, each section was examined under light microscopy. HM formation was assessed semiquantitatively according to the previously used technique (1). The severity of HM formation was graded from 0 to 4+ as follows: 0 = no HM formation; 1+ = occasional fields showing HM formation in a low number (from one to three) of membranes per viewed field (minimal); 2+ = occasional fields showing HM formation in an increased number (more than three) of membranes per viewed field (mild); 3+ = many but not all fields showing HM formation (moderate); 4+ = HM formation in all fields examined (severe). The distribution and severity of intra-alveolar accumulation of PMNLs were graded semiquantitatively from 0 to 4+ as with the grading of HM formation, but with respect to the number of inflammatory cells and the location of these cells.
Statistics
The experiment was started with 12 rats for each dose level of rSP-C surfactant, roflumilast, and the combined treatment with rSP-C surfactant and roflumilast. In both untreated control groups we also started with 12 animals. The influence of treatment on the variables PaO2 and PaCO2 was demonstrated by time-effect curves, using means ± SD. Based on the time interval 90 to 180 min of experimental time (equivalent to 30 to 120 min after treatment) the values of PaO2(30-120') were compared for differences between the treatment with rSP-C surfactant, roflumilast, and combined treatment, using both doses of rSP-C surfactant. The results for formation of HM and intra-alveolar accumulation of PMNL were presented in tabular form, using means ± SD and median and range. The primary variables (PaO2[30-120'], PaCO2[30-120'], HM formation, and intra-alveolar accumulation of PMNL) were analyzed based on each dose level of rSP-C surfactant. The additional effects of roflumilast on these variables were compared with the effects of the rSP-C surfactant alone and roflumilast alone by one-sided Wilcoxon tests. An adjustment for the multiple type I error was done according to Bonferroni-Holm (17). In addition, the effects of either treatment with rSP-C surfactant or roflumilast alone on the histopathologic variables were compared with untreated control animals killed 210 min after lavage using the two-sided Wilcoxon test.
| |
RESULTS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Effects on Gas Exchange
After lavage none of the 12 animals in the control group that were ventilated for the whole experimental period (210 min) showed a spontaneous improvement of the PaO2 values or the PaCO2 values (Figure 1). During the 1-h period after the last lavage all groups (treated and untreated control rats) had no major changes in PaO2 and PaCO2 values.
Figure 1 summarizes the effects of treatment with the PDE-4 inhibitor roflumilast. Roflumilast did not show a statistically significant difference compare with untreated control animals. Figure 2 shows the effects of the combined treatment with 25 mg/kg rSP-C surfactant and roflumilast. Combined treatment with roflumilast showed increased PaO2 values compared with rSP-C surfactant alone which was statistically significant (Figure 2A). This could also be seen for the combined treatment with 100 mg/kg rSP-C surfactant and roflumilast (Figure 3). With respect to the time interval 30 to 120 min after treatment (which is equivalent to 90 to 180 min after the last lavage), both doses of rSP-C surfactant restored the decreased PaO2 values when compared with untreated control animals. This effect was statistically significant (Figure 4). Based on both doses of rSP-C surfactant combined treatment with 6.0 mg/kg body weight PDE-4 inhibitor significantly improved the oxygenation compared with treatment with either rSP-C surfactant alone or roflumilast alone (Figure 4).
|
|
|
PaCO2 values showed an almost inverse pattern of responses to the PaO2 values after administration of the different doses of rSP-C surfactant, roflumilast, and the combined treatment with rSP-C surfactant and roflumilast (Figures 1B-3B). There was no additional improvement of the PaCO2 values detectable after combined treatment with rSP-C surfactant and roflumilast (Figures 2B and 3B). There were also no statistically significant differences detectable between untreated control rats, the group treated with roflumilast, the rSP-C surfactant treated groups, and the groups treated with combined rSP-C surfactant and roflumilast with respect to the PaCO2 for the time interval 30 to 120 min after treatment (which is equivalent to 90 to 180 min after the last lavage).
Histopathologic Evaluation
In this investigation two control groups were used for histologic examination. One group of animals was killed 1 h after the last lavage, and the other group of animals was killed after the whole experimental period (210 min after the last lavage). The histopathologic sequelae of ARDS development in this model was shown previously (3). Again rats killed at 60 min developed a statistically significant lower grading with respect to HM formation (Table 1) and intra-alveolar accumulation of PMNL (Table 2) than lavaged and untreated control rats killed at 210 min. The severity grading of HM formation increased from 2.2 (mean) for the 60-min value up to 3.5 (mean) for the 210-min value (Table 1).
|
|
Treatment with both doses of rSP-C surfactant alone reduced the formation of HM compared with the control group
killed at 210 min (Table 1). The PDE-4 inhibitor roflumilast
alone was able to reduce HM formation. This resulted in a statistically significant prevention of further HM formation (Table 1). A comparison based on intratracheal treatment of roflumilast alone (2.8; mean) with the combined treatment of
rSP-C surfactant and the PDE-4 inhibitor (1.5; mean) showed
a statistically significant lower grading than treatment with
roflumilast alone. In addition, the comparison between treatment with 25 mg/kg of rSP-C surfactant (2.0; mean) and the
combined treatment (rSP-C surfactant and PDE-4 inhibitor)
showed also a lower grading (Figure 5) which was statistically significant (p 
0.05, one-sided Wilcoxon test). Based on the dose of 100 mg/kg PL of rSP-C surfactant (1.8; mean) the effects of combined treatment became even more prominent.
Combined treatment (1.2; mean) led to a statistically significant lower grading (Figure 5) for HM formation than treatment with rSP-C surfactant (p 0.05) or with the PDE-4 inhibitor alone (Table 1).
|
The increase in HM formation was accompanied by a statistically significant increase (p 0.01) in the grading for intra-alveolar accumulation of PMNLs from 1.3 (mean) at 60 min up to 2.3 (mean) at 210 min (Table 2). The effects of
rSP-C surfactant or roflumilast and combined treatment with
rSP-C surfactant and roflumilast on intra-alveolar accumulation of PMNL are presented in Table 2. Only treatment with
roflumilast alone was able to prevent further intra-alveolar accumulation of PMNL. This was not influenced by treatment
with both doses of rSP-C surfactant. There was also no effect
of combined treatment detectable when treatment was performed with either of the doses of rSP-C surfactant.
| |
DISCUSSION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
This is the first study that investigated the effects of combined treatment with rSP-C surfactant and a PDE-4 inhibitor. In accordance with our previous investigations (1, 2), monotherapy with rSP-C surfactant was effective in restoring oxygenation and preventing further formation of HM. The PDE-4 inhibitor alone had no influence on oxygenation in this animal model of acute lung injury induced by repetitive lung lavage; however, intratracheal monotherapy with the PDE-4 inhibitor was able to prevent further HM formation and reduced the influx of PMNL into the lungs. Intravenous administration (data not shown) of 6.0 mg/kg body weight of the PDE-4 inhibitor had also no influence on oxygenation and intra-alveolar accumulation of PMNLs, but prevented further HM formation. For better comparison to intratracheal treatment, the PDE-4 inhibitor was given intravenously at 60 min of experimental time. The HM formation was inhibited by intravenous administration to the same degree as with intratracheal treatment with the PDE-4 inhibitor. Therefore, because one of the effects of surfactant is to spread within the lungs, we conclude that a combined treatment can result in a better distribution of the coadministered drug. The main result of this study is that combined treatment with rSP-C surfactant and a PDE-4 inhibitor showed additional effects on restoring oxygenation and preventing further formation of HM. With respect to further accumulation of PMNL, addition of a PDE-4 inhibitor to rSP-C surfactant showed no additional effects in this model when histopathologic grading was used.
Based on this observation, we conclude that there is an additive effect of the PDE-4 inhibitor on the effects of rSP-C surfactant. This effect was seen very rapidly. We believe that this is an advantage of PDE inhibition compared with the anti- inflammatory potential of GCS. Whereas the GCS may act with a certain delay owing to their mechanism of inhibition of, e.g., cytokine release (18), the PDE inhibition may act immediately after administration. PDE inhibition leads to reduced leakage as described by Suttorp and coworkers (19). They investigated the permeability of pulmonary endothelial monolayer and found that PDE-3 and or PDE-4 are involved in the regulation of the permeability of human endothelial monolayers. Suttorp and coworkers speculated that the inhibition of PDE may represent a new therapeutic approach to treat high-permeability pulmonary edema in patients with ARDS. The current findings give more evidence in this direction because the combined treatment with the PDE-4 inhibitor and the rSP-C surfactant resulted in a decreased severity grading with respect to the formation of HM. Blocking of vascular permeability is one major goal in decreasing HM formation because the HM are mainly the result of plasma protein leakage (20). Thus formation of HM is the endpoint of this pathophysiologic sequelae which is detectable in this animal model. In human situations plasma proteins leak into the airways, which then leads to formation of HM, and this may result in a fibroproliferative stage (5, 7). Furthermore, plasma proteins such as albumin or fibrinogen (21) are also able to inhibit the surfactant function. Based on the report of Suttorp and coworkers (19), it can be concluded that the PDE-4 inhibitor has directly influenced the capillary interstitial leakage, resulting in a lower amount of plasma proteins within the alveolar airspace. This can be derived from the reduced HM formation and the better oxygenation seen after combined treatment with the rSP-C surfactant together with the PDE-4 inhibitor in this animal model.
The control rats killed at 60 min (Table 2) had a lower severity grading with respect to infiltration of PMNL than the control rats killed at 210 min (Table 2) after the last lavage. Again, the massive influx of PMNLs was obvious in this animal model. As Ryan and coworkers (22) have shown, activated PMNLs are capable of impairing surfactant function in vitro. This situation can be tested in vivo in the rat lung lavage model. We assume that the intense infiltration of PMNL might have greater influence on the rSP-C surfactant in the absence of the PDE-4 inhibitor. This was obvious when comparing the influence of rSP-C surfactant on improving oxygenation with that of combined treatment (rSP-C surfactant plus PDE-4 inhibitor). In addition, this infiltration of PMNL may contribute to the formation of HM (14) which then hampers the gas exchange leading to reduced oxygenation. However, the once established inflammatory response observed as intra-alveolar accumulation of PMNL was not affected (Table 2) by the rSP-C surfactant. As was shown by Miotla and coworkers (15) PDE-4 inhibition may also attenuate PMNL activation after sequestration. This effect may be also responsible for the additive effects of rSP-C surfactant and the PDE-4 inhibitor in this animal model. Nevertheless, the histologic results are consistent with the idea that treatment with surfactant should be initiated as early as possible to prevent inflammatory responses. The formation of HM may be reversed even by late treatment with the rSP-C surfactant. The infiltration with PMNL or at least the activation of PMNLs may be targeted by a combined treatment with a PDE-4 inhibitor but even longer studies, or studies focusing on the activity of PMNLs, may be desirable to elucidate the effects of such combined treatment.
In conclusion, treatment with rSP-C surfactant resulted in a clear improvement with respect to oxygenation and ameliorating HM formation. We assume that the intense infiltration of PMNLs and the influx of plasma proteins leading to HM can influence the activity of surfactants in this model. The rationale of combined treatment with a PDE-4 inhibitor and rSP-C surfactant is to block the leakage of plasma proteins (19). This may prevent the inactivation of surfactant activity (21) leading to better oxygenation. From the present investigation it is anticipated that combined treatment with an rSP-C surfactant containing a PDE-4 inhibitor can be an effective treatment in patients with ARDS.
| |
Footnotes |
|---|
Correspondence and requests for reprints should be addressed to Dietrich Häfner, Department of Respiratory Pharmacology, Byk Gulden, Post-box 100310, D-78403 Konstanz, Germany. E-mail: dietrich.haefner{at}byk.de
(Received in original form May 5, 1999 and in revised form October 21, 1999).
Acknowledgments: The skilful technical assistance of Ms. S. Kuklinski, Ms. K. Petersen, and Mr. M. Stade is gratefully acknowledged. Furthermore, the authors wish to thank K. Eistetter (pharmaceutical department) and E. Sturm (analytical chemistry) for preparation and analytical confirmation of the rSP-C surfactant and the mixture of the rSP-C surfactant containing the PDE-4 inhibitor.
| |
References |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
1.
Häfner, D.,
P.-G. Germann, and
D. Hauschke.
1998.
Effects of rSP-C
surfactant on oxygenation and histology in a rat-lung-lavage model of
acute lung injury.
Am. J. Respir. Crit. Care Med.
158:
270-278
2. Häfner, D., P.-G. Germann, and D. Hauschke. 1998. Comparison of rSP-C surfactant with natural and synthetic surfactants after late treatment in a rat model of the acute respiratory distress syndrome. Br. J. Pharmacol. 124: 1083-1090 [Medline].
3. Germann, P.-G., and D. Häfner. 1999. A rat model of acute respiratory distress syndrome (ARDS): Part 1. Time dependency of histological and pathological changes. J. Pharmacol. Toxicol. Meth. 40: 101-107 .
4.
Kawano, T.,
S. Mori,
M. Cybulsky,
R. Burger,
A. Ballin,
E. Cutz, and
A. C. Bryan.
1987.
Effect of granulocyte depletion in a ventilated surfactant-depleted lung.
J. Appl. Physiol.
62:
27-33
5.
Hasleton, P. S., and
T. E. Roberts.
1999.
Adult respiratory distress syndrome
an update.
Histopathology
34:
285-294
[Medline].
6. Bernard, G. R., J. M. Luce, C. L. Sprung, J. E. Rinaldo, R. M. Tate, W. J. Sibbald, K. Kariman, S. Higgins, R. Bradley, C. A. Metz, T. R. Harris, and K. L. Brigham. 1987. High dose corticosteroids in patients with the adult respiratory distress syndrome. N. Engl. J. Med. 317: 1565-1570 [Abstract].
7. Repine, J. F.. 1992. Scientific perspectives on adult respiratory distress syndrome. Lancet 339: 466-469 [Medline].
8. Martin, T. R., B. P. Pistorese, L. D. Hudson, and R. J. Maunder. 1991. The function of lung and blood neutrophils in patients with the adult respiratory distress syndrome. Am. Rev. Respir. Dis. 144: 254-262 [Medline].
9.
Meduri, G. U.,
A. S. Headley,
E. Golden,
S. J. Carson,
R. A. Umberger,
T. Kelso, and
E. A. Tolley.
1998.
Effect of prolonged Methylprednisolone therapy in unresolving acute respiratory distress syndrome.
J.A.M.A.
280:
159-165
10. Häfner, D., P.-G. Germann, D. Hauschke, R. Beume, D. Flockerzi, and U. Kilian. 1994. Effects of phosphodiesterase (PDE)-inhibition or steroid treatment on gas exchange and histopathology in an animal model of adult respiratory distress syndrome (ARDS) (abstract). Am. J. Respir. Crit. Care Med. 149: A421 .
11. Teixeira, M., R. Gristwood, N. Cooper, and P. Hellewell. 1997. Phosphodiesterase (PDE)4 inhibitors: anti-inflammatory drugs of the future? TiPS. 18: 164-170 .
12. Turner, C. R., K. M. Esser, and E. B. Wheeldon. 1993. Therapeutic intervention in a rat model of ARDS: IV. Phosphodiesterase IV inhibition. Circ. Shock 39: 237-245 [Medline].
13.
Howell, R. E.,
L. P. Jenkins, and
D. E. Howell.
1995.
Inhibition of lipopolysaccharide-induced pulmonary edema by isozyme-selective phosphodiesterase inhibitors in guinea pigs.
J. Pharmacol. Exp. Ther.
275:
703-709
14.
Rabinovici, R.,
G. Feuerstein,
F. Abdullah,
M. Whiteford,
P. Borboroglu,
E. Sheikh,
D. R. Phillip,
P. Ovadia,
L. Bobroski,
O. Bagasra, and
L. F. Neville.
1996.
Locally produced tumor necrosis factor-alpha mediates interleukin-2-induced lung injury.
Circ. Res.
78:
329-336
15.
Miotla, J. M.,
M. M. Teixeira, and
P. G. Hellewell.
1998.
Suppression of
acute lung injury in mice by an inhibitor of phosphodiesterase type 4.
Am. J. Respir. Cell Mol. Biol.
18:
411-420
16. Häfner, D., P.-G. Germann, and D. Hauschke. 1994. Effects of lung surfactant factor (LSF) treatment on gas exchange and histopathological changes in an animal model of adult respiratory distress syndrome (ARDS): comparison of recombinant LSF with bovine LSF. Pulm. Pharmacol. 7: 319-332 [Medline].
17. Holm, S.. 1979. A simple sequentially rejective multiple test procedure. Scand. J. Statist. 6: 65-70 .
18.
Hawes, A. S.,
C. S. Rock,
C. V. Keogh,
S. F. Lowry, and
S. E. Calvano.
1992.
In vivo effects of the antiglucocorticoid and cytokine responses
to Escherichia coli endotoxin.
Infect. Immun.
60:
2641-2647
19. Suttorp, N., P. Ehreiser, S. Hippenstiel, M. Fuhrmann, M. Krüll, H. Tenor, and C. Schudt. 1996. Hyperpermeability of pulmonary endothelial monolayer: protective effects of phosphodiesterase isoenzymes 3 and 4. Lung 174: 181-194 [Medline].
20. Pratt, P. C., R. T. Vollmer, and J. D. Shelburne. 1979. Pulmonary morphology in a multihospital collaborative extracorporeal membrane project I: Light microscopy. Am. J. Pathol. 95: 191-208 [Abstract].
21. Seeger, W., C. Grube, A. Günther, and R. Schmidt. 1993. Surfactant inhibition by plasma proteins: differential sensitivity of various surfactant preparations. Eur. Respir. J. 6: 971-977 [Abstract].
22. Ryan, S. F., Y. Ghassibi, and D. F. Liau. 1991. Effects of activated polymorphonuclear leukocytes upon pulmonary surfactant in vitro. Am. J. Respir. Cell Mol. Biol. 4: 33-41 .
This article has been cited by other articles:
 |
|
 |
|
  K. Mikawa, K. Nishina, Y. Takao, and H. Obara Intratracheal Application of Recombinant Surfactant Protein-C Surfactant to Rabbits Attenuates Acute Lung Injury Induced by Intratracheal Acidified Infant Formula Anesth. Analg., May 1, 2004; 98(5): 1273 - 1279. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P.R.M. Rocco, D.P. Momesso, R.C. Figueira, H.C. Ferreira, R.A. Cadete, A. Legora-Machado, V.L.G. Koatz, L.M. Lima, E.J. Barreiro, and W.A. Zin Therapeutic potential of a new phosphodiesterase inhibitor in acute lung injury Eur. Respir. J., July 1, 2003; 22(1): 20 - 27. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. TOBIN Pediatrics, Surfactant, and Cystic Fibrosis in AJRCCM 2000 Am. J. Respir. Crit. Care Med., November 1, 2001; 164(9): 1581 - 1594. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Proc. Am. Thorac. Soc. | Am. J. Respir. Cell Mol. Biol. |