Deneysel Kafa Travması Sonrası Gelişen Akciğer Hasarında, Eritropoetin ve Metilprednizolonun Koruyucu Etkisi
Türk Göğüs Kalp Damar Cerrahisi Dergisi 2006;14(2):122-127
ERKAN YILDIRIM, KANAT ÖZIŞIK, PINAR ÖZIŞIK, MUSTAFA EMİR, ENGİN YILDIRIM, KAMER KILINÇ
Amaç: Sıçanlarda kafa travması sonrası gelişen akciğer hasarında, eritropoetin ve metilprednizolonun akciğer lipid peroksidasyonu ve miyeloperoksidaz seviyesine etkileri araştırıldı. Çalışma planı: Yetmiş altı adet 180-220 gr ağırlığında, dişi Wistar-Albino sıçan 10 gruba ayrıldı. Kafa travması oluşturmak için ağırlık düşürme yöntemi kullanıldı. Örnekler, hasar oluşturulduktan 24 saat sonra sol akciğerden alındı. Akciğer doku miyeloperoksidaz aktivitesi ve lipid peroksidasyon seviyeleri ölçüldü. Lipid peroksidasyon seviyelerindeki ve miyeloperoksidaz aktivitesindeki gruplar arası farklılıkları analiz etmek için tek yönlü varyans analizi (ANOVA) kullanıldı. Daha sonra, post-hoc karşılaştırma yapıldı. Bulgular: Öncelikle, şiddetli travma grubunda lipid peroksidasyon seviyesi ve miyeloperoksidaz aktivitesi önemli ölçüde yüksek bulundu (p<0.05). İkincil olarak, metilprednizolon, orta travma grubunda lipid peroksidasyon seviyesini anlamlı ölçüde düşürüldü (p<0.05), buna karşın şiddetli travma grubunda eritropoietin daha üstündü (p<0.05). Son olarak, eritropoietin her iki travma grubunda da metilprednizolona göre daha etkin bir şekilde miyeloperoksidaz aktivitesini azalttı (p<0.05). Sonuç:Eritropoietin, akciğer dokusunu polimorfonükleer lökosit infiltrasyonuna ve oksidatif hasara karşı etkili bir şekilde korumaktadır. Uygun donör akciğeri ve organ alıcılarında daha iyi sağkalım sağlamak için gerekli klinik çalışmalara yeterli veri transferi yapabilmek amacıyla, kafa travması/ ölümü modelinde akciğerin tedavisini daha da açıklığa kavuşturacak ileri çalışmalara ihtiyaç vardır.
Background:
The effects of erythropoietin and methylprednisolone
on pulmonary lipid peroxidation and myeloperoxidase activity in lung injury following experimental head trauma in rats.
Study design:
Seventy-six female Wistar-Albino rats, weighing 180-220 gr, were evenly allocated into ten groups. A weight-drop method was used to achieve head trauma. Samples were obtained from the left lung 24-h after the injury. Lung tissue-associated myeloperoxidase activity and lipid peroxidation levels were measured. A one-way analysis of variance (ANOVA) was applied to test the differences in the lipid peroxidation levels and myeloperoxidase activities between groups. Then, post-hoc comparison was performed.
Results:
Firstly, head trauma substantially elevated lipid peroxidation and myeloperoxidase activity in lung tissue in the severe trauma group (p<0.05). Secondly, methylprednisolone significantly decreased lipid peroxidation in trauma-moderate group (p<0.05), whereas in trauma-severe group erythropoietin was superior (p<0.05). Thirdly, erythropoietin was more effective than methylprednisolone in decreasing myeloperoxidase activity in both trauma groups (p<0.05).
Conclusion:
Erythropoietin efficiently protected lung tissue against polymorphonuclear leukocytes infiltration and oxidative damage. Further studies are warranted to better clarify the management of lung injury in brain injury/death model to transfer sufficient data to clinical studies providing
suitable donor lungs and better survival rates in recipients.
Key words:
Brain injury/complications/physiopathology; lipid peroxidation; lung/metabolism/pathology; rats; respiratory distress syndrome, adult/etiology /pathology.
Brain injured patients have an increased risk of
extrcerebral organ failure, mainly pulmonary dysfunction.
[
1]
Respiratory failure is a common finding in the
intensive care unit (ICU) and in the management of
complex cases in the operating room.
[2] Since approximately
one-third of these patients suffer respiratory
problems, the efficient management of respiratory failure
in patients with head trauma in ICU has vital importance
in reducing organ failure.
[3]
Direct pulmonary trauma following central nervous
system injury requires immediate treatment to prevent
further compromise of the patient’s condition.
[4]
Treatment with free radical scavengers and antioxidants
is a rational therapeutic strategy for stroke or central
nervous system trauma.
[5] In the present study, both erythropoietin
and methylprednisolone were used to assess
the probable free radical-scavenging effect and the antiinflammatory
effect against induced head injury.
We have recently showed that experimental head
injury resulted in ultrastructural lung tissue injury.
[6] The
aim of the current study, first, was to determine whether
any alteration in the levels of lipid peroxidation and
myeloperoxidase activity existed following traumatic
brain injury. The second aim was to verify to what
extent erythropoietin and methylprednisolone sodium
succinate decrease lung thiobarbituric acid reactive substances
and the severity of polymorphonuclear granulocyte
infiltration in lung tissue.
MATERIALS AND METHODS
The Institutional Review Board for the care of animal
subjects approved the study. The care and handling of
the animals were in accord with the “Principles of
Laboratory animal care” (NIH publication No. 86-23,
revised 1985).
Experimental groups.
Seventy-six female Wistar-
Albino rats, weighing 180-220 g, were randomly allocated
into 10 experimental groups. Tissue samples were
obtained 24 hours after induced brain trauma in all
groups, except the control group. Impact of 200 g-cm
brain injuries was produced in groups 3, 5, 6, and 9.
Additionally, impact of 300 g-cm brain injuries was
produced in groups 4, 7, 8 and 10.
Group 1 (C): Control group (n=8): Tissue samples
were obtained immediately after thoracotomy and neither
head trauma was inducted nor craniotomy was performed.
Group 2 (S): Sham-operated group (n=8): Scalp was
closed after craniotomy and no trauma was stimulated.
Group 3 (Tm): Trauma-moderate group (n=8).
Group 4 (Ts): Trauma-severe group (n=8).
Group 5 (EPOtm): Erythropoietin (trauma-moderate)
group (n=8): Erythropoietin was administered
intraperitoneally by bolus injections of 1000 IU/rat, at
once post trauma.
Group 6 (MPSStm): Methylprednisolone sodium
succinate (trauma-moderate) group (n=8):
Methylprednisolone sodium succinate was given
intraperitoneally by bolus injections of 30 mg/kg,
directly after achieving injury.
Group 7 (EPOts): Erythropoietin (trauma-severe)
group (n=8): Erythropoietin was administered intraperitoneally
by bolus injections of 1000 IU/rat, instantaneously
post trauma.
Group 8 (MPSSts): Methylprednisolone sodium succinate
(trauma-severe) group (n=8): Methylprednisolone
sodium succinate was given intraperitoneally by bolus
injections of 30 mg/kg, immediately after accomplishing
trauma.
Fig. 1.
Lung tissue lipid peroxide levels in all study groups
expressed as nmol /g-wet tissue, mean ± SD. *: Take note that the
severe trauma group has the highest lipid peroxidation level compared
to that of control groups and the moderate trauma group. In
addition, the methylprednisolone sodium succinate is more effective
in lowering lipid peroxidation level in the moderate trauma
group than the severe trauma group. Moreover, erythropoietin is
more effective in decreasing the level of lipid peroxidation in the
severe trauma group than the moderate trauma group.
C: Control group; EPO: Erythropoietin, EPOtm: Erythropoietin (traumamoderate)
group; EPOts: Erythropoietin (trauma-severe) group; LPO: Lipid
peroxidation; MPSS: Methylprednisolone sodium succinate; MPSStm:
Methylprednisolone (trauma-moderate) group; MPSSts: Methylprednisolone
(trauma-severe) group. *: Significant results; S: Sham-operated group;
SD; Standard deviation; TBI: Traumatic brain injury; Tm: Trauma-moderate
group; Ts: Trauma-severe group; Vm: Vehicle-moderate group; Vs:
Vehicle-severe group.
90
*
*
*
80
70
60
50
40
30
20
N= 8
C
S Ts MPSStm Vs
Groups
MPSSts
Tm EPOtm EPOts Vm
8 8 8 8 8 7 8 6 6
LPO activity (nmol/g wet tissue)
Y›ld›r›m ve ark. Deneysel kafa travmas› sonras› geliflen akci¤er hasar›nda, eritropoetin ve metilprednizolonun etkisi
Group 9 (Vm): Vehicle-moderate group (n=6):
Saline (0.9%) was given intraperitoneally by bolus
injections of 0.1 ml/rat, directly after injury.
Group 10 (Vs): Vehicle-severe group (n=6): Saline
(0.9%) was administered intraperitoneally by bolus
injections of 0.1 ml/rat, immediately following injury.
Surgical procedure.
The surgical procedure was performed
under general anaesthesia induced by intramuscular
xylasine (Bayer, Istanbul, Turkey) (10 mg/kg) and
ketamine hydrochloride (Parke Davis, Istanbul, Turkey)
(60 mg/kg) injections. Rats were placed in prone position.
Following midline longitudinal incision, scalp was
dissected over cranium and retracted laterally. Coronal
and sagittal sinuses were observed. Right frontoparietal
craniectomies were carried out laterally to the sagittal
sinus by dental drill system. The dura was exposed and
left intact. Trauma of 200 g-cm and 300 g-cm impacts
were produced by the method of Allen
[7] in different
groups, respectively. Rats were injured by two stainless
steel rods (5 mm diameter, one weighing 200 g and the
other 300 g). Weight dropped vertically through a calibrated
tube from a height of 10 cm onto the exposed
dura. Scalp was sutured with silk sutures. Body temperature
was continuously monitored during the whole
procedure with a rectal thermometer and maintained at
37 °C using a heating pad and an overhead lamp. Rats
were neither intubated nor ventilated between brain
damage and lung sampling. After returning to the cages,
the rats were allowed food and water ad libitum.
Obtaining samples from lung parenchyma.
Twentyfour
hours after traumatic brain injury, animals in all
groups, except the control group, were re-anaesthetized
with the combination of ketamine and xylasine. Rats
were placed supine on the operating table. Midline sternotomy
and left thoracotomy were performed. The systemic
circulation was perfused with 0.9% NaCl. Then,
rats were killed with decapitation under general anaesthesia.
Samples for lipid peroxidation level and
myeloperoxidase activity were simultaneously obtained
from the left pulmonary lobes. Lung samples were collected
in randomly numbered containers and given to
blinded observers. After evaluating the numbered tissues,
results were collected in appropriate group lists.
Lipid peroxidation assay.
The samples were thoroughly
cleansed of blood and were immediately frozen and
stored in a -70 °C freezer for assays of malondialdehyde.
The levels of lipid peroxidation were measured as
thiobarbituric acid-reactive material. The level of lipid
peroxidation in the lung parenchyma was determined
using the method of Mihara and Uchiyama.
[8] Tissues
were homogenized in 10 volumes (w/v) of cold phosphate
buffer (pH 7.4). Half a millilitre of homogenate
was mixed with 3 ml 1% H
3PO4. After the addition of
1 ml 0.67% thiobarbituric acid, the mixture was heated
in boiling water for 45 minutes. The colour was extracted
into n-butanol, and the absorption at 532 nm was
measured. Using tetramethoxypropane as the standard,
tissue lipid peroxidation levels were calculated as
nanomole per gram of wet tissue.
Determination of lung tissue-associated myeloperoxidase
activity.
Lung tissue-associated myeloperoxidase
activity was measured by the modified method of
Suzuki.
[9] Frozen tissue samples were weighed and
homogenized in 1:10 (w/v) ice-cold 10 mM TRIS
Table 1. Lung tissue lipid peroxide levels in each group following graded traumatic brain injury
Groups n Mean±SD
p-value
(nmol/g-wet tissue)
Control group (C) 8 40.312±10.814 –
Sham-operated group (S) 8 40.237±10.622 –
Trauma-moderate group (Tm) 8 52.605±10.088 NS
Ts* 8 61.753±12.327 <0.05
Erythropoietin (trauma-moderate) group (EPOtm) 8 39.310±6.308 NS
MPSStm** 8 35.236±3278 <0.05
EPOts*** 8 44.600±3.428 <0.05
Methylprednisolone (trauma-severe) group (MPSSts) 8 50.531±14.005 NS
Vehicle-moderate group (Vm) 6 52.985±9.808 –
Vehicle-severe group (Vs) 6 62.325±9.515 –
Total
76 47.519±12.817 –
SD: Standard deviation, NS: Non-significant. One-way analysis of variance (ANOVA) was applied to test for differences in lipid peroxidation levels between
groups. Then, post-hoc comparison was performed. The differences were considered significant at a
p value <.05. Ts*: Severe trauma group has the highest lipid
peroxidation level compared to that of control groups and the moderate trauma group. MPSStm**: Methylprednisolone sodium succinate is more effective in lowering
lipid peroxidation level in the moderate trauma group than the severe trauma group. EPOts***: Erythropoietin is more effective in decreasing lipid peroxidation
level in the severe trauma group than the moderate trauma group. EPO: Erythropoietin; EPOts: Erythropoietin (trauma-severe) group; MPSS:
Methylprednisolone sodium succinate; MPSStm: Methylprednisolone (trauma-moderate) group; Ts: Trauma-severe group;
124
Turkish J Thorac Cardiovasc Surg 2006;14(2):122-127
Y›ld›r›m et al. Effects of erythropoietin and methylprednisolone on lung damage after experimental head injury
Türk Gö¤üs Kalp Damar Cer Derg 2006;14(2):122-127
125
Y›ld›r›m ve ark. Deneysel kafa travmas› sonras› geliflen akci¤er hasar›nda, eritropoetin ve metilprednizolonun etkisi
buffer (pH: 7.4) by the use of a dounce homogenizer.
The homogenate (1 ml) was centrifuged at 10000xg for
five times, and the pellet was re-suspended in equal volumes
(1 mL) of 50 mM phosphate buffer (pH: 6.0) containing
0.5% Hexadecyltrimethyl ammonium bromide
(HETAB) and 5 mM EDTA. The resulting suspension
was centrifuged at 5000xg for 2 min and the supernatant
was used for the activity measurement.
Myeloperoxidase activity was measured in a final
volume of 1 ml containing 80 mM phosphate buffer
(pH: 5.4), 0.5% HETAB, 1.6 mM synthetic substrate
tetramethylbenzidine (TMB) initially dissolved in
dimethylformamide, 2 mM H
2O2 and the sample. The
reaction was started at 37 °C by the addition of H
2O2.
Recording the increase of absorbance at 655 nm followed
the initial rate of myeloperoxidase-catalyzed
TMB oxidation. Myeloperoxidase activity was
expressed as the amount of the enzyme producing one
absorbance change per minute under assay conditions.
Tissue-associated myeloperoxidase activity was calculated
as units per gram of wet tissue.
Statistical method.
All the data collected from the
experiment were coded, recorded, and analyzed by
using SPSS 11.5 statistical software package for
Windows. The one-way analysis of variance (ANOVA)
was used to compare lipid peroxidation levels and the
activity of myeloperoxidase. Tukey’s honestly significant
difference (Tukey-HSD) test was applied to determine
the statistically significant differences between
the groups, as post-hoc. The differences were considered
significant at a p value <0.05.
RESULTS
The results below were recorded:
Lipid peroxide levels are shown in Fig. 1 and Table 1:
Only severe trauma significantly increased lipid peroxides
levels (p<0.05), compared to control and sham
groups Additionally, methylprednisolone sodium succinate
caused significant decline in lipid peroxidation level
in the moderate trauma group similar to the moderate
trauma vehicle and the erythropoietin moderate trauma
groups (p<0.05). Moreover, erythropoietin caused significant
decreases in lipid peroxide levels in severe trauma
group compared to methylprednisolone severe trauma
and severe trauma vehicle groups (p<0.05).
Lung tissue-associated myeloperoxidase activities
are shown in Fig. 2 and Table 2:
Only severe trauma caused significant increases in
myeloperoxidase activities (p<0.05). compared to the
control and sham groups. Additionally, erythropoietin
caused a significant decline in myeloperoxidase activities
in both moderate and severe trauma groups. similar to the
methylprednisolone moderate trauma, methylprednisolone
severe trauma and the vehicle groups (p<0.05).
DISCUSSION
Respiratory failure is a common finding in the intensive
care unit and in the management of complex cases in the
operating room.
[2] The development of lung injury is a
critical independent factor affecting mortality in patients
suffering traumatic brain injury and is associated with a
worse long-term neurologic outcome in survivors.
[10]
As approximately one-third of these paitients suffer
respiratory problems, the efficient management of respiratory
failure in patients with head trauma in ICU has
vital importance
[11] in reducing organ failure[3] and providing
higher graft survival rates under conditions of
donor shortage.
[12]
Blunt traumatic brain injury represents one of the
most important causes of death and disability in modern
Fig. 2.
Lung tissue myeloperoxidase activities in all study groups
expressed as IU/g-wet tissue, mean±SD. *Take note that the
severe trauma group has the highest myeloperoxidase activity
compared to control, trauma moderate and treatment groups. In
addition, erythropoietin is more effective in lowering myeloperoxidase
activity in both moderate and severe trauma groups than
methylprednisolone sodium succinate.
C: Control group; EPO: Erythropoietin; EPOtm: Erythropoietin (trauma-moderate)
group; EPOts: Erythropoietin (trauma-severe) group; MPO:
Myeloperoxidase; MPSS: Methylprednisolone sodium succinate; MPSStm:
Methylprednisolone (trauma-moderate) group; MPSSts: Methylprednisolone
(trauma-severe) group; *: Significant results; S: Sham-operated group; SD:
Standard deviation; TBI: Traumatic brain injury; Tm: Trauma-moderate group;
Ts: Trauma-severe group; Vm: Vehicle-moderate group; Vs: Vehicle-severe
group.
700
*
*
*
600
500
400
300
200
100
0
N= 8
C
S Ts MPSStm Vs
Groups
MPSSts
Tm EPOtm EPOts Vm
8 8 8 8 8 8 8 6 6
MPO activity (IU/g tissue weight)
society.
[13] Acute lung injury is common in comatose
victims with an isolated traumatic brain injury and is
associated with an increased risk of death or a severe
neurological morbidity.
[14]
Cerebral hypoxia or ischemia and head trauma or
seizures may all lead to severe neurogenic pulmonary
injury.
[15] The relative contribution of hydrostatic and
permeability mechanisms to the development of human
neurogenic pulmonary oedema had been identified.
[5] In
addition, elevated free radical production after central
nervous system injury may also contribute to the formation
of neurogenic pulmonary oedema.
[16] It seems
that neurogenic pulmonary injury is probably the result
of a combination of all the pathogenetic mechanisms
mentioned above.
Regarding lipid peroxidation, it is reported in detail
in the literature in this field that oxygen radical formation
after trauma results in cell membrane lipid peroxidation
causing membrane lyses.
[17] Additionally, it was
reported that polymorphonuclear granulocyte infiltration
also takes place after injury, which is determined
by myeloperoxidase activity. Moreover, in some
reports, it was clearly declared that the myeloperoxidase
activity in lung tissue of animals after blunt chest
trauma significantly increased.
[18]
A previous study from our laboratory has shown that
absolute ultrastructural damage took place at the pneumocyte
type II cells. Additionally significant increase
has been detected in lipid peroxidation level in lung tissue
after traumatic brain injury.
[6] In the current study,
we investigated whether the levels of lipid peroxidation
and myeloperoxidase activity following brain injury,
could be diminished by erythropoietin and methylprednisolone
sodium succinate. Neutrophil activation as
assessed by myeloperoxidase activity in whole lung tissue,
as well as lipid peroxidation, has significantly
increased in the current weight-drop injury model compared
to that of the control and sham-operated animals.
In a very specialized field dealing with lung transplantation,
the paucity of suitable lung donors and the
high early mortality as the result of primary graft failure
remain major challenges.
[19] It should be kept in mind
that almost half of the organ donors have deceased from
head trauma,
[20] which mostly results in type II cell dysfunction.[
21]
As a result, it should be emphasized that it
is of paramount importance to preserve donor organs as
much as possible to achieve higher graft survival rates
in the world’s organ shortage.
Morbidity and mortality from lung failure will have
lesser impact on patients as physicians treat the consequences
of organ failure in the ICU.
[3]
With regard to treatment, antioxidants may hypothetically
act to avert propagation of tissue damage and
improve both the survival and neurological outcome.
Treatment with free radical scavengers and antioxidants
is a rational therapeutic strategy for stroke or central
nervous system trauma.
[5]
Erythropoietin and methylprednisolone sodium succinate
were used in order to avoid generation of tissue
damage in the current head trauma model. Recent studies
have revealed the significance of the non-erythropoietic
effects of erythropoietin, mainly its free radical
scavenging effect and holding back lipid peroxidation,
hence diminishing oxidant injury.
[22,23]
Table 2. Lung tissue myeloperoxidase activities in each group following graded traumatic brain injury
Groups n Mean±SD
p-value
(IU/g tissue weight)
Control group (C) 8 190.187±129.445 –
Sham-operated group (S) 8 189.500±128.351 –
Trauma-moderate group (Tm) 8 358.125±95.731 NS
Ts* 8 419.062±112.355 <0.05
EPOtm** 8 113.187±27.822 <0.05
Methylprednisolone (trauma-moderate) group (MPSStm) 8 241.625±119.418 NS
EPOts*** 8 233.437±97.194 <0.05
Methylprednisolone (trauma-severe) group (MPSSts) 8 264.000±98.788 NS
Vehicle-moderate group (Vm) 6 420.250±61.625 –
Vehicle-severe group (Vs) 6 461.083±129.543 –
Total
76 281.066±147.411 –
SD: Standard Deviation, NS: Non-significant. The one-way analysis of variance (ANOVA) was applied to test for differences in the myeloperoxidase activity
between groups. Then, post-hoc comparison was performed. The differences were considered significant at a
p value <.05. Ts*: Severe trauma group has the highest
myeloperoxidase activity compared to that of the control groups, trauma moderate group and the treatment groups. In addition, erythropoietin is more effective
in lowering myeloperoxidase activity in both moderate (EPOtm**) and severe (EPOts***) trauma groups than methylprednisolone sodium succinate in both
groups (MPSStm and MPSSts). EPO: Erythropoietin, EPOtm: Erythropoietin (trauma-moderate) group; EPOts: Erythropoietin (trauma-severe) group; MPO:
Myeloperoxidase; MPSS: Methylprednisolone sodium succinate; Ts: Trauma-severe group.
126
Turkish J Thorac Cardiovasc Surg 2006;14(2):122-127
Y›ld›r›m et al. Effects of erythropoietin and methylprednisolone on lung damage after experimental head injury
Türk Gö¤üs Kalp Damar Cer Derg 2006;14(2):122-127
127
Y›ld›r›m ve ark. Deneysel kafa travmas› sonras› geliflen akci¤er hasar›nda, eritropoetin ve metilprednizolonun etkisi
Glucocorticoids are the most potent and widely used
anti-inflammatory agents. Methylprednisolone sodium
succinate has been shown to have protective effect
against traumatic spinal cord injury.
[24] It was shown in
another study that methylprednisolone has biphasic
effect on alveolar capillary integrity after elevated cerebrospinal
fluid pressure.
[13] The features mentioned
above were the main criteria for the selection of these
agents used in this study.
In the current study, it was clearly shown that mostly
erythropoietin was superior to the methylprednisolone
in lowering both the lipid peroxidation levels
and the myeloperoxidase activity in the studied trauma
groups.
In conclusion, inhibitions of lipid peroxidation and
myeloperoxidase activity by administration of erythropoietin
could be a possible approach in the treatment or
the prevention of lung injury in the patients with head
trauma. This point might have a vital importance in a
critical procedure like lung transplantation. An understanding
of the mechanism of donor lung injury could
lead to the development of new treatment strategies for
the donor to reduce lung injury, increase the number of
donors with acceptable lungs, and improve the results
of lung transplantation.
Exact therapeutic agents and procedures have to be
elucidated further to achieve more successful survival
rates and to reduce graft failure rates in the recipients
who have been transplanted the donor lungs harvested
from patients who have suffered brain trauma.
In addition, this study highlights the need for continued
efforts to identify optimal management strategies
for patients with severe brain injury admitted to ICUs.
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Beğenin 
Yazan Uzman
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kafa travması, akciğer hastalığı, akut hasar, eritropoietin, metilprednizolon, koruyucu etki, lipid peroksidasyon, miyeloperoksidaz, travma, donor akciğeri, verici akciğeri, oksidatif hasar, organ alıcı
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