vili - vali - ards: medical treatment approaches · vili - vali - ards: medical treatment...
TRANSCRIPT
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VILI - VALI - ARDS: medical treatment approaches
Nikolaos Maniatis, MD 2nd Dept. Critical Care
University of Athens Medical School “THORAX” Research Ctr for Intensive
and Emergency Thoracic Medicine
THORAXTHORAX
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ARDS mechanisms
Toxins Overdistention
(VILI) Microorganisms
Inflammation
Coagulation
Cell death ↑Vascular
permeability ↓Lung edema
clearance
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Bastarache and Blackwell, Dis Model Mech. 2009
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Experimental approaches
• Cytoprotection (APC) • Permability (angiopoietin-1, ox-P-lipids,
iloprost) • Edema clearance (β2-διεγέρτες, ΤΝF) • Inflammation (anti-TNF, IL-1receptor
antagonist) • Coagulation (thrombomodulin) • Antioxidants (Desferrioxamine, catalase)
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Cytoprotective strategies in ARDS
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http://bbs.bioon.com
Gelsolin and apoptosis
Gsn
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Full length Gsn (82 Kd)
Cleaved Gsn 39 Kd 45 Kd
actin
8mL/Kg 25mL/Kg
Gelsolin activation in VILI
Maniatis et al., AJRCMB 2009
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Apoptosis is attenuated in GSN-/- mice upon VILI
DNAse- treated
sections
TUNEL-positive cells/hpf
* WT GSN-/-
Baseline 25mL/Kg 4 hr
40
80
120
160
0
Maniatis et al., AJRCMB 2009
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Microvascular permeability in GSN-/-
BAL total protein (μg/μL)
* WT
Baseline 25mL/Kg 4 hr
GSN-/-
0
100
200
300
400
500
Maniatis et al., AJRCMB 2009
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NF-κΒ
aPC
Adhesion molecules
iNOS
Apoptosis
Barrier protection
PC PAR-1
TM
Thrombin PMN
Endothelial Cell
EPCR
Actin cytoskeleton
APC and endothelial protection
Orfanos et al., "Update in Intensive Care and Emergency Medicine" 2008
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inhaled APC in intratracheal LPS model: BAL
BALF Cells x 106/ml/
NS 0
1
2
3
4
5
Total Cells
Neutrophils
LPS
* *
APC + LPS
* * # #
Kotanidou et al., Vascular Pharmacol 2006
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Kotanidou et al., Vascular Pharmacol 2006
inhaled APC in intratracheal LPS model: histology
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actin
VCAM-1
APC+ NS LPS LPS
NS LPS APC+ LPS
0
0.5
1
1.5
2
VCAM-1/actin
*
Kotanidou et al., Vascular Pharmacol 2006
inhaled APC in intratracheal LPS model: VCAM
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Inhaled APC in VILI: experimental design
• High tidal volume (HVt): 25mL/Kg • Low tidal volume (LVt): 8 mL/Kg • Inhaled APC: 12.5μg x4 doses
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Experimental design
C57 Bl6 mice
HVt-NS-4hr
HVt-APC-4 hr
LVt-NS-4hr
LVt-NS-30min
Lung elastance ABG BAL
Frozen lung tissue
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Time (hours)
Lung
ela
stan
ce c
oeff
H
10
20
40
Baseline 1 2 3 4 0
30
50
60
Baseline 1 2 3 4
LVt-4 hr
- NS HVt - NS
* * *
- APC - APC HVt
APC preserves lung elastance
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LVt-30min
HVt-NS HVt-APC
LVt-4 hr
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BA
L to
tal p
rote
in (m
g/m
L)
1.2
HVt-APC LVt-30min HVt-NS LVt-4 hr
1.0
0.8
0.6
0.4
0.2
0
*
Ολική πρωτεΐνη BAL
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p-ERK1/2
tubulin
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7
Arb
itrar
y U
nits
*
HVt-APC LVt-30min HVt-NS
ERK activation
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LVt 30min
HVt-NS
HVt-APC
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Plasma membrane failure in ARDS
Gajic O, et al. Am. J. Respir. Crit. Care Med. 2003
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Cell membrane barrier restoration
Intravenous nanoparticles: Triglycerides
lecithine
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tota
l cel
ls/μ
L B
AL
0
50
100
150
200
250
NLC NS NS HCL NLC HCL
NLC in acid aspiration: BAL
* #
#
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NLC in acid aspiration: lung elastance H
*
0
10
20
30
40
50
60
Lung
ela
stan
ce H
NLC NS NS HCL NLC HCL
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Antiinflammatory agents: etanercept
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Etanercept in acid aspiration: lung mechanics
area
of P
V cu
rve
NS-NS HCl-NS HCl-etn 0
2
4
6
8
NS-etn
* #
*
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Tota
l BA
L pr
otei
n μg
/μL
0.0
0.5
1.0
1.5
NS-NS HCl-NS HCl-etn NS-etn
Etanercept in acid aspiration: vascular permeability
* #
*
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0
100
200
300
400 To
tal c
ells
/μL
in B
AL
NS-NS HCl-NS HCl-etn NS-etn
* #
*
Etanercept in acid aspiration: BAL cells
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Conclusion
• Research on ARDS pathogenesis has led to successful treatment strategies on the experimental level
• There are several experimental treatments with potential clinical applicability in ARDS
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Stylianos Orfanos Anastasia Kotanidou Nikolaos Maniatis Matina Kardara Eleftheria Letsiou Aggeliki Sfika Charis Roussos Apostolos Armaganidis
THORAXTHORAX
Vaggelis Harokopos Artemis Thanassopoulou Vassilis Aidinis
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Anti-adhesive, anti-coagulant, fibrinolytic NO, PGI2, AT II,
TxA2, ET-1
O2, CO2
Alveolus
RBC PMN
Plt
Lymphatic drainage
caveolae Aquaporins
Vascular tone
Permeability
Gas exchange
VSMC
Vessel
H2O
Macromolecules
NO, PGI2
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PMN adhesion and migration
, AT II, TxA2, ET-1
O2, CO2
Alveolar edema
RBC
PMN
Plt-PMN complex
Lymphatic drainage
caveolae Aquaporins
vasoconstriction
Clotting
Hyaline membrane
Cytokines Proteolytic
enzymes Thromboxane A2
Increased permeability
Hypoxemia
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Copyright ©2008 American Physiological Society
Le, A. et al. J Appl Physiol 105: 1282-1290 2008; doi:10.1152/japplphysiol.90689.2008
Απόπτωση και VILI
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Copyright ©2008 American Physiological Society
Le, A. et al. J Appl Physiol 105: 1282-1290 2008; doi:10.1152/japplphysiol.90689.2008
Fig. 7. Caspase inhibition prevented ventilation-induced pulmonary capillary leakage
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HVt-NS HVt-APC LVt-30min LVt-4hr
PaO
2 (To
rr)
0
20
40
60
80
100
120
140
160
*
Arterial pO2
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0
4
8
12
16
PMN
/μL
BA
L
*
LVt-30min HVt-NS LVt-4 hr HVt-APC
BAL neutrophils
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Barrier-protective agents in ARDS Angiopoietin 1
Mei et al., PLoS Med 2007
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Mei et al., PLoS Med 2007
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Oxidized phospholipids and barrier protection
Nonas et al., AJRCCM 2006
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0
500
1000
1500
2000
2500
0 lung elastance H
Eva
ns b
lue
lung
acc
umul
atio
n
20 40 60 80 100 120
25/Kg 3 hr 25/Kg 1 hr 7/kg 1 hr
r2=0,92
0.2
0.4
0.6
0.8
Lung
vol
ume
abov
e FR
C (m
l)
0
20
40
60
80
100
Ela
stan
ce H
(cm
H2O
/ml)
7ml/kg 1 hr
25ml/Kg 1 hr
25/Kg 3 hr
*
A
B
0 5 10 15 20 25 30 Paw (cmH2O)
25/Kg 3 hr baseline
C
0
400
800
1200
1600
2000
EB
D
# EBD
H