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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
ARDS mechanisms
Toxins Overdistention
(VILI) Microorganisms
Inflammation
Coagulation
Cell death ↑Vascular
permeability ↓Lung edema
clearance
Bastarache and Blackwell, Dis Model Mech. 2009
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)
Cytoprotective strategies in ARDS
http://bbs.bioon.com
Gelsolin and apoptosis
Gsn
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
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
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
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
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
Kotanidou et al., Vascular Pharmacol 2006
inhaled APC in intratracheal LPS model: histology
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
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
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
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
LVt-30min
HVt-NS HVt-APC
LVt-4 hr
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
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
LVt 30min
HVt-NS
HVt-APC
Plasma membrane failure in ARDS
Gajic O, et al. Am. J. Respir. Crit. Care Med. 2003
Cell membrane barrier restoration
Intravenous nanoparticles: Triglycerides
lecithine
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
* #
#
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
Antiinflammatory agents: etanercept
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
* #
*
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
* #
*
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
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
Stylianos Orfanos Anastasia Kotanidou Nikolaos Maniatis Matina Kardara Eleftheria Letsiou Aggeliki Sfika Charis Roussos Apostolos Armaganidis
THORAXTHORAX
Vaggelis Harokopos Artemis Thanassopoulou Vassilis Aidinis
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
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
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
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
HVt-NS HVt-APC LVt-30min LVt-4hr
PaO
2 (To
rr)
0
20
40
60
80
100
120
140
160
*
Arterial pO2
0
4
8
12
16
PMN
/μL
BA
L
*
LVt-30min HVt-NS LVt-4 hr HVt-APC
BAL neutrophils
Barrier-protective agents in ARDS Angiopoietin 1
Mei et al., PLoS Med 2007
Mei et al., PLoS Med 2007
Oxidized phospholipids and barrier protection
Nonas et al., AJRCCM 2006
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