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