What you need to know about the endothelium

(and why is it important for my patient?)

Danny McAuley @dfmcauley

Royal Victoria Hospital and Queen’s University of BelfastSMACC Dublin

June 2016

• Endothelial injury and the pathogenesis of ARDS• Improving endothelial function

What you need to know about the endothelium

Giving a talk on the endothelium at SMACC

#Ilovetheendothelium

Giving a talk on the endothelium at SMACC

Giving a talk on the endothelium at SMACC

Giving a talk on the endothelium at SMACC

Giving a talk on the endothelium at SMACC

Cecilia O’KaneEndothelial dysfunction and ARDS

Gap

A

B

Endothelial Paracellular Gap Formation In Vivo

Scanning EM

Alveolar oedema

Respiratory failure

Endothelium

Epithelium

Vessellumen

Alveoli

LPS

LPS

vWF/Ang-2

RAGE

SP-D

Cytokines

Proteases

Glycocalyx

Actin/Myosin contractionBarrier

dysfunctionBarrier integrity

Cellular adhesion

Integrin

Adherens junction

Cadherin

Focal adhesion assembly/ disassembly

Integrin

Occludin

ZO-1

catenincatenin

Ca2+Actin stress fibers

Myosin

MLCKMLCK

Cortactin

Rho Kinase

Regulation of lung endothelial cell barrier function

Thrombin

MLCphosphatase

X

RacRho

MLCK P60src

GIT1PAX

FAKTalinVinculin

Jacobson et al. AJRCMB 2004;30:662

Barrier disruption Barrier protection

Macrovascular obstruction in ARDS:detection with pulmonary angiography

Green et al ARRD 1982

Microvascular obstruction and remodeling in ARDS

Normal human lung capillaries Lung capillaries day 14 ARDS

Zapol et al Chest, 1977; Snow et al ARRD 1982

ARDS - lung endothelial injury

Bachofen and Weibel ARRD 1977

Increased plasma vWF is an independent predictor of mortality in ARDS

N = 193366DiedSurvived

800

600

400

200

0

* p < 0.0001

BaselinevWF

(% control)

Ware et al. AJRCCM 2004;170:766

Decreased plasma protein C is a predictor of mortality in ARDS

*Protein C (% control)

Survived 506

Died272

* P < 0.0001 Wilcoxon Test

30

60

90

N =

Ware et al. CCM 2007;35:1821-28

Increased pulmonary dead space fraction predicts pulmonary dysfunction

0

10

20

30

40

No post-op pulmonarycomplications

Post-oppulmonary complications

54 20N =

Norris et al. JBJS 2001;83:1162

Increased pulmonary dead space fraction is associated with mortality in ARDS

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

Survivors Non-Survivors

Dea

d S

pace

Fra

ctio

n (V

d/V

t)

Nuckton et al. NEJM 2002;346:1281

Increased pulmonary dead space fraction is associated with mortality in ARDS

Endothelial dysfunction predicts mortality in the critically ill

Endothelium dysfunction

SOFA score SAPS 2 score

WCC

Duffy et al. CCM 2011;39:269-35

• Tidal volume reduction• Recruitment maneuvres

Helping endothelial cells Ventilatory strategy

Tidal volume reduction

NEJM 2000;342:1301

50 µm

Low tidal volume reduces pulmonary oedema

12 ml/kg 6 ml/kg 3 ml/kg

Frank et al. AJRCCM 2002;165:242

0

2

4

6

8

*

Extravascular Plasma

Equivalents (µl/h)

12 ml/kg

6 ml/kg

3 ml/kg

12 ml/kg

6 ml/kg

3 ml/kg

Lung Injury No Lung Injury

*†

* *

Low tidal volume reduces endothelial permeability

Recruitment manoeuvres

CCM 2003;31:2592

Recruitment manoeuvres improve alveolar endothelial function

Frank et al. CCM 2005;33:181

Helping endothelial cells Pharmacological treatment

Millar et al. Thorax 2016;71:462-473

Simvastatin reduces thrombin-induced endothelial injury

Jacobson et al. AJRCMB 2004;30:662

Statins in ARDS

McAuley et al. NEJM 2014;371:1695-703ARDSNet. NEJM 2014;370:3191-200

LPS

Sphingosine-1-phosphate (S1P) reduces LPS-induced canine lung injury

LPS + S1PApex

Base

2000

1500

1000

500

0B

AL

prot

ein

(mcg

/ml) LPS

LPS/S1P

Time (min) after LPS36060 240

****

McVerry et al, AJRCCM 2004;170:987

Conclusions

• ARDS and other critical illness characterised by endothelial injury

• Severity of endothelial injury correlates with outcome

• Tidal volume reduction reduces endothelial injury

• Potential novel therapeutic interventions