Professional Documents
Culture Documents
er School 2018
Wednesday
VAREM Summay
Tuesday
Monday 11 july 2018
l Prog ra m C A Sunday
9 july 2018
10 july 2018
Educationa
Saturday Breakfast
8 july 2018
Frid
7 july 2018 Breakfast
Thursday 2018 6 july Breakfast
Wednesday Breakfast
5 july 2018 (A)
Breakfast - room 3111.0017
A. Deusinglaan 1
Tuesday 4 july 2018 Breakfast
Monday
Sunday 3 july 2018 Breakfast
2/Jul/18 Breakfast
1/Jul/18 Breakfast
Time Breakfast (A)
- room 3111.0017
8:00
Arrival A. Deusinglaan 1
Patrick van Rijn:
Biomaterials
Breakfast Maarten van der
Laan
9.00-10.00h Group Assignment
9:00 ase s
Large vessel dise Marco Harmsen
/ Final Presentation
arrival 9.00-10.00h
Janette Burgess: to the panel
Marie-Jose Gouman
s: Patrick van Rijn:
cal
t and stem From Organotypi Nanotechnology
Cardiac developmen Marcel Ruiters:
culturing & 10.-11.00j
Guido Krenning: cells Valorisation &
Marco Harmsen: continued 9.00-11.00h 3D BioPrinting to p
entrepreneurshi
Opening & course 10-10.30h Tissue Engineering
10:00
overview Menno de Jong: 9.00-12.00h
ls
Hydrogel materia Inge Zuhorn:
10.00-11.00h Nanomedicine &
Herman Sillje: targeting
Lunch
Patients experie
nce Cardiac disease Lunch
10.30-12.00h Ruud Bank: Lunch
~10.30-12.00h Collagen
11.00-12.00h Lunch
11:00 Alumni
Lunch up 5 Closure and
up 4 Journal Club Gro
Lunch Journal Club Gro
Lunch
Lunch Lunch up 3
12:00 Journal Club Gro Travel
Ruud Bank:
up 2 ction
Journal Club Gro Foreign Body Rea Inge Zuhorn:
up 1
13:30 Matijs van Meurs: Journal Club Gro 13.30-14.30h Nanomedicine &
Sepsis - a microva
scular Excursion to targeting
icine in g
disease Regenerative med Bax bier Schiermonnikoo
13.30-14 .30h 3D perspective
ple Janette Burgess: group assignment:
ends on peo rix
14:00 Bike course - dep Extracellular Mat
arriving 14.00-15.00h preparation of
Guido Krenning: presentation
ment,
Vascular develop
stem cells and Group Assignment
dysfunction
15:00
14.30-15.30h Group Assignment
Group Assignment Group Assignment
18:00
me
BBQ with SSG + The
party
19:00
5 euro
Bowling , O'Mally
euro, quiz 5 Free night 10 euro
Pakhuis dinner 9
Pannekoekeschip euro
20:00 ks
dinner SSG drin
Free night
21:00
Who is he ?
In vitro laboratory In vivo anim al studies: Ex vivo kidney biopsies Critically-ill Patient
techniques SHOCK m odels Blood/plasm a
• Multiple Organ Dysfunction Syndrome (MODS) and AKI (Acute Kidney Injury)
are bad
Neisseria meningitidis
(meningo coccus)
The Disease
Sepsis kills
• 8 UMC’s
– 120 hospitals Amsterdam
• UMCG Leiden
– 1339 beds Utrecht
– 28.779 Rotterdam
inpatients/year Nijmegen
– 500.000
outpatients/year
– large referral area
Maastricht
The Adult Division provides services in
specialized units: 44 beds
http://sketchymedicine.com/category/internal-med/nephro/ AND
Multiple organ failure : Concepts
S o u rc e
A n tib io tic s
c o n tro l
B lo c k a d e
S u p p o rtiv e o f th e
th e ra p y “m e d ia to r
soup’
NO SPECIFIC mediator
therapies are available
http://www.survivingsepsis.org/
Treatment for septic shock:
• If the patient survives, the long-term outcome of AKI varies from complete
recovery, incomplete recovery with progression to Chronic Kidney Disease
(CKD), or End-stage renal disease (ESRD).
(Coca SG. 2012 Kidney Int.)
• Nothing to offer AKI patients once in the ICU except renal replacement
therapy and supportive care
Multiple mechanisms of
Acute Kidney Injury (AKI) in Critically Ill patients
Conduit conduit
vessels vessels
Resistance vessels
capillaries
The micro vascular endothelial cell in sepsis
INPUT OUTPUT
Sepsis induced
stress • Hypotension
• Hypoxia • Vascular Leakage
• Inflammation • Leucocyte influx
• Blood flow
endothelial cell
protein membrane
signal
transduction
RNA translation
nuclear
membrane
DNA
mRNA
gene transcription
The smallest blood vessels in the kidney:
molecular regulation of vascular inflammation and
leakage – road to therapies
Leukocyte
Hypothesis
The microvasculature of the kidney is an active player in
the development of Acute Kidney Injury during and after
Critical Illness
and endothelial cells are key mediators in the underlying
pathophysiological processes.
Angiopoietin-1 protects the adult vasculature
against plasma leakage
Rho
kinase Ca²+
Stabilisation of
cell-cell junctions
NFκB
PI3K/Akt
Ca²+
Blood vessel
Survival Anti-Inflammatory
Ang-1 stabilization
Endothelial cell
Pericyte
van Meurs , Kümpers et al Crit Care. 2009;
Translational research :
Bridging the gap between basic research and clinical practice
In vitro laboratory In vivo anim al studies: Ex vivo kidney biopsies Critically-ill Patient
techniques SHOCK m odels Blood/plasm a
AKI
van Meurs , Kümpers et al Crit Care. 2009; Zonneveld R et al, Shock 2017
Shock conditions induce loss of Tie2 mRNA
and protein in the kidney
relative to GAPDH
Tie-2 mRNA level
relative to GAPDH
Tie-2 mRNA level
0.006
0.010
A: Tie2 mRNA 0.004
0.005
0.002
0.000 0.000
0 4 8 24 0 4 8 24
Time after LPS administration (hours) Time after HS/resuscitation (hours)
*
10 10
*
8 8
6 6
B: Tie2 protein 4
4
2 2
0 0
0 4 8 24 0 4 24
Time after HS/resuscitation (hours)
Time after LPS administration (hours)
40
30
sTie2 (ng/mL)
20
10
0
control AKI
0.020 0.008
0.015 0.006
0.010 0.004
0.005 0.002
0.000 0.000
PB
l
tro
PB
l
tro
C
on
C
on
C
C
mRNA level relative to GAPDH Tie2
0.03
0.02
C
on
C
In AKI patients who died in the ICU,
Ang/Tie2 system is deranged in the kidney
(biomarker?/mediator?)
Ang1 Ang2
0.008
0.06
0.006
0.04
0.004
0.02
0.002
0.00 0.000
I
l
l
tro
AK
tro
AK
on
on
C
C
Ang1/Ang2 ratio Tie2
mRNA level relative to GAPDH
0.4
10
0.3
0.2
5
0.1
0 0.0
I
l
I
l
tro
AK
tro
AK
on
on
C
C
Ang2 mediates vascular leakage and
hypotension
Ang2
Tie2
Li R et al Shock. 2014
Disturbed EC behaviour in human AKI
leads to immune cell invasion in the
kidney
A B
C
neutrophils
D E
macrophages
In vitro laboratory In vivo anim al studies: Ex vivo kidney biopsies Critically-ill Patient
techniques SHOCK m odels Blood/plasm a
Perfused vessels
(vessels/recording)
SHOCK
10 SHOCK+VT
Sham
0 e
n
n
n
n
in
tio
io
tio
io
el
ct
ct
ta
ta
as
du
du
ci
ci
B
us
us
in
in
es
es
ck
ck
rr
R
ho
o
Sh
te
rs
af
te
1h
af
1h
Ang-1 Ang-2
Adhesion Tie-2
molecules Receptor A
Bloodstream
NFκB
Future therapeutic options
Translation ?
In sepsis Negative or Not Evaluated
Ang-1 Ang-2
Adhesion Tie-2
molecules Receptor Ang-2
Bloodstream
Rho
Weibel-Palade-bodies
kinase Ca²+
Stabilisation of
cell-cell junctions
NFκB
PI3K/Akt
Ca²+
Blood vessel
Survival Anti-Inflammatory
Ang-1 stabilization
Endothelial cell
Pericyte
Take home message
• Translational research
– Learn
• Individual
• Local group
• Critical Care/vascular biology community
– Social
• Local
• National
• International
– Teach
m.van.meurs@umcg.nl
Acknowledgements
SHOCK GROUP CSO UMCG Anesthesiology UMCG
Medical Biology UMCG (Ingrid Molema) Jack Ligtenberg Thomas Scheeren
ICV UMCG (Jill Moser & Jan Zijlstra) Vincent Quinten Tony Absalom
Hans de Vries
Michel Struys
Nephrology UMCG
Coen Stegeman
Funding
NVA
Nierstichting China
Scholarship Council
(R. Li, R Yan)
www.ebvdt.nl
Pamgene ‘s Hertogenbosch
Rob Ruitenbeek
VU MC Amsterdam International
Anesthesiology and Physiology Paul van Slyke (Toronto Canada)
Christa Boer Sascha David (Hannover, Germany)
Charissa van den Brom, Philipp Kuempers (Muenster, Germany)
Nick Koning Gregor Theilmeijer (Oldenburg, Germany)
Michelle Trieu & Nicole Dekker