visceral hypersensitivity and gastrointestinal · pdf filevisceral hypersensitivity and...

15
1 Visceral hypersensitivity and gastrointestinal inflammation Benedicte De Winter Laboratory of Experimental Medicine and Pediatrics University of Antwerp Antwerp, Belgium From Elsenbruch, Brain Behav Immun 2011 Brain-gut axis Visceral hypersensitivity: peripheral mechanisms central mechanisms inhibitory or facilitating descending pathways

Upload: hacong

Post on 14-Mar-2018

226 views

Category:

Documents


0 download

TRANSCRIPT

1

Visceral hypersensitivity and gastrointestinal inflammation

Benedicte De Winter

Laboratory of Experimental Medicine and Pediatrics

University of Antwerp

Antwerp, Belgium

From Elsenbruch, Brain Behav Immun 2011

Brain-gut axis

Visceral hypersensitivity:

� peripheral mechanisms

� central mechanisms

� inhibitory or facilitatingdescending pathways

2

IBD and IBS

Inflammatory bowel disease (IBD)

= a chronic disease� acute inflammation / flares (= inflammatory)

� remission (= post-inflammatory)

33-57% of IBD patients have symptoms of IBS

Irritable bowel syndrome (IBS)

= a functional bowel disease� affecting 15-19% of the general population

� 50-94% shows visceral hypersensitivity to colorectal distension

� ± 30% develops IBS after acute gastroenteritis (PI-IBS)

INFLAMMATIINFLAMMATIINFLAMMATIINFLAMMATIONONONON

damaged tissue

peripheral afferents

inflammatory cells

recruitment silent nociceptors

activation / sensitization peripheral afferents

inflammatory cells mast cells platelets

vasodilatation edema

MEDIATORS

Role of inflammation

3

InflammationInflammation

TNBS-colitisTNBS-colitis

7,5-15 mg trinitrobenzene sulphonic acid

(TNBS) in 40-50% of ethanol ↔ NaCl

(control)

Follow-upFollow-up

ColonoscopyColonoscopy

•ocular

Follow-upFollow-up

Control Complications

TNBS-induced ulceration

Vermeulen et al, AGB 2011

4

Gut reflexes

Methodology

altered gut reflexes

Dorsal root ganglionPeripheralPeripheral levellevel

•De De Schepper et al., Gut 2007

Visceral perceptionaltered visceral perception

SupraspinalSupraspinal levellevel

SpinalSpinal levellevel

Acute colitis pelvic afferent set-up

Amplif

Pressurecontrolleddistension

device

ADC

S1

Amplif

Pressurecontrolleddistension

device

ADC Amplif

Pressurecontrolleddistension

device

ADC

S1S1

� female Wistar rat (200-225 g)

� 3 days post TNBS

� anaesthesia: pentobarbital

induction: 45 mg/kg ip

maintenance 7.5 mg/kg/u iv

� vital support:

- heating path (37°C)

- trachea cannulation

- continuous registr art bloodpressure (a car)

- ABP < 80 mmHg � 1 mL 5% dextrose iv

� sacrifice - overdose pentobarbital

5

Effect of inflammation on afferent signalling

De Schepper et al, J Physiol 2008

Effect of TRPV1 inhibition

pre-d

rug

vehic

le

BCTC

0.2

5

BCTC

0.5

BCTC

1

BCTC

2

BCTC

5

0

5

10

15

20

25 control (12)

TNBS (12)* *

## #

Sp

ike r

ate

(H

z)

De Schepper et al, J Physiol 2008

6

Effect of inflammation on afferent signalling& the effect of TRPV1 inhibition

pre-d

rug

vehic

le

BCTC

0.2

5

BCTC

0.5

BCTC

1

BCTC

2

BCTC

5

0

5

10

15

20

25

TNBS (7)

control (7)

* *

# # #

Sp

ike r

ate

(H

z)

pre-d

rug

vehic

le

BCTC

0.2

5

BCTC

0.5

BCTC

1

BCTC

2

BCTC

5

0

5

10

15

20

25

TNBS (5)

control (5)

Sp

ike r

ate

(H

z)

C-fibres Aδ-fibres

De Schepper et al, J Physiol 2008

Conclusion 1

Acute colitis:

� sensitisation of pelvic afferent C-fibres after colorectal distension

� mediated via TRPV1 receptors

� no effect on Aδ fibres

7

Clinical relevance – TRPV1

� Increased TRPV1 expression in sensory neurons in IBD patients.

Yiangou et al, Lancet 2001

� Increased TRPV1-immunoreactive nerve fibers in in IBS patients and in quiescent IBD patients correlate with abdominal pain scores.

Akbar et al, Gut 2008 & Gut 2010

� NCT00461682 ~ SB 705498, a selective TRPV1 antagonist, in phase 2 for rectal pain; two groups faecal urgency ↔ IBS

Clinical trials.gov

Gut reflexes

Methodology

altered gut reflexes

Dorsal root ganglionPeripheralPeripheral levellevel

•De De Schepper et al., Gut, 2007

Visceral perceptionaltered visceral perception

SupraspinalSupraspinal levellevel

SpinalSpinal levellevel

8

VMR – visceromotor responses

Pre

ssu

re (

mm

Hg

) Distention protocol

Electrodes S pike 2 s oftware

B aros tat

Balloon

Analog dig ital c onverter

Amplifier / F ilter

O s c illos cope

Electrodes S pike 2 s oftware

B aros tat

Balloon

Analog dig ital c onverter

Amplifier / F ilter

O s c illos cope

***

******

***

*

(n = 10)

(n = 6/18 )

10 20 30 40 60 80

Control

TNBS

Distension pressure (mmHg)

AU

C

0.0

0.25

0.50

0.75

1.00

1.25

1.50***

******

***

*

(n = 10)

(n = 6/18 )

10 20 30 40 60 80

Control

TNBS

Distension pressure (mmHg)

AU

C

0.0

0.25

0.50

0.75

1.00

1.25

1.50

Vermeulen et al., EJP 2013

Experimental protocol

Day 0Day -1Day -2Day -8

Training • Fasting

Day 3

Colitis-Predrug

Saline-Predrug

30 minControl Colitis-Postdrug

Saline-Postdrug

9

Effect of TRPV1 blockade on VMR

Vermeulen et al., EJP 2013

10 20 30 40 60 80

0

500

1000

1500

Control Colitis (day 3)

Colitis (day 3) + BCTC 5mg/kg i.p.

§§§*

Distension pressure (mmHg)

AU

C (

µV

/.20

s)

10 20 30 40 60 80

0

500

1000

1500

Control Colitis (day 3)

Colitis (day3)+ BCTC 100µg i.t.

§*

Distension pressure (mmHg)

AU

C (

µV

/ 20 s

)

IP IT

Effect of TRPA1 blockade on VMR

10 20 30 40 60 80

0

500

1000

1500

2000

Control Colitis (day 3)

Colitis (day 3) + TCS-5861528 15mg.kg-1 i.p.

§§§*

Distension pressure (mmHg)

AU

C (

µV

/ 20 s

)

10 20 30 40 60 80

0

500

1000

1500

2000

Control Colitis (day 3)

Colitis (day 3) + TCS-5861528 20 µg i.t.

§*

Distension pressure (mmHg)

AU

C (

µV

/ 20 s

)

IP IT

Vermeulen et al., EJP 2013

10

Conclusion 2

Acute colitis:

� sensitisation of visceromotor responses (VMR) after colorectal distension

� mediated via TRPV1 receptors

� mediated via TRPA1 receptors

� Effect located in the periphery and at the level of the spinal cord.

Clinical relevance – TRPA1

� Increased TRPA1 expression in colorectal DRGs and associated visceral hypersensitivity after neonatal colonic irritation in mice.

Christianson et al, Pain 2010

� Increased mesenteric afferent firing in mice after administration of AITC, a TRPA1 agonist.

Jiang et al, NGM 2012

� Colorectal distension initiate an inhibitory rectovesical reflex that can be abolished by lidocaine and increased by AITC, a TRPA1 agonist.

Wyndaele et al, J Urol 2013

11

IBD and IBS

Inflammatory bowel disease (IBD)

= a chronic disease� acute phase (= inflammatory)

� remission (= post-inflammatory)

33-57% of IBD patients have symptoms of IBS

Irritable bowel syndrome (IBS)

= a functional bowel disease� affecting 15-19% of the general population

� 50-94% shows visceral hypersensitivity to colorectal distension

� ± 30% develops IBS after acute gastroenteritis (PI-IBS)

Role of inflammation and stress

stress

mast cell

immune cell

visceral afferent nerve

spinal cord

visceral

hypersensitivityIrritable bowel syndrome (IBS)

- Pathogenesis largely unknown

- Several implicated factors:• Stress

• Mucosal mast cells

• Low-grade inflammation

• Dysregulated brain-gut axis

12

Van Diest, 2012

Role of mast cells

Mast cells (MCs) appear to be involved

� located in close proximity to nerve endings

� bidirectional communication between MCs and nerves

� increased number of MCs, increased mediator release

� effect of MC stabilizers and histamine H1 receptor antagonist

Van Diest, 2012

Role of mast cells

13

Experimental protocol

+3d +7d

Visceral

sensitivity+3d

30 min prior

drug/vehicle ip

Healed

+4d

MC numbers

Histamine release

Conclusion 3

Post-inflammatory colitis:

� sensitisation of visceromotor responsesafter colorectal distension

� mediated via histamine 1 receptors

� peripheral and DRG level

� mediated via histamine 4 receptors

� peripheral mechanism via a reduction of colonic histamine release

14

Clinical relevance - histamine

� Beneficial effect of ketotifen on visceral hypersensitivity in IBS patients.

Klooker et al, Gut 2010

� IBS-biopsy supernatans induced H1R-dependent mesenteric afferent nerve discharge in rat

Barbara et al, Gastroenterology 2007

� Mediators from colonic biopsies from IBS-D but not IBS-C patients sensitised colonic nociceptive DRG neurons mediated via PAR 2 signalling.

Valdez-Morales et al, Am J Gastroenterol 2013

From Elsenbruch, Brain Behav Immun 2011

Visceralhypersensitivity

Inflammation:

� peripheral level

� DRG level

15

Acknowledgements

Lab of Gastroenterology

- Prof. Dr. P. Pelckmans

- Prof. Dr. B. De Winter

- Prof. Dr. T. Moreels

- Ing. Joris De Man

- Dr. Nathalie Ruyssers

- Dr. Heiko De Schepper

- Dr. Wim Vermeulen

- Dr. Annemie Deiteren

- Ap. Marthe Heylen

- Dr. Sara Nullens

LEMP

- Prof. Em. Verpooten

- Petra Aerts

- Angelika Jürgens

- Marleen Vinckx

- André Van Daele

Physiopharmacology

- Rita Van Den Bossche

- Min Fret

Janssen Research & Development

- Dr Thurmond