Opportunities for Electrical Neuromodulation of Respiratory Function

Marian Kollarik The Johns Hopkins University School of Medicine, Baltimore, MD

Nerves play a major role in pathophysiology of respiratory diseases (asthma, COPD).

The lung is a very feasible target for peripheral neuromodulation.

Additional functional and anatomical mapping will enable more refined neuromodulation strategies.

3

RESPIRATORY SYSTEM

NERVES

COUGH

MUCUS SECRETION DYSPNEA

BRONCHOSPASM

Neural regulation of the lung is mediated by vagus nerves

Jugular

5

Reflexes: • Airway smooth muscle constriction

• Secretions

Sensations: • Dyspnea • Cough

6

Parasympathetic regulation of airway smooth muscle

Medulla

Preganglionic (vagus nerve)

Parasympathetic ganglia

Postganglionic

+ acetyl- - VIP choline NO

Airway smooth muscle

Human bronchus

Reversible Airways Obstruction in COPD is DependentUpon Parasympathetic Cholinergic Nerves

30

* * Metaproterenol (1.5 µg)

25 (90 Patients)

Ipratropium Bromide (36 µg) 20 (107 Patients)

15

10

5

0

*

*

*

*

*

0 60 120 180 240 300 360

ME

AN

FE

V1,

% C

HA

NG

E

Minutes After Treatment

(Modified from Tashkin et al. 1986)

Tht NEW ENGLAN D J OU RNAL of MEOTC INE

[_I_________o_R_ 1G_ 1N_ A_L_A_R_T_1c__L_E__________,I[

Tiotropium Bromide Step-Up Therapy for Adults with Uncontrolled Asthma

--

--

--

so

40

.... _

... c 30 a.. ­ooE ·-c-

~ 20E ., 0 "' ::IE""" 10

0

- 10

P=0.26

P<0.001

P<0.001

____ ..___ _,

Tiotropium Double­ Salmeterol Glucocorticoid

so

40

... _ 30

~ .E .. E .E ~ 20

... c -.. 10 ~~

-1:

P..().05

P<0.001

P<0.001

-----------.,.----Tiotropium Oouble­ Salmet>!rol

Glucocor'licoid

Reflexes: • Airway smooth muscle constriction

• Secretions

Sensations: • Dyspnea • Cough

10

Afferent nerve subtypes in the large airways

cough receptor C-fiibers

acid pH=6

(Kollarik & Undem 2002; Canning, 2004)

Afferent nerve subtypes in the large airways

CA B

FD E

Mice and Rats Guinea Pigs Humans

Afferent innervation of the lung

Rat, In vivo, adapted from (Lee et al. 2003)

0

30

Bronchopulmonar y C-fibers

Pt

nerve activity

5 s

lung

infla

tion

A-fiber stretch mechanoreceptors

n=109 n=96

RAR SAR nodose C-fibers

jugular C-fibers

mice, rats, guinea pigs, rabbits, cats, dogs

Bronchopulmonary C-fibers

• relatively quiescent in normal tissue

• readily stimulated by noxious chemicals, inflammatory mediators or excessive physical stimuli

capsaicin 01µM

C-fiber activators initiate cough in humans and animal models

• Capsaicin (TRPV1) • Cinnamaldehyde (TRPA1) • Citric Acid (TRPV1/ASIC) • Bradykinin (B2) • Water (?)

Reviewed in (Coleridge et al., 1984; Lee et al., 2001; Canning 2009).

Central neural circuitry regulating the parasympathetic innervation of the airways

C-fibers

RAR and SAR stretch A-fiber mchanoreceptors

Afferent Efferent

Inflammation-induced neuroplasticity

Reflexes: • Airway smooth muscle constriction

• Secretions

Sensations: • Dyspnea • Cough

In vivo transfection of sensory nerves with AAV virus vectors

In injection into sensory ganglia

Kollarilk et al., J Physiol 2010

Vagal afferent nerve terminals in the trachea

Knockdown of Nav 1.7 expression and function by AAV-delivered shRNA

ctrl shRNA

Nav 1.7 shRNA

Muroi Y, Ru F, Kollarik M, Canning BJ, Hughes SA, Walsh S, Sigg M, Carr MJ, Undem BJ. J Physiol. 2011*

**

Recording from human vagal pulmonary branches – ex vivo optimization of stimulation parameters

CTRL WASH (>3h)

C-wave

Cmpd X (Nav1.7 blocker) 1µM

Isolated branch of the vagus nerve (≈25 mm)

stimulate

record

*

Kollarik, unpublished.

Nerves play a major role in pathophysiology of respiratory diseases (asthma, COPD).

The lung is a very feasible target for peripheral neuromodulation.

Additional functional and anatomical mapping will enable more refined neuromodulation strategies.