Opportunities for Electrical Neuromodulation of Respiratory ......Metaproterenol (1.5 µg) 25 (90...

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)

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(Modified from Tashkin et al. 1986)

Tht NEW ENGLAN D J OU RNAL of MEOTC INE

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Tiotropium Bromide Step-Up Therapy for Adults with Uncontrolled Asthma

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Tiotropium Double­ Salmeterol Glucocorticoid

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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.