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
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0 60 120 180 240 300 360
ME
AN
FE
V1,
% C
HA
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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
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Tiotropium Double Salmeterol Glucocorticoid
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-----------.,.----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.
