EXERCISE-INDUCED BRONCHOSPASM:MECHANISMS

Timothy Craig, DO

Professor of Medicine and Pediatrics

Distinguished Educator

Penn State University

Hershey

CONFLICTS OF INTEREST

Research BI Novartis GSK Sanofi Genentech Merck Forest

Speaker Teva Merck Genentech

OBJECTIVES

1. To understand the physiology of EIB 2. To be able to discuss the changes that occur

in the airway during EIB 3. To be able to understand the immune

changes that occur with exercise in mice and humans with asthma

EIA: the condition in which exercise induces symptoms of asthma in patients who have asthma

EIB: the airways obstruction that occurs in association with exercise without regard to the presence of chronic asthma

Weiler et al. 2006

Working definitions ofExercise-Induced Asthma (EIA)

and Exercise-Induced Brochospasm (EIB)

Post Exercise (min)

5 10 15 20 25 30

% P

red

icte

d F

EV

1

50

60

70

80

90

100

PreRx

PostRx

ControlPlaceboSalbutamol Diskus

Salbutamol PMDI

Changes in FEV1 Before & After 8 minutes Cycling Exercise in 27 adult asthmatics

Anderson SD et al Med Sci Sports Exerc 2001; 33:893-900.

WHAT CAUSES EIB:

A. Hot humid airB. Cold airC. Dry airD. OzoneE. Both cold and dry air

Ans:

WHAT CAUSES EIB:

A. Hot humid airB. Cold airC. Dry airD. OzoneE. Both cold and dry air

Ans:

McFadden ER, Gilbert IA. Exercise-induced asthma, NEJM 1994;330 (19):1362-7.

Deal. J Appl Physiol 57:608-609,1984

RHE= Respiratory Heat ExchangeRHE= Respiratory Heat Exchange

% Change in FEV1

RESPIRATORY WATER LOSS

Mucosal Cooling

Vasoconstriction

Rapid Rewarming of Airways

Vascular Engorgement ± Edema

Exercise-induced bronchoconstriction

Mucosal Dehydration

Increase [Na+][Cl-][Ca++][ K+]

Increased Osmolarity

Cells Shrink Mediators Released

Smooth muscle Contraction± Oedema

Cough Mucus

OSMOTIC THEORY OF EIA

Evidence Water loss from humidifying inspired air Increase in osmolarity, Na/C1/K/Ca and

cough/mucus production Water moves from cells to restore airway surface

liquid Cell shrinkage releases mediators, i.e., histamine,

leukotrienes, prostaglandins Bronchial smooth muscle contraction plus or minus

mucosal edema Exercise-induced asthma with cough, wheezing, or

chest tightnessAnderson SD. JACI 2000;106:453-9.

WATER CONTENT IS IMPORTANT:Evidence Aerobic conditioning that decrease ventilation for a similar

degree of exercise Add water content to air Wear mask to increase water content Breathing through the nose The dryer the air the more generations of airway are needed to

condition the air. In usual conditions the air is fully conditioned by generation 12 Mast cells increase with generations so the greater the

generation to condition the air the greater probability of causing EIB

MECHANISMS

Drying of the airway causes osmotic strain and release of mediators from mast cells and eosinophils, which causes smooth muscle contraction

Number of eosinophils in the sputum correlate with severeity of EIB

Eosinophil release of LT Mast cell release of PGD2, histamine and LT cause the

changes Increase PGD2 noted by metabolite PGF2 in urine with

EIB

Reproduced from Daviskas E, Anderson SD, Gonda I, Chan HK, Cook P, Fulton R. Changes in mucociliary clearance during and after isocapnic hyperventilation in asthmatic and healthy subjects. Eur Respir J 1995;8:742-751.

INFLAMMATORY CELLS IN EIB

Hallstrand et al, JACI 2005;116:586-593

INFLAMMATORY MEDIATORS IN EIB

Curr Opin Allergy Clin Immunol 2006,6:37-42

EXHALED NITRIC OXIDE DECREASES DURING EXERCISE INDUCED BRONCHOCONSTRICTION

Am J Respir Crit Care Med 2001; 164:1879-1884

ASTHMOGENIC SPORTS ACTIVITIES

Most asthmogenic: highest minute ventilationBasketballCyclingLong distance runningSoccerCold air sports: Cross country skiing; Hockey; Skating (Storms, WW. Medical Science and Sports Exercise (1Suppl):S33-8.1999.)

EIB AGGRAVANTSContinuous exercise from 6-8 minutes at

80-90% maximum heart rateCold and/or dry weatherAtopyAir pollution (e.g. ozone, nitrogen oixides,

sulfur dioxides)Poorly controlled asthmaViral InfectionSinusitisUncontrolled GERD ???Poorly controlled rhinitis

(Storms, WW. Medical Science and Sports Exercise (1Suppl):S33-8.1999.)

POLLUTION

Cysteinyl leukotrienes are unregulated by particulate matter (PM) from combustion and can cause EIB and be inhibited by montelukast

PM also oxidizes glutathione leading to reduction of antioxidant ability and treatment with N-acetyl-L-cysteine can reverse this

Ozone is an oxidant and important in that it depletes antioxidants

EXERCISE CHALLENGE: EXTERNAL SOURCE DRY AIR

Step Duration Target HR

Treadmill

Rate

Treadmill

Incline

1 2 minutes

50% MHR

2.5 mph 0%

2 2 minutes

70% MHR

increase increase

3 6 minutes

>80% MHR

increase increase

ACRN Manual of Operations

% fall in FEV1 after exercise in relation to PD15 to mannitol

% fall in FEV1 to Exercise

0 10 20 30 40 50 60 70

PD

15

Ma

nn

ito

l (m

g)

10

100

1000

rp = - 0.68

p < 0.01

n = 13

Brannan et al, AJRCCM 1998; 158:1120-6

21

14

7

0Ran

k o

rder

of

sen

siti

vity

to

eu

cap

nic

hyp

erve

nti

lati

on

Rank order of sensitivity to 4.5% hypertonic saline

0 7 14 21

r = 0.90

P < 0.001

Smith CM & Anderson SD Eur Respir J 1989; 2: 36-43

Relationship of sensitivity to EVH & sensitivity to 4.5% saline

PATHOGENESIS

Irritant asthma: inflammatory asthma with eosinophilia demonstrated in airways of some Olympic swimmers (Helenius, IJ et al. Allergy 123:222.1998.) and neutrophils in the airways of cross country skiers (Sue Chu et al

WHAT IS THE IMPORTANCE OF EXERCISE IN THE MOUSE MODEL WITH ASTHMA

EFFECT OF EXERCISE ON INFLAMMATORY MEDIATORS OF ASTHMA

Pastva. J Immunol 2004;172;4520-4526

IGE PRODUCTION IN SEDENTARY AND EXERCISING MICE

Pastva. J Immunol 2004;172;4520-4526

EXERCISE DECREASED VCAM-1 SURFACE EXPRESSION IN THE LUNGS OF OVA-SENSITIZED MICE

Pastva. J Immunol 2004;172;4520-4526

THE NUMBER OF TOTAL CELLS, EOSINOPHILS AND EPITHELIAL CELLS IN THE BRONCHOALVEOLAR LAVAGE

R.P. Vieira et al. / Respiratory Physiology & Neurobiology 175 (2011) 383–389

IGF-1, EGFR, VEGF AND TGF-BETA WHEN COMPARED AMONG ALL GROUPS

R.P. Vieira et al. / Respiratory Physiology & Neurobiology 175 (2011) 383–389

EXERCISE IMPROVES ASTHMA OUTCOMES“QUALITY OF LIFE”

Dogra. ERJ June 7, 2010

EXERCISE IMPROVES ASTHMA OUTCOMES“SYMPTOM FREE DAYS”

Mendes. CHEST / 138 / 2 / AUGUST, 2010

EXERCISE IMPROVES ASTHMA OUTCOMES

“ OXYGEN CONSUMPTION”

Mendes. CHEST / 138 / 2 / AUGUST, 2010

Thank you and

have a great day,

tcraig@hmc.psu.edu