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Exercise-induced Bronchospasm : Mechanisms. Timothy Craig, DO Professor of Medicine and Pediatrics Distinguished Educator Penn State University Hershey. Research BI Novartis GSK Sanofi Genentech Merck Forest. Speaker Teva Merck Genentech. Conflicts of Interest. Objectives. - PowerPoint PPT Presentation
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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