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Airway injury as a mechanism for exercise-induced bronchoconstriction in elite athletes

2008; Elsevier BV; Volume: 122; Issue: 2 Linguagem: Inglês

10.1016/j.jaci.2008.05.001

1097-6825

Sandra D. Anderson, Pascale Kippelen,

Inhalation and Respiratory Drug Delivery

Exercise-induced bronchoconstriction (EIB) is a consequence of evaporative water loss in conditioning the inspired air. The water loss causes cooling and dehydration of the airway surface. One acute effect of dehydration is the release of mediators, such as prostaglandins, leukotrienes, and histamine, that can stimulate smooth muscle, causing contraction and a change in vascular permeability. Inspiring cold air increases dehydration of the surface area and causes changes in bronchial blood flow. This article proposes that the pathogenesis of EIB in elite athletes relates to the epithelial injury arising from breathing poorly conditioned air at high flows for long periods of time or high volumes of irritant particles or gases. The evidence to support this proposal comes from many markers of injury. The restorative process after injury involves plasma exudation and movement of cells into the airways, a process repeated many times during a season of training. This process has the potential to expose smooth muscle to a wide variety of plasma- and cell-derived substances. The exposure to these substances over time can lead to an alteration in the contractile properties of the smooth muscle, making it more sensitive to mediators of bronchoconstriction. It is proposed that cold-weather athletes have airway hyperresponsiveness (AHR) to pharmacologic agents as a result of epithelial injury. In those who are allergic, AHR can also be expressed as EIB. The role of β2-receptor agonists in inhibiting and enhancing the development of AHR and EIB is discussed. Exercise-induced bronchoconstriction (EIB) is a consequence of evaporative water loss in conditioning the inspired air. The water loss causes cooling and dehydration of the airway surface. One acute effect of dehydration is the release of mediators, such as prostaglandins, leukotrienes, and histamine, that can stimulate smooth muscle, causing contraction and a change in vascular permeability. Inspiring cold air increases dehydration of the surface area and causes changes in bronchial blood flow. This article proposes that the pathogenesis of EIB in elite athletes relates to the epithelial injury arising from breathing poorly conditioned air at high flows for long periods of time or high volumes of irritant particles or gases. The evidence to support this proposal comes from many markers of injury. The restorative process after injury involves plasma exudation and movement of cells into the airways, a process repeated many times during a season of training. This process has the potential to expose smooth muscle to a wide variety of plasma- and cell-derived substances. The exposure to these substances over time can lead to an alteration in the contractile properties of the smooth muscle, making it more sensitive to mediators of bronchoconstriction. It is proposed that cold-weather athletes have airway hyperresponsiveness (AHR) to pharmacologic agents as a result of epithelial injury. In those who are allergic, AHR can also be expressed as EIB. The role of β2-receptor agonists in inhibiting and enhancing the development of AHR and EIB is discussed. Information for Category 1 CME CreditCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.Date of Original Release: August 2008. Credit may be obtained for these courses until July 31, 2010.Copyright Statement: Copyright © 2008-2010. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.List of Design Committee Members:Authors: Sandra D. Anderson, PhD, DSc, and Pascale Kippelen, PhDActivity Objectives1. To understand the mechanisms of exercise-induced bronchoconstriction (EIB) and airway hyperresponsiveness in elite athletes.2. To understand the role of inflammatory cells and mediators in EIB.3. To review the therapeutic approaches for EIB in athletes.Recognition of Commercial Support: This CME activity has not received external commercial support.Disclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: Sandra D. Anderson owns stock in Pharmaxis Pty Ltd and has received research support from the National Health and Medical Research Council of Australia. Pascale Kippelen has received research support from NHS Grampian and the British Olympic Association.In 1999, the year before the Summer Olympic Games in Sydney, there was still debate about the mechanism whereby exercise provokes airway narrowing.1Anderson S.D. Daviskas E. The mechanism of exercise-induced asthma is ….J Allergy Clin Immunol. 2000; 106: 453-459Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar The initiating stimulus had been identified 20 years earlier as evaporative water loss after it was shown that exercise-induced bronchoconstriction (EIB) was markedly inhibited or even completely abolished by preventing that loss.2Chen W.Y. Horton D.J. Heat and water loss from the airways and exercise-induced asthma.Respiration. 1977; 34: 305-313Crossref PubMed Google Scholar, 3Strauss R.H. McFadden E.R. Ingram R.H. Deal E.C. Jaeger J.J. Stearns D. Influence of heat and humidity on the airway obstruction induced by exercise in asthma.J Clin Invest. 1978; 61: 433-440Crossref PubMed Google Scholar, 4Anderson S.D. Daviskas E. Schoeffel R.E. Unger S.F. Prevention of severe exercise-induced asthma with hot humid air.Lancet. 1979; 2: 629Abstract PubMed Google Scholar The relative importance of the thermal (cooling) and osmotic (drying) consequences of the water loss, however, remained unclear. It was clear that abnormal cooling of the airways was not necessary for them to narrow because severe EIB could occur when hot dry air was inspired.5Anderson S.D. Schoeffel R.E. Black J.L. Daviskas E. Airway cooling as the stimulus to exercise-induced asthma—a re-evaluation.Eur J Respir Dis. 1985; 67: 20-30PubMed Google Scholar, 6Aitken M.L. Marini J.J. Effect of heat delivery and extraction on airway conductance in normal and in asthmatic subjects.Am Rev Respir Dis. 1985; 131: 357-361PubMed Google Scholar, 7Argyros G.J. Phillips Y.Y. Rayburn D.B. Rosenthal R.R. Jaeger J.J. Water loss without heat flux in exercise-induced bronchospasm.Am Rev Respir Dis. 1993; 147: 1419-1424Crossref PubMed Google Scholar Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions. Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted. Date of Original Release: August 2008. Credit may be obtained for these courses until July 31, 2010. Copyright Statement: Copyright © 2008-2010. All rights reserved. Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity. List of Design Committee Members:Authors: Sandra D. Anderson, PhD, DSc, and Pascale Kippelen, PhD Activity Objectives 1. To understand the mechanisms of exercise-induced bronchoconstriction (EIB) and airway hyperresponsiveness in elite athletes. 2. To understand the role of inflammatory cells and mediators in EIB. 3. To review the therapeutic approaches for EIB in athletes. Recognition of Commercial Support: This CME activity has not received external commercial support. Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: Sandra D. Anderson owns stock in Pharmaxis Pty Ltd and has received research support from the National Health and Medical Research Council of Australia. Pascale Kippelen has received research support from NHS Grampian and the British Olympic Association. Both release of inflammatory mediators and contraction of airway smooth muscle (ASM) were central to the osmotic theory of EIB.1Anderson S.D. Daviskas E. The mechanism of exercise-induced asthma is ….J Allergy Clin Immunol. 2000; 106: 453-459Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar, 8Anderson S.D. Is there a unifying hypothesis for exercise-induced asthma?.J Allergy Clin Immunol. 1984; 73: 660-665Abstract Full Text PDF PubMed Google Scholar In 2000, it was proposed that EIB, as described in asthmatic subjects, is an exaggerated response to airway dehydration in the presence of inflammatory cells and their mediators.1Anderson S.D. Daviskas E. The mechanism of exercise-induced asthma is ….J Allergy Clin Immunol. 2000; 106: 453-459Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar By contrast, the thermal theory proposed a purely mechanical cause of airway narrowing involving vasoconstriction of the bronchial vasculature in response to airway cooling, followed by a reactive hyperemia accompanied by vascular leakage and airway edema.9McFadden E.R. Hypothesis: exercise-induced asthma as a vascular phenomenon.Lancet. 1990; 1: 880-883Abstract Google Scholar, 10McFadden E.R. Lenner K.A. Strohl K.P. Postexertional airway rewarming and thermally induced asthma.J Clin Invest. 1996; 78: 18-25Crossref Google Scholar The cooling and osmotic aspects of water loss were brought together by the suggestion that cold dry air be considered not only for its capacity to cool the airways but also for its potential to increase the area of the airway surface becoming dehydrated and hyperosmotic during exercise.1Anderson S.D. Daviskas E. The mechanism of exercise-induced asthma is ….J Allergy Clin Immunol. 2000; 106: 453-459Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar Everyone has to condition inspired air, and therefore respiratory water loss is common to all during exercise. The ability to return water to the airway surface, however, is likely to be different for the healthy and the inflamed lower airway, just as it is in the upper airway.11Rouadi P. Baroody F.M. Abbott D. Naureckas E. Solway J. Naclerio R.M. A technique to measure the ability of the human nose to warm and humidify air.J Appl Physiol. 1999; 87: 400-406PubMed Google Scholar In healthy persons the upper limit of the decrease in FEV1 is less than 10% in response to breathing dry air at high flows, and the response can be enhanced by breathing cold air.12Nicolai T. Mutius E.V. Reitmeir P. Wjst M. Reactivity to cold-air hyperventilation in normal and in asthmatic children in a survey of 5,697 schoolchildren in southern Bavaria.Am Rev Respir Dis. 1993; 147: 565-572Crossref PubMed Google Scholar, 13O'Cain C.F. Dowling N.B. Slutsky A.S. Hensley M.J. Strohl K.P. McFadden E.R. et al.Airway effects of respiratory heat loss in normal subjects.J Appl Physiol. 1980; 49: 875-880PubMed Google Scholar It appears that the return of water to the airway surface is not sufficiently fast to prevent the progressive recruitment of generations of airways into the humidifying process over 6 to 8 minutes of intense exercise while breathing dry air.1Anderson S.D. Daviskas E. The mechanism of exercise-induced asthma is ….J Allergy Clin Immunol. 2000; 106: 453-459Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar, 14Daviskas E. Gonda I. Anderson S.D. Local airway heat and water vapour losses.Respir Physiol. 1991; 84: 115-132Crossref PubMed Scopus (27) Google Scholar That water is not replaced almost instantaneously in response to an osmotic force seems surprising. It can be explained in part by the increase in concentrations of Na+ and Cl− ions delaying the water flux caused by the osmotic gradient because the restoration of a normal balance of Cl− and Na+ ions on the airway surface takes precedence over restoration of normal osmolarity.15Chen B.T. Yeates D.B. Ion transport and regulation of respiratory tract fluid output in dogs.J Appl Physiol. 2001; 90: 821-831PubMed Google Scholar, 16Chen B.T. Yeates D.B. Differentiation of ion-associated and osmotically driven water transport in canine airways.Am J Respir Crit Care Med. 2000; 162: 1715-1722Crossref PubMed Google Scholar The water flux in response to ion concentration occurs through activation of ion channels,16Chen B.T. Yeates D.B. Differentiation of ion-associated and osmotically driven water transport in canine airways.Am J Respir Crit Care Med. 2000; 162: 1715-1722Crossref PubMed Google Scholar whereas the water flux in response to osmotic changes is through activation of aquaporins.17Folkesson H.G. Matthay M.A. Frigeri A. Verkman A.S. Transepithelial water permeability in microperfused distal airways. Evidence for channel-mediated water transport.J Clin Invest. 1996; 97: 664-671Crossref PubMed Google Scholar The release of adenosine triphosphate at the airway surface in response to sheer stress, a change in osmolarity of the airway surface liquid (ASL), or both is also likely to be an important mechanism for restoration of normal ASL volume during exercise.18Button B. Picher M. Boucher R.C. Differential effects of cyclic and constant stress on ATP release and mucociliary transport by human airway epithelia.J Physiol. 2007; 580: 577-592Crossref PubMed Scopus (59) Google Scholar In persons with clinically recognized asthma, airway hyperresponsiveness (AHR) to water loss appears early in the disease as EIB and is related to airway inflammation, particularly the presence of eosinophils.19Yoshikawa T. Shoji S. Fujii T. Kanazawa H. Kudoh S. Hirata K. et al.Severity of exercise-induced bronchoconstriction is related to airway eosinophilic inflammation in patients with asthma.Eur Respir J. 1998; 12: 879-884Crossref PubMed Scopus (99) Google Scholar Inflammation is implied by the significant reduction in severity of EIB in most asthmatic subjects when they are treated with inhaled steroids daily for 3 to 12 weeks.20Jonasson G. Carlsen K.H. Hultquist C. Low-dose budesonide improves exercise-induced bronchospasm in schoolchildren.Pediatr Allergy Immunol. 2000; 11: 120-125Crossref PubMed Scopus (73) Google Scholar, 21Hofstra W.B. Neijens H.J. Duiverman E.J. Kouwenberg J.M. Mulder P.G. Kuethe M.C. et al.Dose-response over time to inhaled fluticasone propionate: treatment of exercise- and methacholine-induced bronchoconstriction in children with asthma.Pediatr Pulmonol. 2000; 29: 415-423Crossref PubMed Scopus (81) Google Scholar, 22Subbarao P. Duong M. Adelroth E. Otis J. Obminski G. Inman M. et al.Effect of ciclesonide dose and duration of therapy on exercise-induced bronchoconstriction in patients with asthma.J Allergy Clin Immunol. 2006; 117: 1008-1013Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar The reduction in severity of EIB increases with the dose of steroid and is usually associated with a reduction in the number of eosinophils.23Duong M. Subbarao P. Adelroth E. Obminski G. Strinich T. Inman M. et al.Sputum Eosinophils and the response of exercise-induced bronchoconstriction to corticosteroid in asthma.Chest. 2008; 133: 404-411Crossref PubMed Scopus (49) Google Scholar By the late 1990s, EIB was being reported quite frequently in cold-weather athletes.24Provost-Craig M.A. Arbour K.S. Sestili D.C. Chabalko J.J. Ekinci E. The incidence of exercise-induced bronchospasm in competitive figure skaters.J Asthma. 1996; 33: 67-71Crossref PubMed Google Scholar, 25Mannix E.T. Manfredi F. Farber M.O. A comparison of two challenge tests for identifying exercise-induced bronchospasm in figure skaters.Chest. 1999; 115: 649-653Crossref PubMed Scopus (71) Google Scholar, 26Wilber R.L. Rundell L. Szmedra L. Jenkinson D.M. Im J. Drake S.D. Incidence of exercise-induced bronchospasm in Olympic Winter Sport athletes.Med Sci Sports Exerc. 2000; 32: 732-737Crossref PubMed Google Scholar The possibility was raised that edema and excessive mucus could amplify the small decrease in FEV1 that normally occurs and account for this increase in prevalence of EIB in cold-weather athletes.27Anderson S.D. Holzer K. Exercise-induced asthma: is it the right diagnosis in elite athletes?.J Allergy Clin Immunol. 2000; 106: 419-428Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar It was proposed that the amplifying effect would be sufficient for a mild responder to achieve the 10% decrease required for the diagnosis of EIB. There also appeared to be a difference in symptoms and AHR when the ambient environment for training varied, as it did between Norway at −5°C and Sweden at −20°C. Thus Swedish cross-country skiers reported more cough on winter training (64% vs 42%, P < .01) and had a higher prevalence of respiratory symptoms on exposure to cold (45% vs 14%, P < .001), AHR to methacholine (43% vs 14%, P < .001), current asthma (28% vs 9%, P < .01), and clinically diagnosed asthma (42% vs 12%, P < .001).28Sue-Chu M. Larsson L. Bjermer L. Prevalence of asthma in young cross-country skiers in central Scandinavia: differences between Norway and Sweden.Respir Med. 1996; 90: 99-105Abstract Full Text PDF PubMed Scopus (80) Google Scholar The Swedish skiers were also more likely to consult their doctor, to be given a diagnosis of asthma, and to take medication. Self-reported allergy was not associated with asthma symptoms, AHR, or current asthma. One in 3 skiers with a positive response to methacholine had no symptoms at all.28Sue-Chu M. Larsson L. Bjermer L. Prevalence of asthma in young cross-country skiers in central Scandinavia: differences between Norway and Sweden.Respir Med. 1996; 90: 99-105Abstract Full Text PDF PubMed Scopus (80) Google Scholar It was also considered at the time that the “asthma” symptoms of breathlessness, cough, and increased mucus production (on exercise), reported frequently by cold-weather athletes, could be accounted for by the cooling and osmotic effects of airway dehydration.27Anderson S.D. Holzer K. Exercise-induced asthma: is it the right diagnosis in elite athletes?.J Allergy Clin Immunol. 2000; 106: 419-428Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar For example, stimulation of sensory nerves29Pisarri T.E. Jonzon A. Coleridge H.M. Coleridge J.C. Vagal afferent and reflex responses to changes in surface osmolarity in lower airways in dogs.J Appl Physiol. 1992; 73: 2305-2313PubMed Google Scholar and mucous glands30Dwyer T.M. Farley J.M. Mucus glycoconjugate secretion in cool and hypertonic solutions.Am J Physiol Lung Cell Mol Physiol. 1997; 272: L1121-L1125Google Scholar could cause cough, breathlessness, and the excessive mucus production reported in cold-weather athletes.31Rundell K.W. Im J. Mayers L.B. Wilber R.L. Szmedra L. Schmitz H.R. Self-reported symptoms and exercise-induced asthma in the elite athlete.Med Sci Sports Exerc. 2001; 33: 208-213Crossref PubMed Google Scholar, 32Sont J.K. Booms P. Bel E.H. Vandenbroucke J.P. Sterk P.J. The severity of breathlessness during challenges with inhaled methacholine and hypertonic saline in atopic asthmatic subjects. The relationship with deep breath-induced bronchodilation.Am J Respir Crit Care Med. 1995; 152: 38-44Crossref PubMed Google Scholar Athletes performing endurance sports were also reported to have a higher prevalence of nonspecific AHR than those performing other sports,33Larsson K. Ohlsén P. Malmberg P. Rydström P.-O. Ulriksen H. 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In 2002, it was reported that elite summer athletes were less sensitive to provocation with methacholine than they were to provocation with EVH or inhaled dry powder mannitol.35Holzer K. Anderson S.D. Douglass J. Exercise in elite summer athletes: challenges for diagnosis.J Allergy Clin Immunol. 2002; 110: 374-380Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar, 36Holzer K. Anderson S.D. Chan H.-K. Douglass J. Mannitol as a challenge test to identify exercise-induced bronchoconstriction in elite athletes.Am J Respir Crit Care Med. 2003; 167: 534-547Crossref PubMed Google Scholar These findings were not accounted for by the higher (20%) decrease in FEV1 from baseline required to identify AHR to methacholine compared with EVH (10%) or mannitol (15%). There are at least 2 possible explanations for these findings. First, the mediators involved in EIB and hyperosmolar aerosols (prostaglandin [PG] D2 and leukotriene [LT] E437Brannan J.D. Gulliksson M. Anderson S.D. 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The distribution of bronchial responsiveness to histamine and exercise in 527 children and adolescents.J Allergy Clin Immunol. 1991; 88: 68-76Abstract Full Text PDF PubMed Google Scholar Both these observations might explain why EIB precedes AHR to pharmacologic agents by many years in children.45Ernst P. Ghezzo H. Becklake M.R. Risk factors for bronchial hyperresponsiveness in late childhood and early adolescence.Eur Respir J. 2002; 20: 635-639Crossref PubMed Scopus (32) Google Scholar, 46Jones A. Bowen M. Screening for childhood asthma using an exercise test.Br J Gen Pract. 1994; 44: 127-131PubMed Google Scholar In contrast to summer athletes, winter athletes with good lung function have a high prevalence of AHR to methacholine, and yet the same athletes have a low prevalence of positive responses to EVH, mannitol, AMP,47Sue-Chu M. Brannan J.D. Anderson S.D. Chew N. Bjermer L. Airway responsiveness to methacholine (Mch), adenosine 5-monophosphate (AMP), mannitol (Man), eucapnic voluntary hyperpnea (EVH) and sport specific field exercise challenge (Ex) in cross country ski athletes.Eur Respir J. 2002; 20: 410sGoogle Scholar or exercise.48Stensrud T. Mykland K.V. Gabrielsen K. Carlsen K.H. Bronchial hyperresponsiveness in skiers: field test versus methacholine provocation?.Med Sci Sports Exerc. 2007; 39: 1681-1686Crossref PubMed Scopus (25) Google Scholar This raises the question as to whether the AHR in cold-weather/dry-weather athletes is a reflection of airway injury rather than a sign of classical asthma. The AHR in these winter athletes is also much milder than would be expected in subjects with classical asthma.49Langdeau J.-B. Turcotte H. Bowie D.M. Jobin J. Desgagné P. Boulet L.-P. Airway hyperresponsiveness in elite athletes.Am J Respir Crit Care Med. 2000; 161: 1479-1484Crossref PubMed Google Scholar There are some summer athletes who also appear to have airway injury. Thus swimmers who train for long hours in irritant environments might also have a high prevalence of reported AHR to methacholine.50Potts J. Factors associated with respiratory problems in swimmers.Sports Med. 1996; 21: 256-261Crossref PubMed Google Scholar, 51Potts J. Adverse respiratory health effects of competitive swimming: the prevalence of symptoms, illnesses and bronchial responsiveness to methacholine and exercise [MD thesis] Vancouver: University of British Columbia; 1994.Google Scholar There are differences in the mode of action of the provoking stimuli used to assess athletes. For example, the pharmacologic agent methacholine acts directly on acetylcholine receptors to cause bronchial smooth muscle contraction. The transient hyperosmotic effects of evaporative water loss or the inhalation of hyperosmolar aerosols are not a direct stimulus to the smooth muscle. Rather the hyperosmolar stimulus acts indirectly through release of mediators from inflammatory cells (mast cells and eosinophils) situated in or close to the airway surface. These mediators, including PGD2, LTE4, and histamine, then act on receptors to cause contraction of the smooth muscle and narrowing of the airways. The same mediators can increase vascular permeability. Hyperosmolarity is a stimulus for epithelial cells to produce PGE2 and 15 hydroxyeicosatetraenoic acid (15 HETE) and for neuronal cells to release tachykinins.52Koskela H. Di Sciascio M. Anderson S.D. Andersson M. Chan H.-K. Gadalla S. et al.Nasal hyperosmolar challenge with a dry powder of mannitol in patients with allergic rhinitis. Evidence for epithelial cell involvement.Clin Exp Allergy. 2000; 30: 1627-1636Crossref PubMed Google Scholar, 53Baraniuk J.N. Ali M. Yuta A. Fang S.Y. Naranch K. Hypertonic saline nasal provocation stimulates nociceptive nerves, substance P release, and glandular mucous exocytosis in normal lumens.Am J Respir Crit Care Med. 1999; 160: 655-662Crossref PubMed Google Scholar Adenosine is also released in response to hyperosmolarity.54Lazarowski E.R. Tarran R. Grubb B.R. van Heusden C.A. Okada S. Boucher R.C. Nucleotide release provides a mechanism for airway surface liquid homeostasis.J Biol Chem. 2004; 279: 36855-36864Crossref PubMed Scopus (133) Google Scholar All these outcomes help to restore the ASL toward normal ion concentration, volume, and osmolarity. Another unexpected finding was that the AHR in cross-country skiers with symptoms of asthma was not improved by treatment with inhaled steroids, a benefit well-described in asthmatic subjects.55Sue-Chu M. Karjalainen E.-M. Laitinen A. Larsson L. Laitinen L.A. Bjermer L. Placebo-controlled study of inhaled budesonide on indices of airways inflammation in bronchoalveolar lavage fluid and bronchial biopsies in cross country skiers.Respiration. 2000; 67: 417-425Crossref PubMed Google Scholar Respiratory symptoms and airway responses only improved after a reduction in workload during training, a finding in keeping with less injury.55Sue-Chu M. Karjalainen E.-M. Laitinen A. Larsson L. Laitinen L.A. Bjermer L. Placebo-controlled study of inhaled budesonide on indices of airways inflammation in bronchoalveolar lavage fluid and bronchial biopsies in cross country skiers.Respiration. 2000; 67: 417-425Crossref PubMed Google Scholar An important and unexpected finding was that montelukast provided greater protection against EIB (90%) in a high-particulate-matter environment compared with that seen in a low-particulate-matter environment (35%), suggesting the response to the particulate matter is predominantly LT mediated.56Rundell K.W. Spiering B.A. Baumann J.M.