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Exercise-induced Bronchospasm : Mechanisms

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.

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Exercise-induced Bronchospasm : Mechanisms

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  1. Exercise-induced Bronchospasm:Mechanisms Timothy Craig, DO Professor of Medicine and Pediatrics Distinguished Educator Penn State University Hershey

  2. Research BI Novartis GSK Sanofi Genentech Merck Forest Speaker Teva Merck Genentech Conflicts of Interest

  3. 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

  4. Working definitions of Exercise-Induced Asthma (EIA) and Exercise-Induced Brochospasm (EIB) 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

  5. Changes in FEV1 Before & After 8 minutes Cycling Exercise in 27 adult asthmatics 100 90 80 % Predicted FEV1 70 60 Control Placebo Salbutamol Diskus 50 Salbutamol PMDI Pre Rx Post Rx 5 10 15 20 25 30 Post Exercise (min) Anderson SD et al Med Sci Sports Exerc 2001; 33:893-900.

  6. What causes EIB: • A. Hot humid air • B. Cold air • C. Dry air • D. Ozone • E. Both cold and dry air • Ans:

  7. What causes EIB: • A. Hot humid air • B. Cold air • C. Dry air • D. Ozone • E. Both cold and dry air • Ans:

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

  9. Deal. J Appl Physiol 57:608-609,1984 % Change in FEV1 RHE= Respiratory Heat Exchange

  10. RESPIRATORY WATER LOSS Mucosal Dehydration Mucosal Cooling Increase [Na+][Cl-][Ca++][ K+] Vasoconstriction Increased Osmolarity Cough Mucus Rapid Rewarming of Airways Cells Shrink Mediators Released Vascular Engorgement ± Edema Smooth muscle Contraction ± Oedema Exercise-induced bronchoconstriction

  11. 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 tightness Anderson SD. JACI 2000;106:453-9.

  12. 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

  13. 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

  14. 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.

  15. Inflammatory Cells in EIB Hallstrand et al, JACI 2005;116:586-593

  16. Inflammatory mediators in EIB Curr Opin Allergy Clin Immunol 2006,6:37-42

  17. Exhaled Nitric Oxide Decreases During Exercise induced Bronchoconstriction Am J Respir Crit Care Med 2001; 164:1879-1884

  18. ASTHMOGENIC SPORTS ACTIVITIES • Most asthmogenic: highest minute ventilation • Basketball • Cycling • Long distance running • Soccer • Cold air sports: Cross country skiing; Hockey; Skating (Storms, WW. Medical Science and Sports Exercise (1Suppl):S33-8.1999.)

  19. EIB AGGRAVANTS • Continuous exercise from 6-8 minutes at 80-90% maximum heart rate • Cold and/or dry weather • Atopy • Air pollution (e.g. ozone, nitrogen oixides, sulfur dioxides) • Poorly controlled asthma • Viral Infection • Sinusitis • Uncontrolled GERD ??? • Poorly controlled rhinitis (Storms, WW. Medical Science and Sports Exercise (1Suppl):S33-8.1999.)

  20. 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

  21. Exercise Challenge: external source dry air ACRN Manual of Operations

  22. % fall in FEV1 after exercise in relation to PD15 to mannitol 1000 100 PD15 Mannitol (mg) rp = - 0.68 p < 0.01 n = 13 10 0 10 20 30 40 50 60 70 % fall in FEV1 to Exercise Brannan et al, AJRCCM 1998; 158:1120-6

  23. Relationship of sensitivity to EVH & sensitivity to 4.5% saline r = 0.90 P < 0.001 21 14 Rank order of sensitivity to eucapnic hyperventilation 7 0 0 7 14 21 Rank order of sensitivity to 4.5% hypertonic saline Smith CM & Anderson SD Eur Respir J 1989; 2: 36-43

  24. 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

  25. What is the importance of exercise in the mouse model with asthma

  26. Effect of exercise on inflammatory mediators of asthma Pastva. J Immunol 2004;172;4520-4526

  27. IgE production in sedentary and exercising mice Pastva. J Immunol 2004;172;4520-4526

  28. Exercise decreased VCAM-1 surface expression in the lungs of OVA-sensitized mice

  29. Pastva. J Immunol 2004;172;4520-4526

  30. 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

  31. IGF-1, EGFr, VEGF and TGF-beta when compared among all groups R.P. Vieira et al. / Respiratory Physiology & Neurobiology 175 (2011) 383–389

  32. Exercise Improves Asthma Outcomes“Quality of Life” Dogra. ERJ June 7, 2010

  33. Exercise Improves Asthma Outcomes“Symptom Free Days” Mendes. CHEST / 138 / 2 / AUGUST, 2010

  34. Exercise Improves Asthma Outcomes“ Oxygen consumption” Mendes. CHEST / 138 / 2 / AUGUST, 2010

  35. Thank you and have a great day, tcraig@hmc.psu.edu

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