Hasan Yüksel, Özlem Günay, Ayhan Söğüt, Özge Yılmaz,

1. Evaluation of the Benefit of Exercise Added to Treatment in Children with Asthma By the Biochemical Mediators Hasan Yüksel, Özlem Günay, Ayhan Söğüt, Özge Yılmaz, Ahmet Var, Pınar Dündar, Canan Tıkız, Ece Onur Celal Bayar University Medical Faculty Dept. Of Pediatric Allergy and Pulmonology

2. Introduction Exercise and Asthma • Exercise response varies in patients with asthma. • Heavy exercise may provoke bronchoconstriciton. • However, regular exercise contributes to the control of asthma. • Exercise has been reported to increase aerobic capacity, neuromuscular coordination and self esteem. • Yet, the exact role of exercise on clinical control of the disease is not clear. Fanelli A, Cabral AL, Neder JA, et al. Exercise training on disease control and quality of life in asthmatic children. Med Sci Sports Exerc. 2007; 39:1474-80. Ram FS, Robinson SM, Black PN, PICOT J. Physicaltraining for asthma. Cochrane Database Syst. Rev.:CD001116, 2005.

3. Asthma and Inflammatory Mediators • Asthma, has an inflammatory nature that involves bronchial epithelium, endothelium, mucosa ans submucosal smooth muscle. • Severity of the inflammatory state determines the extent of the microenvironmental destruction. • Therefore, it is essential to evaluate the inflammatory mediatros of asthma as well as the mediators that will lead to microenvironmetal destruction when evaluating the state of this inflammation. • LTE4 is a useful marker to establish the total inflammatory state while MDA and MMP-9 are useful for the evalaution of microenvironmetal destruction. Nevertheless, ET-1 is an important marker of smooth muscle and angiomyogenic activation which lead to asthma symptoms. Fanelli A, Cabral AL, Neder JA, et al. Exercise training on disease control and quality of life in asthmatic children. Med Sci Sports Exerc. 2007; 39:1474-80. Ram FS, Robinson SM, Black PN, PICOT J. Physicaltraining for asthma. Cochrane Database Syst. Rev.:CD001116, 2005.

4. Malondialdehyde Levels in Asthma Oxidative stress might take role in asthma pathogenesis. Inflammatory cells in the airway secrete oxygen radicals. Toxic oxygen radicals lipid peroxidation airway hyperreactivity Synthesis of chemoattractants Lipid peroxides and oxygen radicals are involved in may of the cytotoxic reactions in patients with asthma. Malondialdehyde levels are measured in this study to evaluate the levels of lipid peroxide levels. Alzoghaibi MA, Bahammam AS. Lipid peroxides in stable asthmatics receiving inhaled steroids and long-acting beta2 -agonists. Respirology. 2007; 12: 439-42.

5. Metalloproteinase Levels in Asthma Metalloproteinases degrade type 4 collagen that forms most of the airway basement membrane. Tissue metalloproteinases play a role in tissue remodelling. Ko FW, et al. A comparison of airway and serum matrix metalloproteinase-9 activity among normal subjects, asthmatic patients, and patients with asthmatic mucus hypersecretion. Chest. 2005; 127: 1919-27. Endothelin-1 Levels in Asthma Endothelin 1 is thought to contribute to increased smooth muscle mass in the airway via hypertrophy and decrease in apoptosis. It has vasoconstrictive and bronchoconstrictive characteristics. It has been shown to have proinflammatory effects. McWhinnie R, et al.Endothelin-1 induces hypertrophy and inhibits apoptosis in human airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2007; 292: L278-86. Nikolaou E, et al.Evaluation of arterial endothelin-1 levels, before and during a sleep study, in patients with bronchial asthma and chronic obstructive pulmonary disease. Respiration. 2003; 70: 606-10.

6. Aim Leukotriene E4 in Asthma • Increased response of cysteinyl leukotrienes in lungs stimulates bronchoconstriction. • Leukotriene E4 that is a product of Cys-lökotriene metabolism has powerful bronchoconstrictor effects. Oommen A, Grigg J. Urinary leukotriene E4 in preschool children with acute clinical viral wheeze. Eur Respir J. 2003; 21: 149-54. The aim of this study was to evaluate the levels of malondialdehyde (MDA), endothelin 1 (ET1), metalloproteinase-9 (MMP-9) ve lökotriene E4 (LtE4) that are thought to have a role in asthma pathogenesis and symptoms and to determine the effects of exercise added to the standard drug treatment.

7. Methods Study Population: Thirty children that had not received asthma treatment were included in the study. Group 1: 15 patients that use standard inhaled drug treatment. Group 2: 15 patients who were started on exercise along with the standard drug therapy

8. Methods Study Design: Children in group 1 were started on inhaled steroid treatment of flutikasone 250 gr/g. Children in group 2 were started on an eight week long exercise program of bicycling an hour two days a week at a speed that achieved 80% of the maximal heart rate for age along with inhaled steroids. At the beginning and end of the study symptom score and lung function tests were evaluated serum levels of MMP-9, ET-1, MDA and urinary levels of LTE4, were measured.

9. Results Levels of serum MDA and MMP-9 and urinary LTE4 were found to decrease significantly after treatment in group 1 Table 1. Biochemical parameters in group 1 before and after treatment

10. Levels of serum MDA, Endothelin, MMP-9 and urinary LTE4were found to decrease significantly after in group 2 Table 2. Biochemical parameters in group 2 before and after treatment

11. Before treatment, levels of LTE4, MDA, endotheline and MMP-9 were not significantly different between the groups Table 3. Comparison of the values of groups 1 and 2 before treatment

12. Endothelin level in group 2 was significantly lower than that in group 2 after treatment. Table 4. Comparison of the values of groups 1 and 2 after treatment

13. Endothelin 1 level Group 1 Group 2 Figure 1.Levels of Endothelin 1 in the groups after treatment.

14. FEV1 levels in group 2 were higher than group 1 though the difference was not statistically different Table 5. Lung function tests in group 1 and 2 after treatment

15. Mean symptom score in group 2 was significantly lower than that in group 1 after treatment (2.2 ± 1.2 ‘e 4.7 ±2.1, p=0.001) Symptom score Group 1 Group 2 Figure 2.Symptom scores in the groups after

16. Discussion • In this study, decrease in MMP-9, MDA and LTE4 was detected in both groups after treatment that is concordant with the decrease in inflammation. • The finding that ET-1 has decreased significantly only in the group that received exercise along with inhaled treatmet, and that it was lower in this group when compared to the group that received only inhaled steroids, may indicate that exercise shows effect by decrease in smooth muscle tone. • Increase in FEV1 in this group might be attributable to the decrease in smooth muscle tone.

17. Conclusion • In conclusion, inhaled steroid treatment, leads to significant decrease in inflammation markers in asthma due to its anti-inflammatory effects. • Addition of exercise to this treatment, has been shown to improve symptom score and lung function tests by an ET-1 mediated mechanism especially by decreasing smooth muscle tone.