Allergy Asthma Respir Dis.  2014 Mar;2(1):30-37. 10.4168/aard.2014.2.1.30.

Serum leptin levels correlate with bronchial hyper-responsiveness to mannitol in asthmatic children

• Yoo JK
• Shin JY
• You JS
• Jeong SI
• Song JS
• Yang S
• Hwang IT
• Lee HB
• Baek HS

• KMID: 2168569
• DOI: http://doi.org/10.4168/aard.2014.2.1.30

Abstract

PURPOSE
Epidemiological data indicate that obesity is a risk factor in asthma, however effects related to obesity and adipokines on airway inflammation and bronchial hyper-responsiveness (BHR) have not yet been demonstrated in the human airway. The aim of this study was to investigate the relationship between serum adipokine levels and BHR to mannitol in asthmatic children.
METHODS
Serum adipokine levels were measured and pulmonary function tests were perfomed: baseline, postbronchodilator inhalation, methacholine inhalation, and mannitol inhalation. The response to mannitol was expressed as the dose causing a 15% decrease in forced expiratory volume in one second (FEV1) (PD15), and as the response-dose ratio (RDR) (% fall in FEV1/cumulative dose).
RESULTS
Sixty-nine prepubertal children between the ages of 6 and 10 years were participated in the study. They comprised asthmatic children (n=40) and healthy (n=29). Twenty-two subjects (55.5%) with asthma had a positive mannitol bronchial provocation test (BPT) result. The body mass index (BMI) was higher in those asthmatics with positive mannitol BPTs than in asthmatics with negative mannitol BPTs and in the control group (19.30 kg/m2 vs. 17.60 kg/m2 vs. 17.93 kg/m2, P=0.035, P=0.046). Serum leptin levels were also significantly higher in asthmatics with positive mannitol BPTs than in asthmatics with negative mannitol BPTs and in the control group (10.58 ng/mL vs. 5.49 ng/mL vs. 6.75 ng/mL, P=0.002, P=0.016). Leptin values were significantly associated with a PD15 (r=-0.498, P=0.022) and RDR to mannitol (r=0.346, P=0.033) in asthmatic children after adjustment for BMI.
CONCLUSION
Serum leptin levels were significantly associated with BHR to mannitol in asthmatic children.

Keyword

Asthma; Leptin; Mannitol; Bronchial hyper-responsiveness; Child; Obesity

MeSH Terms

Adipokines
Asthma
Body Mass Index
Bronchial Provocation Tests
Child*
Forced Expiratory Volume
Humans
Inflammation
Inhalation
Leptin*
Mannitol*
Methacholine Chloride
Obesity
Respiratory Function Tests
Risk Factors
Adipokines
Leptin
Mannitol
Methacholine Chloride

Figure

• 

  Fig. 1 Relationship between serum leptin and PD15 and RDR to mannitol in children with asthma. (A) Serum leptin levels were significantly related to PD15 (r=-0.498, r=partial correlation coefficient adjusted for BMI, P=0.022) in both obese (n=9, r=-0.327, P=0.042) and normal-weight asthmatics (n=13, r=-0.322, P=0.048). (B) Serum leptin levels were significantly related to RDR to mannitol (r=0.346, r=partial correlation coefficient adjusted for BMI, P=0.033) in both obese (n=11, r=-0.302, P=0.039) and normal-weight asthmatics (n=29, r=-0.318, P=0.043). PD15, cumulative provocative dose causing a 15% fall in FEV1; RDR, response-dose ratio (% fall in FEV1/cumulative dose of mannitol); FEV1, orced expiratory volume in one second; BMI, body mass index.

Reference

1. Hargreave FE, Ryan G, Thomson NC, O'Byrne PM, Latimer K, Juniper EF, et al. Bronchial responsiveness to histamine or methacholine in asthma: measurement and clinical significance. J Allergy Clin Immunol. 1981; 68:347–355.

2. Brannan JD, Gulliksson M, Anderson SD, Chew N, Kumlin M. Evidence of mast cell activation and leukotriene release after mannitol inhalation. Eur Respir J. 2003; 22:491–496.

3. Litonjua AA, Gold DR. Asthma and obesity: common early-life influences in the inception of disease. J Allergy Clin Immunol. 2008; 121:1075–1084.

4. Sood A, Ford ES, Camargo CA Jr. Association between leptin and asthma in adults. Thorax. 2006; 61:300–305.

5. Bustos P, Amigo H, Oyarzun M, Rona RJ. Is there a causal relation between obesity and asthma? Evidence from Chile. Int J Obes (Lond). 2005; 29:804–809.

6. Schachter LM, Salome CM, Peat JK, Woolcock AJ. Obesity is a risk for asthma and wheeze but not airway hyperresponsiveness. Thorax. 2001; 56:4–8.

7. del Río-Navarro B, Cisneros-Rivero M, Berber-Eslava A, Espinola-Reyna G, Sienra-Monge J. Exercise induced bronchospasm in asthmatic and non-asthmatic obese children. Allergol Immunopathol (Madr). 2000; 28:5–11.

8. Lopes WA, Radominski RB, Rosario Filho NA, Leite N. Exercise-induced bronchospasm in obese adolescents. Allergol Immunopathol (Madr). 2009; 37:175–179.

9. Baek HS, Kim YD, Shin JH, Kim JH, Oh JW, Lee HB. Serum leptin and adiponectin levels correlate with exercise-induced bronchoconstriction in children with asthma. Ann Allergy Asthma Immunol. 2011; 107:14–21.

10. Sin DD, Sutherland ER. Obesity and the lung: 4. Obesity and asthma. Thorax. 2008; 63:1018–1023.

11. Jartti T, Saarikoski L, Jartti L, Lisinen I, Jula A, Huupponen R, et al. Obesity, adipokines and asthma. Allergy. 2009; 64:770–777.

12. Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, et al. Identification and importance of brown adipose tissue in adult humans. N Engl J Med. 2009; 360:1509–1517.

13. Fantuzzi G. Adipose tissue, adipokines, and inflammation. J Allergy Clin Immunol. 2005; 115:911–919.

14. Shore SA, Schwartzman IN, Mellema MS, Flynt L, Imrich A, Johnston RA. Effect of leptin on allergic airway responses in mice. J Allergy Clin Immunol. 2005; 115:103–109.

15. Shore SA, Terry RD, Flynt L, Xu A, Hug C. Adiponectin attenuates allergen-induced airway inflammation and hyperresponsiveness in mice. J Allergy Clin Immunol. 2006; 118:389–395.

16. Johnston RA, Zhu M, Rivera-Sanchez YM, Lu FL, Theman TA, Flynt L, et al. Allergic airway responses in obese mice. Am J Respir Crit Care Med. 2007; 176:650–658.

17. Kim KW, Shin YH, Lee KE, Kim ES, Sohn MH, Kim KE. Relationship between adipokines and manifestations of childhood asthma. Pediatr Allergy Immunol. 2008; 19:535–540.

18. Jang AS, Kim TH, Park JS, Kim KU, Uh ST, Seo KH, et al. Association of serum leptin and adiponectin with obesity in asthmatics. J Asthma. 2009; 46:59–63.

19. Crapo RO, Casaburi R, Coates AL, Enright PL, Hankinson JL, Irvin CG, et al. Guidelines for methacholine and exercise challenge testing-1999. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med. 2000; 161:309–329.

20. Chai H, Farr RS, Froehlich LA, Mathison DA, McLean JA, Rosenthal RR, et al. Standardization of bronchial inhalation challenge procedures. J Allergy Clin Immunol. 1975; 56:323–327.

21. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. Standardisation of spirometry. Eur Respir J. 2005; 26:319–338.

22. American Thoracic Society. European Respiratory Society. ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am J Respir Crit Care Med. 2005; 171:912–930.

23. Human IL-6 quantikine ELISA kit [Internet]. Minneapolis (MN): R&D systems;2014. cited 2011 Apr 30. Available from: http://www.rndsystems.com/Products/D6050.

24. Brannan JD, Anderson SD, Perry CP, Freed-Martens R, Lassig AR, Charlton B, et al. The safety and efficacy of inhaled dry powder mannitol as a bronchial provocation test for airway hyperresponsiveness: a phase 3 comparison study with hypertonic (4.5%) saline. Respir Res. 2005; 6:144.

25. Anderson SD, Charlton B, Weiler JM, Nichols S, Spector SL, Pearlman DS, et al. Comparison of mannitol and methacholine to predict exercise-induced bronchoconstriction and a clinical diagnosis of asthma. Respir Res. 2009; 10:4.

26. Brannan JD, Gulliksson M, Anderson SD, Chew N, Seale JP, Kumlin M. Inhibition of mast cell PGD2 release protects against mannitol-induced airway narrowing. Eur Respir J. 2006; 27:944–950.

27. Ford ES. The epidemiology of obesity and asthma. J Allergy Clin Immunol. 2005; 115:897–909.

28. Beuther DA, Weiss ST, Sutherland ER. Obesity and asthma. Am J Respir Crit Care Med. 2006; 174:112–119.

29. Shore SA. Obesity and asthma: possible mechanisms. J Allergy Clin Immunol. 2008; 121:1087–1093.

30. Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity. Annu Rev Immunol. 2011; 29:415–445.

31. Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006; 444:860–867.

32. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003; 112:1796–1808.

33. Theoharides TC, Makris M, Kalogeromitros D. Allergic inflammation and adipocytokines. Int J Immunopathol Pharmacol. 2008; 21:1–4.

34. Liu J, Divoux A, Sun J, Zhang J, Clement K, Glickman JN, et al. Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice. Nat Med. 2009; 15:940–945.

35. Mito N, Kitada C, Hosoda T, Sato K. Effect of diet-induced obesity on ovalbumin-specific immune response in a murine asthma model. Metabolism. 2002; 51:1241–1246.

36. Bäck M, Sultan A, Ovchinnikova O, Hansson GK. 5-Lipoxygenase-activating protein: a potential link between innate and adaptive immunity in atherosclerosis and adipose tissue inflammation. Circ Res. 2007; 100:946–949.

37. Taildeman J, Perez-Novo CA, Rottiers I, Ferdinande L, Waeytens A, De Colvenaer V, et al. Human mast cells express leptin and leptin receptors. Histochem Cell Biol. 2009; 131:703–711.

38. O'Sullivan S, Roquet A, Dahlen B, Larsen F, Eklund A, Kumlin M, et al. Evidence for mast cell activation during exercise-induced bronchoconstriction. Eur Respir J. 1998; 12:345–350.

39. Porsbjerg C, Brannan JD, Anderson SD, Backer V. Relationship between airway responsiveness to mannitol and to methacholine and markers of airway inflammation, peak flow variability and quality of life in asthma patients. Clin Exp Allergy. 2008; 38:43–50.

40. Anderson SD. Indirect challenge tests: Airway hyperresponsiveness in asthma: its measurement and clinical significance. Chest. 2010; 138:2 Suppl. 25S–30S.