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Exhaled nitric oxide: The missing link between asthma and obesity?

2005; Elsevier BV; Volume: 115; Issue: 2 Linguagem: Inglês

10.1016/j.jaci.2004.11.025

1097-6825

Karin M. de Winter–de Groot, Cornelis K. van der Ent, Ingeborg Prins, Joyce Tersmette, Cuno S.P.M. Uiterwaal,

Respiratory Support and Mechanisms

To the Editor: Asthma and obesity affect millions of persons worldwide. Both cross-sectional and longitudinal cohort studies have shown a positive association between both entities in children1Von Mutius E. Schwartz J. Neas L.M. Dockery D. Weiss S.T. Relation of body mass index to asthma and atopy in children: the national health and nutrition examination study III.Thorax. 2001; 56: 835-838Crossref PubMed Scopus (373) Google Scholar and adults.2Shaheen S.O. Sterne J.A. Montgomery S.M. Azima H. Birth weight, body mass index and asthma in young adults.Thorax. 1999; 54: 396-402Crossref PubMed Scopus (331) Google Scholar However, a pathophysiologic explanation for this association has not yet been established. We hypothesized that obesity might result in upregulation of pulmonary inflammatory mechanisms and studied the relationship between body mass index (BMI) and nitric oxide in exhaled air (eNO), which is an important inflammatory marker in patients with atopic asthma.3Baraldi E. de Jongste J.C. European Respiratory Society American Thoracic Society Measurement of exhaled nitric oxide in children, 2001.Eur Respir J. 2002; 20: 223-237Crossref PubMed Scopus (316) Google Scholar We studied 24 (10 male and 14 female) healthy nonsmoking subjects. Subjects with a history of allergic rhinitis or lower respiratory complaints more severe than common colds were not included. After informed consent, eNO was measured during a 10-second expiration at 50 mL/s according to the American Thoracic Society guidelines (Niox; Aerocrine AB, Solna, Sweden).3Baraldi E. de Jongste J.C. European Respiratory Society American Thoracic Society Measurement of exhaled nitric oxide in children, 2001.Eur Respir J. 2002; 20: 223-237Crossref PubMed Scopus (316) Google Scholar eNO values are reported as the mean value of 6 repeated measurements. None of the subjects took medications or nitrate-rich foods before the eNO measurements. The following lung function tests were performed (Masterlab, Viasys Healthcare, Hochberg, Germany): forced vital capacity, FEV1, maximal expiratory volumes at 50% and 25% of total lung capacity, total lung capacity, residual volume, and carbon monoxide diffusion capacity corrected for alveolar volume and hemoglobin levels. Mean (SD) age of the subjects was 27.9 (5.4) years, mean (SD) BMI was 23.0 (2.6) kg/m2, and mean (SD) eNO level was 18.1 (7.4) ppb. Lung function parameters of all subjects were within the normal range. None of the subjects had airflow obstruction, and mean (SD) FEV1/forced vital capacity was 85.0% (6.2%). BMI was positively associated with mean eNO (linear regression coefficient, 1.5 ppb/kg/m2; 95% CI, 0.5-2.6; P = .007; Fig 1). This association did not change after adjustment for sex and age (1.5 ppb/kg/m2; 95% CI, 0.2-2.7; P = .02). No significant relationships between BMI or eNO and any of the lung function parameters were observed. The association between BMI and eNO was not influenced by adjustment for FEV1 (1.8 ppb/kg/m2; 95% CI, 0.6-3.0; P = .005). Exclusion of the subject with the highest eNO value (Fig 1) did not materially influence the results. Recent studies have shown that obesity leads to an increased release of proinflammatory molecules that contribute to obesity-associated complications. In obese subjects macrophage numbers in adipose tissue increase, producing significant amounts of TNF-α, inducible nitric oxide synthase, and IL-6.4Weisberg S.P. McCann D. Desai M. Rosenbaum M. Leibel R.L. Ferrante Jr., A.W. Obesity is associated with macrophage accumulation in adipose tissue.J Clin Invest. 2003; 112: 1796-1808Crossref PubMed Scopus (7727) Google Scholar These data are supported by the finding that leptin, the protein of the putative obesity gene, upregulates the inflammatory immune response.5Loffreda S. Yang S.Q. Lin H.Z. Karp C.L. Brengman M.L. Wang D.J. et al.Leptin regulates proinflammatory immune responses.FASEB J. 1998; 12: 57-65Crossref PubMed Google Scholar Until now, no data on enhancement of inflammatory responses in the airways of obese subjects were available. eNO has been established as a specific inflammatory marker in children and adults with atopic asthma. This marker in patients with asthma is strongly increased in comparison with healthy control subjects.3Baraldi E. de Jongste J.C. European Respiratory Society American Thoracic Society Measurement of exhaled nitric oxide in children, 2001.Eur Respir J. 2002; 20: 223-237Crossref PubMed Scopus (316) Google Scholar Our findings show a significant increase in eNO levels in subjects with a high BMI. None of the subjects had a history or current symptoms of asthma or atopic disease. Lung function parameters were not negatively affected by increasing BMI. These data suggest direct or indirect upregulation of inflammatory processes outside the adipose tissue and suggest a contribution of obesity-related inflammatory activity to the pathophysiology of asthma. Linkage between obesity genes and nitric oxide synthase genes might be another explanation. Although our data from healthy subjects do not justify conclusions about pathophysiologic processes in disease states, our findings highly suggest a linking role between asthma and obesity. Future studies should further elucidate the effects of obesity on the inflammatory system both inside and outside the adipose tissue.