New Insights Into Exercise-induced Bronchoconstriction
Collectively, the epidemiology of EIB indicates that patients with this disorder represent a discrete phenotype. Whether or not this phenotype is a durable clinical phenotype awaits further longitudinal epidemiological studies. One recent study found that increased bronchodilator response is associated with asthma symptoms during exercise suggesting that patients with more variability in airway tone may be more susceptible to EIB. In another very provocative study, the authors related pilocarpine-induced sweat secretion with methacholine reactivity and found that patients with a negative methacholine challenge had more salivary secretion and higher sweat rate. Since prior studies have found that the rate of water transfer out of the airways is a major determinant of the severity of bronchoconstriction after exercise challenge, these findings suggest that the there may be an alteration in water handling by the airway epithelial surface. It is also recognized both in humans and in animal models that dietary salt is a modifier of the severity of EIB, also possibly indicating an alteration in water handling by the epithelium. In line with evidence that the epithelium may play a major role in this disorder is that the number of airway epithelial cells shed into induced sputum is substantially higher among asthmatic patients with EIB compared with asthmatic patients without EIB.
The intensity of cellular airway inflammation and the generation of inflammatory mediators, particularly eicosanoids (i.e. products of arachidonic acid) such as leukotrienes have been associated with the susceptibility to EIB. Although sputum eosinophilia per se does not appear to be required for EIB, several prior studies have associated the degree of sputum eosinophilia with the severity of EIB. A recent study of the inhaled corticosteroid (ICS) ciclesonide further refined these observations by demonstrating that the magnitude and onset of the suppression of EIB in response to high-dose but not low-dose ICS therapy was associated with the degree of sputum eosinophilia. Patients without sputum eosinophilia were less likely to have an improvement in EIB on an ICS. Mast cell infiltration of the airways has also been implicated in EIB. In a genome-wide expression study of airway cells, the expression of the mast cell genes tryptase and carboxypeptidase A3 (CPA3) were significantly increased in EIB-positive asthmatic patients. This intraepithelial mast cell phenotype with high expression of tryptase and CPA3, but low expression of chymase, was recently described in the Th2 high-molecular phenotype of asthma. Since this Th2 high phenotype is IL-13 driven, it is interesting to note that a genetic study found an association between IL-13 gene polymorphisms and the severity of EIB, and with the response to a leukotriene receptor antagonist (LTRA) among these patients with EIB.
Several studies have noted an increase in the concentration of cysteinyl leukotrienes (CysLTs) in the airways of patients with EIB, particularly the ratio of CysLTs to prostaglandin E2 (PGE2). A recent study also found that patients with EIB relative to asthmatic patients without EIB have a reduction in the levels of the protective eicosanoid lipoxin A4. The levels of 8-isoprostanes, nonenzymatic products of phospholipid oxidation, were increased in exhaled breath condensate (EBC) of asthmatic patients with EIB and correlated with the severity of EIB. As in prior studies a recent study found that the fraction of exhaled nitric oxide (FENO) is elevated in asthmatic patients with EIB, and furthered the understanding of this relationship by showing that the relationship between FENO and EIB was restricted to patients with atopy. Angiopoetin 2, a mediator that enhances microvascular permeability, is increased in the airways in asthma and is correlated with the severity of EIB. Among children with asthma, including obese children, the severity of EIB was positively correlated with serum leptin and negatively with serum adiponectin. In addition, the levels of 25-hydroxy-vitamin D were reduced among patients with asthma and were lower in asthmatic patients with EIB relative to those without EIB.
Pathophysiological Determinants of Exercise-induced Bronchoconstriction
Collectively, the epidemiology of EIB indicates that patients with this disorder represent a discrete phenotype. Whether or not this phenotype is a durable clinical phenotype awaits further longitudinal epidemiological studies. One recent study found that increased bronchodilator response is associated with asthma symptoms during exercise suggesting that patients with more variability in airway tone may be more susceptible to EIB. In another very provocative study, the authors related pilocarpine-induced sweat secretion with methacholine reactivity and found that patients with a negative methacholine challenge had more salivary secretion and higher sweat rate. Since prior studies have found that the rate of water transfer out of the airways is a major determinant of the severity of bronchoconstriction after exercise challenge, these findings suggest that the there may be an alteration in water handling by the airway epithelial surface. It is also recognized both in humans and in animal models that dietary salt is a modifier of the severity of EIB, also possibly indicating an alteration in water handling by the epithelium. In line with evidence that the epithelium may play a major role in this disorder is that the number of airway epithelial cells shed into induced sputum is substantially higher among asthmatic patients with EIB compared with asthmatic patients without EIB.
The intensity of cellular airway inflammation and the generation of inflammatory mediators, particularly eicosanoids (i.e. products of arachidonic acid) such as leukotrienes have been associated with the susceptibility to EIB. Although sputum eosinophilia per se does not appear to be required for EIB, several prior studies have associated the degree of sputum eosinophilia with the severity of EIB. A recent study of the inhaled corticosteroid (ICS) ciclesonide further refined these observations by demonstrating that the magnitude and onset of the suppression of EIB in response to high-dose but not low-dose ICS therapy was associated with the degree of sputum eosinophilia. Patients without sputum eosinophilia were less likely to have an improvement in EIB on an ICS. Mast cell infiltration of the airways has also been implicated in EIB. In a genome-wide expression study of airway cells, the expression of the mast cell genes tryptase and carboxypeptidase A3 (CPA3) were significantly increased in EIB-positive asthmatic patients. This intraepithelial mast cell phenotype with high expression of tryptase and CPA3, but low expression of chymase, was recently described in the Th2 high-molecular phenotype of asthma. Since this Th2 high phenotype is IL-13 driven, it is interesting to note that a genetic study found an association between IL-13 gene polymorphisms and the severity of EIB, and with the response to a leukotriene receptor antagonist (LTRA) among these patients with EIB.
Several studies have noted an increase in the concentration of cysteinyl leukotrienes (CysLTs) in the airways of patients with EIB, particularly the ratio of CysLTs to prostaglandin E2 (PGE2). A recent study also found that patients with EIB relative to asthmatic patients without EIB have a reduction in the levels of the protective eicosanoid lipoxin A4. The levels of 8-isoprostanes, nonenzymatic products of phospholipid oxidation, were increased in exhaled breath condensate (EBC) of asthmatic patients with EIB and correlated with the severity of EIB. As in prior studies a recent study found that the fraction of exhaled nitric oxide (FENO) is elevated in asthmatic patients with EIB, and furthered the understanding of this relationship by showing that the relationship between FENO and EIB was restricted to patients with atopy. Angiopoetin 2, a mediator that enhances microvascular permeability, is increased in the airways in asthma and is correlated with the severity of EIB. Among children with asthma, including obese children, the severity of EIB was positively correlated with serum leptin and negatively with serum adiponectin. In addition, the levels of 25-hydroxy-vitamin D were reduced among patients with asthma and were lower in asthmatic patients with EIB relative to those without EIB.
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