New Insights Into Pathogenesis of Exercise-induced Bronchoconstriction

Teal S. Hallstrand

Disclosures

Curr Opin Allergy Clin Immunol. 2012;12(1):42-48. 

In This Article

Inflammatory Mediator Release in the Airways During Exercise-induced Bronchoconstriction

Although the precise nature of the underlying stimulus for mediator release in the airways is not known with certainty, there is strong evidence that mediators from mast cells and eosinophils are released into the airways during EIB, and that this mediator release is the predominant cause of EIB.[14,30] During exercise, heat and water are transferred out of the airways to equilibrate the inspired air to the temperature and humidity of the lower airways. At the epithelial surface there is a transfer of water from the osmotically sensitive epithelial cells via the tight junctions, as well as a thermal gradient. Though osmotic stimuli are also known to directly activate inflammatory cells such as mast cells,[31] it is reasonable to also consider that the stimulus of exercise or hyperpnea is predominantly sensed by the airway epithelium leading to the activation of inflammatory mediator release from leukocytes residing in close contact to the epithelium. Two recent studies[32,33] indicate that epithelial stress occurs during exercise in vivo by demonstrating that clara cell secretory protein (CC16) measured in the urine following challenge is increased after exercise and isocapnic hyperpnea challenge.

The noninvasive method of EBC has been used recently to better understand the nature of mediator release in the airways following exercise challenge. The levels of CysLTs in EBC were higher in the asthma group with EIB and increased after exercise challenge most notably in the EIB-positive group; further, the change in CysLTs in EBC following challenge was correlated with the severity of EIB.[34] These findings are consistent with the findings identified in induced sputum demonstrating a sustained increase in CysLTs and other bronchoconstrictive eicosanoids such as PGD2 in the airways following exercise challenge to induce EIB.[14,30] Mast cells and eosinophils are strongly implicated as the cellular sources of CysLTs and other eicosanoids in EIB. The eosinophil product eosinophilic cationic protein (ECP) is released into the airways following exercise challenge in patients with EIB.[14] Mast cell degranulation occurs during exercise challenge as evidenced by histamine and tryptase release into the airways following challenge.[30]

The connection between inflammatory eicosanoid release by leukocytes and epithelial stress is not initially obvious, since the epithelium itself is thought to have relatively limited capacity to synthesize CysLTs. The epithelium may directly lead to eicosanoid release through 15-lipoxygenase-1 (15-LO-1) since the levels of the 15-LO product 15S-hydroxyeicosatetranoic acid (15S-HETE) are increased after exercise challenge in patients with EIB.[35] The epithelium is also a major source of PGE2 that is known to inhibit EIB when given by inhalation. The production of PGE2 actually decreases post exercise challenge among asthmatic patients with EIB,[30] and the ratio of CysLTs to PGE2 increases in asthmatic patients post challenge, whereas there is a decrease in this ratio in normal individuals[35] (Fig. 1). A unifying explanation for these findings is that the epithelium serves as a key regulator of the balance of eicosanoids in the airways by activating the release of bronchoconstrictive eicosanoids in inflammatory cells in close contact and by alterations that reduce the synthesis of PGE2. The epithelium has reduced in-vitro capacity for PGE2 synthesis when treated with IL-13 through a reduction in the synthetic enzymes cyclooxygenase-2 (COX-2) and PGE synthase 1.[36]

Figure 1.

Opposing effects of exercise challenge on the CysLT to PGE2 ratio in induced sputum. Asthmatic patients with EIB have an increase in the CysLT to PGE2 ratio in response to exercise (a), whereas normal controls have a decrease in the CysLT to PGE2 ratio following exercise challenge (b). CysLT, cysteinyl leukotriene; EIB, exercise-induced bronchoconstriction; PGE2, prostaglandin E2. Adapted from reference [30].

Recent provocative data from a single research group contradict older studies that have generally failed to demonstrate a cellular influx into the airways following exercise challenge,[37,38] or an increase in AHR.[39,40] An increase in high-sensitivity C-reactive protein (CRP) was identified only in asthmatic patients with EIB following exercise challenge.[41] In addition, the FENO, serum ECP and AHR to inhaled histamine were all increased following exercise challenge in asthmatic patients with EIB.[41] Further they found that RANTES (regulated on activation normal T cell expressed and secreted) and eotaxin were increased in EBC in asthmatic patients relative to controls, and that the levels of RANTES and eotaxin were increased in EBC after exercise challenge only in the group with EIB, but not in asthmatic patients without EIB.[42,43] These are provocative findings that require further confirmation, but suggest that exercise challenge may trigger chemokines involved in leukocyte recruitment and AHR in patients who are susceptible to this disorder.

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