Assessment of Bronchoalveolar Cell and Mediator Response to Isocapnic Hyperpnea in Asthma

Abstract

The purpose of this study was to test the hypothesis that mediators and cells associated with bronchoconstriction or inflammation are locally synthesized and/or released in the airways of asthmatic subjects in response to isocapnic hyperpnea (ISH). Seven atopic, mildly asthmatic subjects were studied. Baseline measurements were reported previously and included forced expiratory volumes, flow rates, bronchoalveolar lavage (BAL), and methacholine reactivity. Approximately 1 yr later, spirometry and BAL were repeated, but BAL was performed immediately after ISH challenge. As indices of inflammation, BAL measurements were made of eosinophils, neutrophils, epithelial cells, leukotrienes B4, C4, D4, and E4, prostaglandins D2, E2, and F2 alpha, thromboxane B2, histamine, and total protein. Compared with baseline, ISH was associated with higher BAL concentrations of the following: leukotriene B4 (10 versus 121 pg/ml, p = 0.02), leukotrienes C4/D4/E4 (46 versus 251 pg/ml, p = 0.02), eosinophils (0.8 versus 2.2%, p = 0.04), and epithelial cells (2.1 versus 6.1%, p = 0.05). Trends toward significant increases were seen in BAL concentrations of neutrophils and prostaglandin D2. No statistically significant increases were found in BAL measurements of total protein, histamine, prostaglandins E2 or F2 alpha, thromboxane B2, lymphocytes, or macrophages. The magnitude of the response to ISH, as measured by change in FEV1, did not correlate with BAL levels of cells or mediators. This study indicates that ISH, even in mildly asthmatic subjects, is associated with airway increases in a spectrum of bronchoactive mediators and inflammatory cells, supporting the observations of others that antagonists of a single mediator are unlikely to have major clinical effectiveness in ISH or exercise-induced asthma.

Dry air- and hypertonic aerosol-induced bronchoconstriction and cellular responses in the canine lung periphery

“…Surprisingly, there was no difference in BALF protein concentrations from control, dry air and NaCl exposed segments, 5 min after challenge. BALF recovered from asthmatic subjects after 5 min of isocapnic hyperventilation revealed similar results: although epithelial cell numbers were elevated in BALF, BALF total protein was not increased after challenge [12]. Either BALF total protein is too insensitive to be used as a marker of dry air-induced airway injury, or airway drying transiently alters epithelial cell adhesion, and increases the probability that these cells would be washed out during lavage.…”

“…Although mediator release has been implicated in AIB [12,19,21,33] and HIB [34][35][36], the role of biochemical mediators in the initiation of these responses remains controversial. The protection provided by antihistamines [19,34,35], mast cell "stabilizers" [36], cyclooxygenase inhibitors [11,19], and leukotriene receptor antagonists [21,37,38] suggest at least a partial role for these mediators in the development of AIB and HIB.…”

“…Airway mucosal cell damage, as assessed by differential cell analysis of bronchoalveolar lavage fluid (BALF), is associated with AIB in canine peripheral airways [11], and in asthmatic humans [12]. BALF cell profile data also suggest that challenge with warm, wet air [10,11,13], and pretreatment with β-agonists [14,15], attenuate AIB and significantly protect the canine mucosa from airway desiccation, when compared to untreated dry air challenged segments.…”

Efficacy and duration of action of the antileukotriene zafirlukast on cold air-induced bronchoconstriction

“…Different investigators have not found increased cysLT-levels in urine or BAL after exercise in adults [33±35] whereas other investigators have reported increased urinary leukotriene E 4 levels in asthmatic children after exer-cise and in adults [36]. In accordance with this, PLISS et al [1] described increased cysLT-levels in BAL fluid after hyperventilation. There are only very few and preliminary data about cysLTlevels in sputum samples from asthmatics [36].…”

“…11 showed such a high degree of variability under placebo conditions that it was impossible to draw any conclusion about the potential effects of zafirlukast. In previous studies with cysLT 1 -receptor antagonists and 5-lipoxygenase inhibitors it has been shown that 30±40% of the subjects did not show any beneficial effect on protection against bronchoconstriction induced by exercise or cold air [4,5]. In a more recent study FISCHER et al [28] analysed the protective effect of a 5-lipoxygenase inhibitor against cold air challenge.…”