Bronchoalveolar lavage (BAL) of canine peripheral airways was performed at various times after hyperventilation, and BAL fluid (BALF) cell and mediator data were used to evaluate two hypotheses: 1) hyperventilation-induced mucosal injury stimulates mediator production, and 2) mucosal damage is correlated with the magnitude of hyperventilation-induced bronchoconstriction. We found that epithelial cells increased in BALF immediately after a 2- and a 5-min dry air challenge (DAC). Prostaglandins D(2) and F(2alpha) and thromboxane B(2) were unchanged immediately after a 2-min DAC but were significantly increased after a 5-min DAC. Leukotriene C(4), D(4), and E(4) did not increase until 5 min after DAC. Hyperventilation with warm moist air did not alter BALF cells or mediators and caused less airway obstruction that occurred earlier than DAC. BALF epithelial cells were correlated with mediator release, and mediator release and epithelial cells were correlated with hyperventilation-induced bronchoconstriction. These observations are consistent with the hypothesis that hyperventilation-induced mucosal damage initiates peripheral airway constriction via the release of biochemical mediators.
This study was designed to test the hypotheses that (1) neurokinin (NK) receptor activity modulates hyperventilation-induced bronchoconstriction (HIB) in canine peripheral airways and (2) NK receptor activity is stimulated via hyperventilation-induced eicosanoid production and release. A bronchoscope was used in anesthetized dogs to record peripheral airway resistance (Rp); to test airway reactivity to NK A (NKA), substance P, and hypertonic saline; and to examine HIB before and after combined treatment with NK-1 (CP 99,994) and NK-2 (SR 48,968) receptor antagonists. Bronchoalveolar lavage fluid cells, prostaglandin D2, and cysteinyl leukotrienes from hyperventilated airways pretreated with either vehicle or NK antagonists were also measured. Pretreatment with NK-1 and NK-2 antagonists significantly attenuated HIB and the response to substance P, virtually abolished the response to NKA, and had little effect on the response to HS. Blockade of NK-1 and NK-2 receptors did not affect either the cell profiles or the mediator concentrations recovered in bronchoalveolar lavage fluid after hyperventilation. We conclude that NKs modulate the development of HIB and appear to do so via hyperventilation-induced eicosanoid production and release.
This study was designed to test the hypothesis that hyperventilation-induced bronchoconstriction (HIB) results from the combined effects of prostanoid and leukotriene metabolism. A bronchoscope was used in anesthetized dogs to record peripheral airway resistance and HIB before and after combined treatment with inhibitors of cyclooxygenase (indomethacin) and 5-lipoxygenase (MK-0591). Bronchoalveolar lavage fluid (BALF) cells and mediators from hyperventilated and control airways were also measured. Pretreatment with MK-0591 and indomethacin significantly attenuated, but did not abolish, HIB. However, addition of atropine nearly eliminated the residual response. Blockade of eicosanoid metabolism markedly reduced the concentrations of eicosanoids recovered in BALF after hyperventilation. Positive correlations between posthyperventilation BALF prostanoid and epithelial cell concentrations are suggestive of mucosal injury-induced mediator production and release. We conclude that HIB is prevented in the presence of eicosanoid and muscarinic-receptor blockade and that both classes of eicosanoids contribute similarly to the development of HIB.
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