Hydrogen peroxide (H 2 O 2 ) (0.1 μ m ‐3 mM) induced variable contractions of guinea‐pig isolated trachea which were attenuated by catalase (100 u ml −1 ) and mannitol (15 mM) suggesting that contractions were induced by H 2 O 2 and/or the hydroxyl anion. Epithelial removal potentiated contractile responses of tracheal preparations to H 2 O 2 with a leftward shift of the concentration‐response curve and an increase in the maximal response. Indomethacin (3 μ m ) inhibited contractions to H 2 O 2 of intact preparations and preparations without epithelium suggesting that contractions may be mediated by cyclo‐oxygenase products. Intact preparations (but not preparations without epithelium) contracted in response to high concentrations (>0.1 mM) of H 2 O 2 in the presence of indomethacin suggesting that other excitatory factor(s) released by the epithelium may induce contraction. Preincubation of intact tracheal preparations with H 2 O 2 (1 mM) for 1 h had no effect on responses to histamine or isoprenaline. These results suggest that hydrogen peroxide generated during the inflammatory process may play a role in bronchoconstriction.
The role of p38 mitogen-activated protein (MAP) kinase, and extracellular-regulated protein kinase -1 and -2 in regulating constitutive apoptosis and interleukin (IL)-5-induced survival of human eosinophils have been investigated. Two populations of donors were identified whose eosinophils, in the absence of exogenous cytokines, underwent apoptosis at different rates. Eosinophils were thus arbitrarily classified as either "fast"- or "slow"-dying cells, where greater or less than 15% of the cells were apoptotic at 2 days, respectively. The selective p38 MAP kinase inhibitor, SB 203580, increased constitutive eosinophil apoptosis in both populations (EC(50) approximately 2 microM) as evinced from morphological analysis, flow cytometry, and DNA laddering. The ability of SB 203580 to kill eosinophils was not due to nonspecific toxicity or through the inhibition of prostanoid or leukotriene production. Exposure of eosinophils to IL-5, at a concentration (10 pM) that enhanced survival maximally, abolished SB 203580-induced apoptosis. In contrast PD 098059, which selectively blocks MAP kinase kinase (MEK) 1, did not affect apoptosis of fast- or slow-dying eosinophils, or the enhanced survival of cells effected by IL-5. Collectively, these results suggest that: 1) the basal activity of p38 MAP kinase may regulate the survival of cytokine-deprived eosinophils through inhibition of apoptosis, 2) the enhancement of eosinophil survival effected by IL-5 is mediated by a mechanism(s) divorced from the activation of p38 MAP kinase, and 3) neither spontaneous eosinophil apoptosis nor their enhanced survival by IL-5 involves the activation of MEK-1.
