Ozone-induced airway hyperresponsiveness in patients with asthma: role of neutrophil-derived serine proteinases.
Proteinase inhibitors may be of potential therapeutic value in the treatment of respiratory diseases such as chronic obstructive pulmonary disease (COPD) or asthma. Our aim was to study the role of neutrophils, and neutrophil-derived serine proteinases in an acute model in patients with asthma. Exposure to ozone induces an acute neutrophilic inflammatory reaction accompanied by an increase in airway hyperresponsiveness. It is thought that these two effects of ozone are linked, and that neutrophil-derived serine proteinases (i.e. elastase) may play a role in the ozone-induced airway hyperresponsiveness. Therefore, we examined the effect of recombinant antileukoprotease (rALP), one of the major serine proteinase inhibitors in the lung, on ozone-induced changes in airway hyperresponsiveness in this model. We observed that 16 h after exposure to ozone, airway hyperresponsiveness to methacholine was increased both following placebo and rALP treatment. There was no significant difference between placebo and rALP treatment (change in area under the dose-response curve to methacholine: 117.3+/-59.0 vs 193.6+/-59.6 % fall x DD; p=.12). Moreover, the immediate decrease in FEV1 after ozone exposure was not significantly different between the two groups (placebo: -29.6+/-6.7%; rALP: -20.9+/-3.8%; p=.11). In addition, no significant differences were observed in plasma levels of fibrinogen degradation products generated by neutrophil serine proteinases before and after exposure to ozone. We conclude that neutrophil-derived serine proteinases are not important mediators for ozone-induced hyperresponsiveness.
Hiltermann
T J
TJ
Department of Pulmonology, Leiden University Hospital, The Netherlands.
Peters
E A
EA
Alberts
B
B
Kwikkers
K
K
Borggreven
P A
PA
Hiemstra
P S
PS
Dijkman
J H
JH
van Bree
L A
LA
Stolk
J
J
D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D001249:Asthma / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D009504:Neutrophils / Q000201:enzymology*; D010126:Ozone / Q000009:adverse effects*; D015990:Placebo Effect; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000008:administration & dosage; D011994:Recombinant Proteins / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000502:physiology*; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage
D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D011994:Recombinant Proteins; D015842:Serine Proteinase Inhibitors; D010126:Ozone; D012697:Serine Endopeptidases