Tryptase-induced airway microvascular leakage in guinea pigs: involvement of tachykinins and leukotrienes.
Tryptase, a serine protease synthesized by and stored in mast cells, is implicated as an important mediator in the pathogenesis of airway inflammation. In this study, tryptase was evaluated for its ability to induce microvascular leakage into the airways of guinea pigs. Dose- and time-dependent increases in airway microvascular leakage were produced by intratracheal tryptase (0.3-3 microg). Intratracheal tryptase (3-30 microg) had no effect on airway tone as measured by pulmonary insufflation pressure. Tryptase-induced airway microvascular leakage was partially blocked by the tachykinin NK1 receptor antagonist CP 99994 [(+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine] and an inhibitor of leukotriene formation SCH 37224 (1-(1,2-dihydro-4-hydroxy-2-oxo-1-phenyl-1,8-naphthyridin-2-yl)pyrrolidinium, hydroxide inner salt). Neither CP 99994 nor SCH 37224 inhibited tryptase proteolytic activity in-vitro. Pretreatment of guinea pigs with histamine H1 receptor antagonists or a tachykinin NK2 receptor antagonist had no affect on the airway microvascular leakage induced by tryptase. It is speculated that tryptase may be important in the pathogenesis of airway inflammation, particularly in disorders that involve increased airway microvascular leakage such as asthma.
Greenfeder
S
S
Department of Allergy, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. scott.greenfeder@spcorp.com
Sehring
S
S
McHugh
N
N
Corboz
M
M
Rivelli
M
M
Anthes
J C
JC
Billah
M
M
Egan
R W
RW
Chapman
R W
RW
D000704:Analysis of Variance; D000818:Animals; D006224:Cricetinae; D004347:Drug Interactions; D006801:Humans; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D008297:Male; D009287:Naphthyridines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D018039:Receptors, Tachykinin / Q000187:drug effects*; D012697:Serine Endopeptidases / Q000633:toxicity*; D014132:Trachea / Q000187:drug effects*; D053802:Tryptases
D020024:Leukotriene Antagonists; D009287:Naphthyridines; D010880:Piperidines; D018039:Receptors, Tachykinin; C058078:Sch 37224; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D012697:Serine Endopeptidases; D053802:Tryptases