Many mediators activate eosinophils via transduction pathways involving the
enzyme phosphatidylinositol 3-kinase. The initial investigation of
wortmannin, a specific inhibitor of
PI3-kinase, was of its effect on human and guinea pig eosinophil
superoxide (O(2)(-)) release and degranulation in vitro. Subsequently, the effect on
allergen- and
Sephadex-induced bronchial
inflammation and
airway hyperresponsiveness (AHR) in vivo in guinea pigs was investigated.
Wortmannin potently inhibited
complement C5a-induced O(2)(-) generation and
eosinophil peroxidase (EPO) release from human eosinophils, with 50% inhibition produced by a 1-10 nM concentration. Both
aerosol allergen challenge of sensitized guinea pigs and
intravenous injection of
Sephadex beads in normal guinea pigs caused, in 24 h, significant
eosinophilia and increased EPO activity in bronchoalveolar lavage fluid (BALF) and AHR to intravenous
acetylcholine and
histamine. In the allergic model, intranasal pretreatment with
wortmannin had no effect on BALF
eosinophilia, but dose dependently inhibited BALF EPO activity. At 1 mg/kg, the
drug abolished the AHR to
histamine, but not
acetylcholine. In the
Sephadex model, the
drug significantly inhibited all three parameters (
eosinophilia, increased EPO activity, and AHR to both spasmogens). These results show that
wortmannin is a potent inhibitor of human eosinophil degranulation and that when administered intranasally can prevent AHR in
allergen-challenged guinea pigs, probably by inhibiting eosinophil degranulation, but not their accumulation in BALF. This may be relevant to the possible clinical utility of
wortmannin in conditions involving eosinophilic
inflammation and AHR.