Kirsten Blensly

Physiology & Pharmacology

KC Blensly, DB Jacoby, AD Fryer

IL-1 Mediates Chronic but not Acute Airway Hyperreactivity Following Ozone

Ozone (O3) exposure causes airway hyperreactivity, lasting at least 3

days, and increases interleukin-1 (IL-1) expression in the lungs. One

and 2 days following a single exposure to O3, hyperreactivity is

mediated by eosinophil major basic protein that blocks inhibitory M2

muscarinic receptors on parasympathetic nerves, increasing

acetylcholine release. However, 3 days post O3, hyperreactivity in no

longer mediated by eosinophils, since eosinophil depletion protects M2

function but does not reverse hyperreactivity. Thus, the mechanism of

hyperreactivity changes from 1 to 3 days following O3 exposure.

Hyperreactivity 3 days post O3 is blocked not by eosinophil depletion,

but by an IL-1 receptor antagonist. These experiments were designed to

test whether IL-1 was also important 1 day post O3. Guinea pigs were

exposed to 2ppm O3 or to filtered air (controls) for 4 hours. 24 hours

or 3 days later electrical stimulation of the vagus nerves, in

anesthetized animals, caused bronchoconstriction that was

significantly potentiated in O3 exposed animals compared to controls.

One day post O3, hyperreactivity was not inhibited by the IL-1

receptor antagonist (anakinra, 30mg/kg i.p.) given 30min before O3 and

daily thereafter, although the IL-1 receptor antagonist inhibited

hyperreactivity 3 days post O3. Acetylcholine (1-10ug/kg, i.v.)

induced bronchoconstriction 1 day post O3 was not changed by O3

exposure but was increased in O3 exposed animals treated with the IL-1

receptor antagonist. In bronchoalveolar lavage, only neutrophils were

increased 1 day post O3 and the IL-1 receptor antagonist did not

change cell numbers compared to controls. These data demonstrate that,

although IL-1 is a key mediator of airway hyperreactivity 3 days after

O3, it does not mediate earlier hyperreactivity.

Steinberg Fellowship; NIH: HL-55543, HL54659, HL071795; RR023424