Abstract
Polymorphonuclear neutrophils (PMNs) play a major role in inflammatory diseases.
They act as a first line of defense against invading infectious microorganisms. For this purpose,
PMNs contain granules filled with proteolytic and other cytotoxic enzymes. Besides releasing
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enzymes, PMNs are also able to phagocytose and to convert oxygen into highly reactive oxygen
species (ROS). Following phagocytosis, ingested microorganisms may be killed inside the
phagosome by a combined action of enzyme activity and ROS production. Although the
formation of ROS by stimulated PMNs is a physiological response which is advantageous to the
host, it can also be detrimental in many inflammatory states in which these radicals give rise to
excessive tissue damage. Therefore, there is an ongoing search for anti-inflammatory compounds
which are able to prevent this damaging ROS production without affecting the other killing
capacities of the PMN.
In 1971, the isolation of apocynin from the roots of Picrorhiza kurroa Royle ex Benth. was
reported. Picrorhiza kurroa is a small, perennial plant growing at high altitudes in the western
Himalayas and which has been used extensively for ages and is still in use in the Ayurvedic
system of medicine in India and Sri Lanka. Following experiments showed that apocynin was a
potent anti-inflammatory agent, based on the selective inhibition of the production of ROS by
activated human PMNs. Although proven to be an active anti-inflammatory compound in several
experimental animal models, the exact mechanism of action of apocynin was still not fully
understood.
In this thesis, experiments are described that have led to a better understanding of the mode of
action by which apocynin inhibits the ROS production by activated human PMNs. One of the
conclusions is that apocynin itself is not active, but that it is converted into an active dimer inside
the phagosomes of activated PMNs.
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