Project: Research project

Project Details


Viral infections such as influenza are characterized by an increased
bronchoconstriction to a variety of stimuli in vivo. Although this
hyperreactivity is usually temporary, viral infections in childhood are
associated with development of asthma. The hyperreactivity to any
specific agonist could result from direct effects on smooth muscle or
effects on cells that control smooth muscle contraction. A major
indirect route of hyperreactivity Is via the vagus nerve. The vagus
nerve releases acetylcholine that binds to muscarinic receptors on the
smooth muscle resulting in bronchoconstriction. In preliminary data I
have shown that the amount of acetylcholine released by the nerve
terminals is regulated by muscarinic receptors which are located on the
nerve terminals, and that these neuronal receptors are a different
subtype than the muscarinic receptors on the smooth muscle. The neuronal
muscarinic receptors are inhibitory in that when stimulated, they limit
the amount of acetylcholine released from the nerves. Damage to these
neuronal receptors would remove both the tonic inhibition and the
negative feedback that occurs with all stimuli which increase vagal
activity. It is my hypothesis that the pathologic absence of this normal
negative feedback will result in airways hyperreactivity. Viral infections such as influenza and parainfluenza,
temporarily increases the bronchoconstriction produced by a variety of
stimuli. The mechanism of viral-induced airway hyperreactivity is poorly
understood. However, there is evidence to suggest that part of the
defect lies in the vagus nerves. Viruses contain enzymes on their
surface which can damage cells and receptors on cells. One of these
enzymes, neuraminidase, can damage receptors like the muscarinic receptor
which inhibits acetylcholine release from the vagus nerves in the lung.
Neuraminidase may be produced in large quantities during viral infection
as new viruses grow in the airways. I have shown that during viral infection neuronal inhibitory
muscarinic receptors are not functioning. The experiments in this
proposal are designed to test whether damage to these receptors on the
vagus nerves play an important role in the reactivity of the lungs,
whether this effect is due specifically to inhibition of neuronal
muscarinic receptors by neuraminidase, and what role neuraminidase plays
in other models of airways disease, especially antigen challenge. This
grant proposes studying muscarinic receptor function in vivo and in vitro
as well as studying the receptors at a genetic level. It is expected
that results from this study will provide important new insights into the
mechanism of airway hyperreactivity induced by viral infection and may
yield results which further our understanding of other models of airway
Effective start/end date8/1/917/31/97


  • National Institutes of Health
  • National Institutes of Health: $117,004.00
  • National Institutes of Health: $107,121.00
  • National Institutes of Health
  • National Institutes of Health


  • Medicine(all)

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