MECHANISMS OF LATE PHASE PULMONARY RESPONSES

  • Abraham, William W, (PI)

Project: Research project

Description

Some asthmatic patients respond to inhalation of specific antigen with both
early and late bronchial obstructions (late response). The mechanisms
underlying the pathogenesis of late responses are unknown, but are of
clinical interest because late responses are associated with prolonged
airway hyperresponsiveness and a worsening of symptoms. Studies in this
proposal use the disciplines of physiology, pharmacology, biochemistry and
pathology to test the hypothesis that the late response is dependent upon
lipoxygenase and/or cyclooxygenase metabolites of arachidonic acid. Two
subgroups of sheep with airway hypersensitivity to Ascaris suum antigen
will be used: those which have only an acute bronchoconstriction (acute
responders) and those which have both acute and late bronchial obstructions
(dual responders) following inhalation challenge with Ascaris suum. The
specific aims of this proposal with respect to the above hypothesis are to
demonstrate that: 1) dual responders release increased levels of
lipoxygenase metabolites of arachidonic acid during the acute response to
antigen and that these metabolites stimulate pathways important for the
expression of the late response; 2) the late response is a constrictor
response to a secondary release of slow reacting substance of anaphylaxis;
3) dual responders are more responsive to inhalation challenge with
leukotrienes C4 and D4 (major components of slow reacting substance of
anaphylaxis) than are acute responders; and 4) inflammatory cells which
appear in the bronchial wall at the time of the late response are the
source of the mediator(s) inducing the late response, and/or contribute to
the non-specific airway hyperresponsiveness observed in late responders.
In these studies, antigen-induced changes in airway mechanics will be
correlated with the appearance of mediators in the lung as measured by
radioimmunoassay and bioassay of bronchoalveolar lavage fluid. These
parameters will also be correlated with the inflammatory state of the
bronchial wall as assessed by bronchial biopsies. The roles of suspected
pathways and/or mediators involved in the late response will be confirmed
by using selective pharmacologic intervention. Comparisons of these
end-points between acute and dual responders will help to define the
mechanism(s) of the late response and will contribute to a better
understanding of the pathogenesis of asthma. This study could provide the
basis for introducing new, more specific, and possibly more effective,
therapies for bronchial asthma.
StatusFinished
Effective start/end date4/1/853/31/91

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $143,023.00
  • National Institutes of Health

Fingerprint

metabolite
asthma
antigen
Antigens
Lung
biochemistry
acid
Arachidonate 5-Lipoxygenase
Sheep
sheep
mechanics
physiology
bioassay
Hypersensitivity
Asthma
fluid
Ascaris
Leukotrienes
Organized Financing
Bronchoalveolar Lavage

ASJC

  • Medicine(all)