Project: Research project

Project Details


Patients with pulmonary fibrosis experience numerous functional
limitations which are associated with a decreased lung compliance, gas
exchange, rapid shallow breathing pattern and the subjective sensation
of dyspnea, The underlying mechanisms leading to the observed breathing
pattern and dyspnea response in these patients remains undefined. It
has been suggested based on findings from acute studies that lung vagal
afferents may initiate or influence these responses. There is, however,
no information relating how these receptors respond to chronic
conditions and therefore inferences drawn from acute studies are
tenuous. I hypothesize that the inflammatory components of pulmonary
fibrosis excite nonmyelinated C fibers to evoke a rapid shallow
breathing pattern and that a chronic decrease in lung compliance
results in a chronic stimulation of myelinated vagal afferents (slowly
and rapidly adapting pulmonary stretch receptors) that evoke a slow
shallow breathing pattern with frequent augmented breaths: acutely the
C fiber response predominates but regresses as the acute inflammation
is resolved. To test these hypotheses I will undertake a series of
reflex and neurophysiological experiments in rats with progressive
interstitial pulmonary fibrosis. This fibrosis will be induced by the
repeated intratracheal instillations of bleomycin. To test my
hypotheses I have devised the following strategy. First, I will
characterize the acute (14 days) and chronic (90 days) alterations in
baseline breathing pattern associated with progressive pulmonary
fibrosis, while measuring arterial blood gases, arterial blood pressure
and heart rate. Second, at these two time points I will determine which
group of lung vagal afferents (myelinated versus nonmyelinated)
contributes to fibrosis evoked alterations in breathing pattern by
first blocking vagal C fiber conduction with perineural capsaicin
treatment and then combining the C fiber block with cold block of vagal
myelinated fibers. Third, I will investigate using single nerve fiber
recording techniques the discharge pattern of vagal afferent fibers
with special emphasis on how they respond in rats with experimentally
induced progressive pulmonary fibrosis. Fourth, I will examine at the
beginning of the experiment the extent of the disease process by
measuring lung volumes and quasi-static lung compliance and at the end
of the experiment by removing the lungs and examining them
histologically. By providing a better understanding of pulmonary
regulatory mechanisms and the role they play in chronic lung disease
this area of investigation could lead to better treatment protocols for
individuals suffering from chronic lung disease.
Effective start/end date8/1/937/31/98


  • National Institutes of Health


  • Medicine(all)


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