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.
