Dr. Hershenson has the long term goal of pursuing independent investigation of the mechanisms operative in the pathogenesis of bronchopulmonary dysplasia. Receipt of a Clinical Investigator Award will facilitate the development of Dr. Hershenson's investigative skills and experience, by expanding his knowledge of several new cellular and molecular techniques as outlined in the proposed studies. The learning objectives set out in this proposal, combined with the support of his sponsor, Dr. Julian Solway, and the stimulating, productive, and critical environment within the University of Chicago Adult and Pediatric Sections of Pulmonary land Critical Care Medicine, will foster Dr. Hershenson's progression to independent lines of investigation into the mechanisms of reactive airway diseases.
The specific aims i n this proposal will extend earlier inquiries into hyperoxia-induced airway hyperreactivity and remodeling in immature rats, a novel animal model which Dr. Hershenson has developed under the guidance of Dr. Solway. Three immediate goals are defined: (1) Identify the time course and local mechanisms of hyperoxia-induced increases in airway epithelial mass and smooth muscle layer mass in immature rats. Morphometric analyses of light and electron micrographs of airways from air- and O2-exposed rats, and evaluation of airway cell S-phase traversal in vivo, will test the hypothesis that abnormally increased cellular proliferation contributes to the observed airway thinckening. (2) Investigate the expression of polypeptide growth factors in hyperoxia- exposed immature rat lungs, and identify their cellular sources. BAL fluid and medium conditioned by bronchoalveolar macrophages or lung fibroblasts from air- and O2-exposed animals will be assayed for mitogenic activities for mesenchymal and epithelial cells, and for the antigenic presence of platelet-derived growth factor and/or insulin-like growth factor-1; in situ appearance of growth factors will also be determined immunohistochemically. (3) Evaluate the potential causal relationship between O2-induced, growth factor-mediated airway remodeling and airway hyperresponsiveness in immature rats. The structure and responsiveness of bronchial cylinders from 3 airway generations will be correlated. Then, 2 interventions will be used to inhibit airway remodeling--administration of heparan sulfate, and administration of blocking anti-growth factor antibodies. Airway morphometry and airway reactivity in vivo will be measured, to test the hypothesis that inhibition of hyperoxia-induced airway remodeling blunts O2-induced airway hyperresponsiveness. This work is particularly relevant given recent advances in research which identify the roles of growth factors in a variety of lung diseases. From these studies, Dr. Hershenson hopes to learn whether airway remodeling can influence airway responsiveness. Insight gained from this work may shed light on parallel mechanisms that may operate in bronchopulmonary dysplasia.
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